Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.Br[CH2:13][CH2:14][CH2:15][CH3:16]>CCOC(C)=O>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[CH:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: COc1cccc2cc[nH]c12
Solvent: CCOC(C)=O
Product: CCCCn1ccc2cccc(OC)c21
Yield: 74 %

Procedure:
Compound 2 was synthesized from commercially available 7-Methoxyindole using the general procedure and 1-bromobutane to afford 0.51 g (74% yield) as a clear oil. TLC system: 10% EtOAc/90% n-hexanes. Spectral data matched previously reported data.35
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15](OC(=O)C)(=[O:17])[CH3:16].S(=O)(=O)(O)O>>[C:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:17])[CH3:16]
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)n1c2ccccc2c2cc(Br)ccc21

Procedure:
20 g of 3-bromocarbazole was converted to its acetyl derivative by refluxing with acetic anhydride (3 vol) with traces of conc. sulfuric acid. Aqueous workup yielded an off-white solid, which was then washed with n-hexane and dried under vacuum to obtain 23 g 9-acetyl-3-bromocarbazole, quantitatively. And N-acetyl derivative of carbazole, benzocarbaole and dibenzocarbazoles were prepared following the same procedure.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH2:29]([O:28][C:26]1[C:25]([CH3:31])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[CH:27]=1)[CH3:30]
Reactant: CCOc1cc(CCl)ncc1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)ncc1C

Procedure:
6.1 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 100 ml of alcohol and treated while cooling with ice with 5.2 g of 2-chloromethyl-4-ethoxy-5-methylpyridine hydrochloride. Thereafter, a solution of 1.9 g of sodium hydroxide in 50 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 300 ml of methylene chloride. The solution was washed firstly with 200 ml of 1.5N sodium hydroxide solution and then with 3×200 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 120 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 2-[[(4-ethoxy-5-methyl-2-pyridyl)methyl]thio]-5,7-dihydro-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 187°-189°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[CH:3]=1
Reactant: CC1NCCc2ccccc21
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Yield: 50.2 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 6-methyl-2,4-dichloropyrimidine (6.52 g, 40 mmol), 1-methyl-1,2,3,4-tetrahydroisoquinoline (6.6 g, 44 mmol), triethylamine(6.8 ml, 48.8 mmol) and N,N-dimethylformamide(30 ml) were used as starting materials, 5.5 g of the titled compound was prepared. (Yield: 50.2%)
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1.[OH-].[K+].Cl.CN([CH:23]=[O:24])C>O>[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:23]=[O:24])=[CH:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2c(C=O)c[nH]c2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of DMF (7 mL, 90 mm) and POCl3 (2.25 mL, 24.5 mmol) which had been cooled to 5° C., was treated with known 6-methoxy-1H-indole. After stirring at room temperature for 1 hour, the mixture was heated at 45° C. for 1 hour, then allowed to cool to room temperature overnight. The reaction mixture was poured into ice (100 mL), and stirred for 30 minutes at which time a solution of KOH (9.6 g, 171 mm) in H2O (20 mL) was added dropwise. After stirring for 30 minutes, then heating for 1 hour at 60° C., the reaction was cooled to 30° C., and the pH adjusted to 7 with 1N HCl. The mixture was extracted with EtOAc(50 mL×3), the organic fractions were combined, dried over MgSO4, filtered and evaporated. The residue was purified by crystallization from methanol to afford 6-methoxy-1H-indole-3-carboxaldehyde (1.65 g, 69%).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:13][CH3:14].[Na].[CH2:16]([OH:18])C>O>[CH3:14][O:13][C:4]1[CH:3]=[CH:12][C:11]([O:18][CH3:16])=[C:10]2[C:5]=1[CH2:6][CH:7]=[CH:8][CH2:9]2
Reactant: COc1ccc2ccccc2c1OC
Reactant: CCO
Agent: [Na]
Solvent: O
Product: COc1ccc(OC)c2c1CC=CC2

