Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccccc2[N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1cccc(O)c1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
2-(3-Methoxyphenyl)nitrobenzene, as described above in Step A, (8.6 g, 37.52 mmol) was dissolved in CH2Cl2 (500 mL) and cooled to −78° C. BBr3 (1.0 M sol. in CH2Cl2, 43 mL, 43 mmol) was slowly added and the reaction was warmed to ambient temperature and stirred for 18 hours. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:34])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:33])[CH2:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1)#[N:2].Cl.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(OCC)(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:34])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:33])[CH2:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:5][CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCCC[C@@H]1CC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCCC[C@@H]1CC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of the compound (26.7 g, 57 mmol) obtained in the item (c) inchloroform (50 ml), a 4-N hydrochloride in ethyl acetate (30 ml) is added at 0° C. The mixture is stirred for 3 hours and then the solvent isevaporated. The resulting residue was dissolved in dichloromethane (250 ml)and triethylamine (19 ml) is added. Then, a solution of methanesulfonyl chloride (7.9 g, 68 mmol) in dichloromethane (50 ml) is added at 0°C. and the mixture is stirred for 3 hours. The organic layer is washed oncewith a saturated sodium bicarbonate solution, water and saturated brine, successively, and then dried over sodium sulfate. The resulting residue ispurified with silica gel chromatography (hexane-ethyl acetate) to give 18.6g of the titled compound (73%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(O[C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:21]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (446 mg), (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (450 mg), potassium carbonate (692 mg) in DMF (5.0 ml) was stirred at 85° C. for 6 hours. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (354 mg). Physical properties: m/z [M+H]+ 431.1
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([C:16](N(OC)C)=[O:17])=[CH:14][C:13]=1[S:24](=[O:27])(=[O:26])[NH2:25]>O1CCCC1>[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:14][C:13]=1[S:24]([NH2:25])(=[O:27])=[O:26]
Reactant: c1ccsc1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2cccs2)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of thiophene (0.27 g, 3.20 mmol) dissolved in tetrahydrofuran (10 mL) at −78° C. under nitrogen is dropwisely added 1.6 M of n-butyllithium (2 mL, 3.40 mmol). The reaction mixture is stirred at −78° C. for 1 h then a solution 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (0.3 g, 1.08 mmol) in tetrahydrofuran (2 mL) is added slowly and the reaction mixture is allowed to warm to room temperature and stirred for 1 h. The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 0.059 g (18%) of the title compound as a yellow solid. 1H NMR (DMSO): δ 8.33 (d, J=2 Hz, 1H), 8.15 (dd, J=4, 1 Hz, 1H), 8.05 (dd, J=8, 4 Hz, 1H), 7.85 (m, 4H), 7.35 (m, 1H). Analytics calculated for C11H8ClO3S2: C, 43.78; H, 2.67; N, 4.64. Found: C, 43.70; H, 2.61; N, 4.61. MS (m/z): 300.0 (M−1).
Reaction SMILES: O[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>O>[CH3:11][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=[C:2]([Cl:14])[CH:10]=1
Reactant: Cc1cc(O)ncc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(Cl)ncc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
6-Hydroxy-4-methylnicotinic acid (10 g, 65.3 mmol) and phosphorus oxychloride (33 mL) were combined and refluxed for 3 hours. The reaction solution was poured into 300 mL of ice and then 600 mL of water was added. The solution was boiled for 30 minutes before cooling and extracting the product into ether. The solvent was removed and the residue was recrystallized from 900 mL of hot water. Yellow solid, 9.06 g (81% yield). Mp 170-172° C. 1H NMR (CD3OD): δ 2.61 (s, 3H), 7.41 (s, 1H), 8.80 (s, 1H). LC-MS, M+1=172.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH3:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([N:23]([CH3:24])[C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1cccnc1Br
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1C=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 2-bromo-3-formylpyridine (XVI, EXAMPLE 1, 2.67 g, 14.4 mmol), 1-tert-butoxycarbonyl-4-methylaminopiperidine (XIII, 2.8 g, 13.1 mmol), and diisopropylethylamine (2.3 ml), the title compound is obtained, mp 90°-91°.