Procedure:
The dimethoxynaphthalene compound (66.5 mmol) was dissolved in 120 ml of ethanol. The resulting mixture was heated to reflux under nitrogen, and 11.7 g (0.51 mol) of sodium were added in portions. Stirring at reflux under nitrogen was continued until all of the solid had dissolved. The mixture then was stirred for 15 minutes at room temperature then cautiously diluted with 50 ml of water. The mixture was evaporated in vacuo to remove ethanol, and the remainder was diluted with water and extracted with ether. The organic extracts were combined, dried over sodium sulfate, and evaporated in vacuo to give 11.1 g of 5,8-dimethoxy-1,4-dihydronaphthalene as a yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH:31][CH:32]([CH2:37][NH:38][CH3:39])[C:33]([O:35]C)=[O:34].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:38]([CH3:39])[CH2:37][CH:32]([OH:31])[C:33]([OH:35])=[O:34])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CNCC(O)C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CC(O)C(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A solution of 4-{[cyclohexyl(2-methyl-5-phenylfuran-3-yl)methyl]amino}benzoic acid (117 mg), methyl 2-hydroxy-3-(methylamino)propanoate hydrochloride (61 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg), hydroxybenzotriazole monohydrate (55 mg) and triethylamine (50 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (98 mg, 69%).
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:15])[C:5]=1[NH:4][C:3]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:15])[C:5]=1[NH:4][C:3]2=[S:26]
Reactant: O=C1Nc2c(F)cccc2C2CCCC12F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Fc1cccc2c1NC(=S)C1(F)CCCC21

Procedure:
A solution of 60 mg (0.27 mmol) of 3a,6-difluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 15 ml of THF is mixed with 288 mg (0.71 mmol) of Lawesson's reagent and refluxed for 1.5 hours. Then, the reaction mixture is concentrated by evaporation, and the residue is purified by column chromatography on silica gel (eluant: hexane-ethyl acetate): 50 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([C:26](OCC)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.B.[OH-].[Na+].O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:26][OH:27])=[C:20]([C:22]([F:24])([F:23])[F:25])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2c(OCCCc3ccc(Cl)cc3Cl)cccn12
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: OCc1c(C(F)(F)F)nc2c(OCCCc3ccc(Cl)cc3Cl)cccn12
Temperature: 25 °C
Reaction time: 42 h
Yield: 46.6 %

Procedure:
To a stirred solution of ethyl 8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoro-methyl)imidazo[1,2-α]pyridine-3-carboxylate (0.223 g, 0.483 mmol, see example 35) in anhydrous diethyl ether (20 mL) was added dropwise borane-methyl sulfide complex (2.0 mL, 20 mmol). The reaction mixture was stirred at ambient temperature for 42 h under argon and then heated at reflux for 3.5 h. Excess borane was subsequently hydrolyzed by dropwise addition of 5M aq sodium hydroxide (4 mL) to the cold (0° C.) reaction mixture. The resultant solution was stirred for 30 min and water (50 mL) was added. After successive extraction of the solution with diethyl ether (2×30 mL) and dichloromethane (30 mL), the organic extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude desired product as a white solid. Purification by chromatography with a mixture of ethyl acetate-hexanes (1:1 v/v, containing 0.5% v/v isopropylamine) yielded 94.3 mg (47% yield) of {8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridin-3-yl}methanol as a pale yellow solid (Rf=0.41 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5% v/v isopropylamine). A stirred suspension of {8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridin-3-yl}methanol (0.142 g, 0.339 mmol) in anhydrous methanol (5 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. Concentration of the solution in vacuo and trituration of the residue in anhydrous diethyl ether afforded the title compound as an off-white solid (0.144 g, 93% yield). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.46 (d, 1H, Ar), 7.39–7.45 (m, 2H, Ar), 7.35 (d, 1H, Ar), 7.27 (d, 1H, Ar), 7.19 (dd, 1H, Ar), 5.09 (s, 2H, CH2OH), 4.36 (t, 2H, CH2O), 2.99 (t, 2H, CH2Ar), 2.26 (m, 2H, CH2CH2CH2); 13C-NMR (100 MHz, CDCl3/CD3OD, APT) δ 146.38 (+), 138.09 (+), 136.58 (+), 135.35 (+), 133.50 (+), 132.24 (−), 129.94 (−), 128.28 (+), 128.06 (−), 124.01 (+), 122.05/119.36 (+), 120.49 (−), 119.12 (−), 112.57 (−), 70.26 (+), 52.25 (+), 29.76 (+), 29.10 (+); LRMS-ES m/z: M+ 419.2 (100%); Anal. calcd for C18H15N2O2Cl2F3.HCl: C, 47.44; H, 3.54; N, 6.15%. found: C, 47.04; H, 3.54; N, 6.02%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH:18]=[O:19])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:25]([Mg]Br)#[CH:26]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH:18]([OH:19])[C:25]#[CH:26])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1ccccc1-c1ccn2nc(-c3ccc(F)cc3)cc2c1
Solvent: C1CCOC1
Product: C#CC(O)c1ccccc1-c1ccn2nc(-c3ccc(F)cc3)cc2c1
Yield: 30.3 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.245 g (0.77 mmol) of 2-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde obtained in stage 5.1, in solution in 15 ml of tetrahydrofuran, followed by addition of 4.65 ml (2.32 mmol) of an ethynylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with dichloromethane, 0.08 g (30%) of the expected product is obtained in the form of a pale yellow powder.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:2]1[C:1]2([CH2:6][CH2:12][C:10](=[O:11])[CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C=CC2(CCCC2)CC1
Temperature: 45 °C