Reaction SMILES: [Li].[S].[F:3][C:4](=[C:8]([F:10])[F:9])[CH2:5][CH2:6]S.[Br:11]CCC(F)=C(F)F.[Mg:19]>>[F:3][C:4](=[C:8]([F:10])[F:9])[CH2:5][CH2:6][Mg:19][Br:11]
Reactant: FC(F)=C(F)CCBr
Reactant: FC(F)=C(F)CCS
Reactant: [Mg]
Agent: [Li]
Agent: [S]
Product: FC(F)=C(F)CC[Mg]Br

Procedure:
For example, glyoxylic acid may be reacted with hydroxylamine hydrochloride in an aqueous medium, forming the corresponding oxime. This oxime is then reacted with chlorine in aqueous methylene chloride to form dichloroformaldoxime. Treatment of dichloroformaldoxime with silver nitrate in the presence of cyanogen chloride produces 3,5-dichloro-1,2,4-oxadiazole. If cyanogen bromide is substituted for cyanogen chloride, the product recovered is 5-bromo-3-chloro-1,2,4-oxadiazole. The final product, 3-chloro-5-(3,4,4-trifluoro-3-buten-1-ylthio)-1,2,4-oxadiazole, may be produced by reacting the dihalo-1,2,4-oxadiazole with lithium metal, then with elemental sulfur, and finally with 4-bromo-1,2,2-trifluoro-1-butene. An alternate final step involves the reaction of 3,4,4-trifluoro-3-butene-1-thiol with 5-halo-3-chloro-1,2,4-oxadiazole. Preparation of 3,4,4-trifluoro-3-butene-1-thiol may be accomplished by reacting 4-bromo-1,1,2-trifluoro-1-butene with magnesium metal to form 3,4,4-trifluoro-3-buten-1-ylmagnesium bromide. This Grignard reagent is then reacted with elemental sulfur in diethyl ether to form the desired 3,4,4-trifluoro-3-butene-1-thiol. In a like manner, the corresponding 2-or 5-halo-substituted 1,3,4-oxadiazole may be prepared.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH2:14][NH:13][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: NCCN1CCCC1
Product: CCCCCCC/C=C/C(=O)NCCN1CCCC1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-(2-aminoethyl)pyrrolidine as starting materials to give the aimed compound.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>CO>[ClH:4].[NH:12]1[CH2:13][CH2:14][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Solvent: CO
Product: Cl
Product: N#Cc1ccc(OC2CCNCC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
Add dropwise acetyl chloride (2.5 mL) to methanol (5.0 mL) at 0° C. Stir the resulting solution at 0° C. for 90 min. Then add a solution of 4-(4-cyano-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (284 mg, 0.94 mmol) in methanol. Stir the resulting mixture for 3 h. Evaporate the solvent and triturate with diethyl ether to provide the title compound (216 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][N:14](B(N(C)C)N(C)C)[CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC=CC=1P>[CH3:13][N:14]([CH3:15])[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: CN(C)B(N(C)C)N(C)C
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(OC(F)(F)F)cc1
Yield: 29.3 %

Procedure:
A mixture of 1-bromo-4-(trifluoromethoxy)benzene (2.41 g), tris(dimethylamino)borane (1.43 g), sodium t-butoxide (1.34 g), tris(dibenzylideneacetone)dipallidium (18 mg), and o-tolylphosphine (12 mg) in toluene (30 ml) was heated under reflux for 4 h. The mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (99:1 increasing to (95:5) to give the title compound as an oil (600 mg). 1H NMR (360 MHz, CDCl3) δ2.95 (6 H, s), 6.66 (2 H, d, J 9 Hz), and 7.08 (2 H, d, J 8.5 Hz). m/z (ES+) m/z 206 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16].Cl.[C:18]([O-:21])(=[O:20])C.[Na+].[C:23]([Si:27]([CH3:33])([CH3:32])[O:28][CH2:29][CH:30]=O)([CH3:26])([CH3:25])[CH3:24]>C(O)C>[Si:27]([O:28][CH2:29][CH:30]1[C:5]2([C:13]3[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=3)[N:7]([C:18]([O:21][C:5]([CH3:13])([CH3:6])[CH3:4])=[O:20])[C:6]2=[O:16])[CH2:4][CH2:3][CH2:2][NH:1]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:33])[CH3:32]