Procedure:
To a solution of cyclopentanecarbaldehyde (Aldrich) (0.82 g, 8.36 mmol) in dry toluene (10 mL), methyl vinyl ketone (Alfa Aesar) (0.684 mL, 8.36 mmol) was added followed by a catalytic amount of concentrated H2SO4 (0.045 mL, 0.836 mmol). The mixture was heated at 45° C. for 1.5 hours, then refluxed for 1 hour using a Dean-Stark trap. The reaction mixture was cooled to room temperature and further methyl vinyl ketone (Alfa Aesar) (0.684 mL, 8.36 mmol) was added. The reaction mixture was heated at reflux for 1 hour, allowed to cool to room temperature and treated with an aqueous 1M NaHCO3 (30 mL) solution. The aqueous was extracted with toluene and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-20% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:29][N:30]1[C:39]2[NH:38][C:37]3[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][C:36]=3[NH:35][CH2:34][C:33]=2[CH:32]=[N:31]1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:35]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:29])[C:39]=3[NH:38][C:37]3[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][C:36]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluorobenzoic acid from Example E3.1 (538 mg, 2.0 mmol) and DMAP (220 mg, 1.8 mmol) in dichloromethane (20 ml) at room temperature was treated with DIEA (0.93 ml, 5.4 mmol) and WSCD (460 mg, 2.4 mmol), and the resulting solution was stirred at room temperature for 1 h. 3,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (385 mg, 1.8 mmol) was added and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with saturated NaHCO3 and brine and concentrated in vacuo. The residue was purified by preparative HPLC (eluant 10% methanol:90% dichloromethane) to yield the title compound (265 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[O:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:16][CH:14]2[CH2:15][O:12][CH2:13]2)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(OC2COC2)c(Cl)cn1
Temperature: 120 °C
Reaction time: 25 h
Yield: 110.8 %

Procedure:
To a solution of 5-chloro-4-iodo-pyridine-2-carboxylic acid (CAN 120643-06-3, 360 mg, 1.27 mmol) in DMF (10 mL) was added with stirring Oxetan-3-ol (CAN 7748-36-9, 104 mg, 1.4 mmol) and sodium hydride 60% (107 mg, 2.67 mmol). The resulting mixture was stirred at room temperature for 30 min and at 120° C. for 25 h, cooled and the reaction mixture was concentrated in vacuo. The residue was suspended with ethylacetate, transferred into a separatory funnel and extracted with 4.0 mL of 0.5M aqueous solution hydrochloric acid. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness to give the title compound (323 mg, 111%) as a solid which was used crude without any further purification. MS (ESI, m/z): 228.4 (M−H+)
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[Cl-].[NH4+]>C(OCC)C>[C:4]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]([OH:13])[CH3:1])=[CH:14][CH:15]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc(C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
Methylmagnesium bromide (3 mol/L diethyl ether solution, 5 mL, 15.0 mmol) was added dropwise to a solution of 4-tert-butylbenzaldehyde (1.62 g, 10.0 mmol) in diethyl ether (20 mL) while cooling in ice, and the mixture was stirred at the same temperature for 30 min. Aqueous ammonium chloride solution was added thereto and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and then the filtrate was concentrated under reduced pressure to afford 1-(4-tert-butylphenyl)ethanol as a colorless solid (1.84 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccs2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccs2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixed solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (276 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 168 mg, 70%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C@H:13]1[CH2:18][CH2:17][C@H:16](O)[CH2:15][CH2:14]1>>[Cl:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14]1
Reactant: O[C@H]1CC[C@H](Cl)CC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@@H](Cl)CC1)C(C)=O

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (3.18 g) was treated with trans-4-chlorocyclohexanol as described in Example 4a, method 3 to give the title compound as a colourless oil (2.02 g). (Found: MH+, 276.0995. C12H19ClNO4 requires MH+, 276.1002; δH (CDCl3) 1.36 (3H, t, J 7H), 1.79, 1.96 and 2.09 (8H, 3m), 2.40 (3H, s), 4.11 (1H, qt, J 6 Hz), 4.38 (2H, q, J 7 Hz), and 4.41 (1H, qt, J 6 Hz). A small quantity of the trans-isomer was obtained from faster-eluting column fractions.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].[NH4+].[Cl-]>C(OCC)(=O)C.C1COCC1>[F:30][C:31]([F:33])([F:32])[C:27]([C:24]1[CH:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)([OH:29])[CH3:28]
Reactant: COc1ccc(C(C)=O)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.0M Tetra-butyl ammonium fluoride in THF (13.23 mL, 13.23 mmol) was added to a THF solution (20 mL) of 1-(6-methoxypyridin-3-yl)ethanone (2 g, 13.23 mmol) and (trifluoromethyl)trimethylsilane (3.76 g, 26.5 mmol) under nitrogen at 0° C. The reaction was warmed to 25° C. and stirred for 18 hours, at which time LCMS showed >95% conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL saturated NH4Cl; the organic layer was washed with 100 mL brine, dried over sodium sulfate, filtered and the filtrate concentrated. Silica gel chromatography using a linear gradient of 0-100% ethyl acetate/hexanes gave the title compound as a white solid. LCMS (M+H)+: 222.0. 1H NMR (500 MHz, CDCl3): δ 8.36 (d, J=1.9 Hz, 1H), 7.81 (dd, J=1.9 and 8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 3.97 (s, 3H), 2.80 (s, 1H), 1.80 (s, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]1([S:37]([C:40]2[N:41]([CH3:47])[C:42]([C:45]#[CH:46])=[CH:43][N:44]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([S:37]([C:40]2[N:41]([CH3:47])[C:42]([C:45]3[N:3]=[N:2][N:1]([C:4]4[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:7]([NH:9][C:10]4[CH:15]=[C:14]([C:16]([CH3:18])([CH3:19])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]=4[O:25][CH3:26])=[O:8])[CH:46]=3)=[CH:43][N:44]=2)(=[O:38])=[O:39])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C#Cc1cnc(S(=O)(=O)c2ccccc2)n1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(S(=O)(=O)c5ccccc5)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 36 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 2-benzenesulfonyl-5-ethynyl-1-methyl-1H-imidazole in the same manner as Example 15. ESI MS m/z 678 [C32H35N7O6S+H]+.
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[CH:7]2[O:10][CH:4]([CH:5]=[CH:6]2)[C:3]1=[O:11]>Cl.[Zn]>[CH:7]12[O:10][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:11])[CH2:2][C:8]2=[O:9]
Reactant: O=C1C2C=CC(O2)C(=O)C1Cl
Agent: Cl
Agent: [Zn]
Product: O=C1CC(=O)C2C=CC1O2
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 3-chloro-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione (6.44 g) in aqueous hydrochloric acid (35 ml, 2M) was added zinc powder (4.88 g) in portions maintaining the reaction temperature below 25° C. by cooling with an icebath. After 45 minutes, the mixture was filtered through a bed of celite then extracted with ethyl acetate. the extract was dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford the required product. 1H NMR (d6-DMSO) δ: 6.50 (2H, s), 5.18 (2H, s), 4.15 (1H, d), 3.34 (1H, d).