Reactant: COc1ccc2c(c1)NC(=O)C2CCCN
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)C(=O)C21CCCNC1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 1 mol of 3-(3-amino-propyl)-6-methoxy-1,3-dihydro-indol-2-one in 5 ml of ethanol is treated with 5 mmol of sodium acetate hydrochloride and 5 mmol of (tert-butyl-dimethyl-silanyloxy)-acetaldehyde [102191-92-4] and stirred at 60° C. for 3 hours. The reaction mixture is concentrated in vacuo and treated with aqueous saturated potassium carbonate solution and diethyl ether. The phases are separated and the aqueous phase is extracted with diethyl ether (2×). The combined organic phases are washed with water, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][CH:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][CH2:23][C:24]5[N:40]=[CH:39][C:27]6[O:28][CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[C:26]=6[CH:25]=5)[CH2:18][CH2:17]4)[C:3]=1[C:4]=23.[ClH:41]>ClCCl.CO.O1CCOCC1>[ClH:41].[ClH:41].[NH:31]1[CH2:30][CH2:29][O:28][C:27]2[CH:39]=[N:40][C:24]([CH2:23][NH:22][CH:19]3[CH2:18][CH2:17][N:16]([CH2:15][CH:14]4[C:3]5[C:4]6[N:5]([C:6](=[O:12])[CH:7]=[N:8][C:9]=6[CH:10]=[CH:11][C:2]=5[F:1])[CH2:13]4)[CH2:21][CH2:20]3)=[CH:25][C:26]1=2
Reactant: CC(C)(C)OC(=O)N1CCOc2cnc(CNC3CCN(CC4Cn5c(=O)cnc6ccc(F)c4c65)CC3)cc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1cnc2ccc(F)c3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCCN3)CC1
Reaction time: 2.5 h

Procedure:
1,1-Dimethylethyl 7-[({1-[(7-fluoro-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl]-4-piperidinyl}amino)methyl]-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (91 mg, 0.165 mmol) in dichloromethane (2 ml) and methanol (1.5 ml) was treated with 4M hydrogen chloride in 1,4-dioxane (3.5 ml). After standing at room temperature for 2.5 h, the mixture was evaporated. The residue was triturated twice with ether and dried to give the title compound (89 mg).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][N:8]([CH3:16])[C:9]([O:11][CH:12]=[CH:13][CH:14]=[CH2:15])=[O:10]>C(=O)([O-])O.[Na+]>[CH3:6][O:5][C:1]([CH:2]1[O:3][CH:12]([O:11][C:9]([N:8]([CH3:16])[CH3:7])=[O:10])[CH:13]=[CH:14][CH2:15]1)=[O:4]
Reactant: COC(=O)C=O
Reactant: C=CC=COC(=O)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1CC=CC(OC(=O)N(C)C)O1
Temperature: -70 °C
Reaction time: 10 h
Yield: 36 %

Procedure:
In the same manner as in Example 1, a solution of an (R)-binaphthol-dichlorotitanium complex was obtained. This solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 282 mg (2 mmole) of 1-dimethylaminocarbonyloxy-1,3-butadiene. Reaction was then allowed to proceed at -30° C. for 10 hours, and 10 ml of a sodium hydrogencarbonate aqueous solution was added to the reaction mixture to terminate the reaction. This reaction mixture was filtered through Celite and then subjected to extraction once with 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 82 mg of desired optically active 6-methoxycarbonyl-2-dimethylaminocarbonyloxy-5,6-dihydropyran (yield: 36%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[Li]C(CC)C.[CH2:18]([O:20][Si:21]([O:34][CH2:35][CH3:36])(Cl)[C:22]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=1[F:32])[CH3:19]>CCOCC>[F:8][C:7]1[C:2]([Si:21]([C:22]2[C:23]([F:32])=[C:24]([F:31])[C:25]([F:30])=[C:26]([F:29])[C:27]=2[F:28])([O:34][CH2:35][CH3:36])[O:20][CH2:18][CH3:19])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: CCO[Si](Cl)(OCC)c1c(F)c(F)c(F)c(F)c1F
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
39.52 g (0.195 mol) chloropentafluorobenzene is weighed to a 1000 mL vessel and 250 mL Et2O is added. The vessel is cooled down to −70° C. and 150 mL (0.195 mol) of sec-BuLi (1.3 M) is added dropwise during one hour. The temperature of the solution is kept below −50° C. all the time. The solution is stirred for 30 minutes and 62.54 g (0.195 mol) of diethoxychloropentafluorophenylsilane in Et2O (100 mL) is added in small portions. The solution is stirred for over night allowing it to warm up to room temperature. Formed clear solution is filtered and evaporated to dryness to result di(pentafluorophenyl)diethoxysilane, (C6F5)2Si(OEt)2.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl.C(Cl)Cl>C(O)(C)C.O>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(CCc2c[nH]c3ccc(Oc4nc5ccccc5s4)cc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(O)C1CCN(CCc2c[nH]c3ccc(Oc4nc5ccccc5s4)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
To a solution of 1-{2-[5-(benzothiazol-2-yloxy)-1H-indol-3-yl]-ethyl}-piperidine-4-carboxylic acid ethyl ester (44 mg, 0.098 mmol) in isopropanol (2.5 mL) was added H2O (1.1 mL) followed by KOH (11 mg, 0.19 mmol) in H2O (2.5 mL) and the resulting reaction mixture was stirred (rt, 16 h). The reaction mixture was acidified with 6 N HCl to pH 6 and treated with DCM (10 mL). The layers were separated and the aqueous layer was extracted with 25% isopropanol/DCM (2×10 mL). The combined organic layers were dried, filtered and concentrated in vacuo to afford the title compound as a white solid (43 mg, 100%). MS (ESI): mass calcd. for, C23H23N3O3S, 421.5; m/z found, 422.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.76 (d, J=8.0, 1H), 7.66 (m, 2H), 7.51 (d, J=8.7, 1H), 7.43 (m, 1H), 7.36 (s, 1H), 7.31 (m, 1H), 7.16 (dd, J=8.7, 2.3, 1H), 5.20 (s, 2H), 3.94 (m, 1H), 3.30-3.14 (m, 2H), 2.54-2.30 (m, 1H), 2.23-2.04 (m, 2H), 1.30 (s, 2H), 1.17 (d, J=6.2, 4H).
Reaction SMILES: [OH-].[Na+].CC[O:5][C:6]([CH3:8])=[O:7].[CH3:9]O.[CH2:11]1[CH2:15]O[CH2:13][CH2:12]1.CO>>[C:6]([OH:5])(=[O:7])/[CH:8]=[CH:13]/[CH2:12][CH2:11][CH2:15][CH3:9]
Reactant: CO
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CCCC/C=C/C(=O)O
Yield: 25 %

Procedure:
To a cooled (0° C.) solution of 293.6 mg (0.74 mmol) of the pyridyl ketone and 670.4 mg (1.48 mmol) of (5-carboxypentyl)-triphenylphosphonium bromide in 2.5 mL of THF was added dropwise 2.95 mL (2.95 mmol) of 1.0 M t-BuOK in THF over 10 min period. The dark brown solution was stirred at 0° C. for 1.5 h, and then the reaction was quenched with 20 mL of saturated aqueous NH4Cl. The mixture was extracted with 3× 50 ML of CH2Cl2. The combined extract was dried over MgSO4, concentrated and purified by preparative HPLC with MeOH--AcOH--CH2Cl2 (2:1:97) as the eluent to afford 56.1 mg (8.4%) of the less polar (Z)-heptenoic acid and 434.9 mg of the (E)-isomer containing a byproduct from the Wittig salt. In order to purify it, the (E)-isomer was therefore esterified with CH2N2 which was generated by a standard method from MNNG and aqueous NaOH in Et2O. The ester was isolated cleanly by flash chromatography with EtOAc-hexanes-CH2Cl2 (2:1:1) as the eluent. The ester (102.5 mg) was then hydrolyzed with 1 N NaOH in THF--MeOH (1:1). Flash chromatography with EtOAc--MeOH--AcOH--CH2Cl2 (50:1:1:48) yielded 92.5 mg (25%) of the pure (E)-heptenoic acid: mp 56-61° C.; 1H NMR (CDCl3) δ8.58 (s, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.26 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.35-7.16 (m, 9H), 6.19 (t, J=7.4 Hz, 1H), 3.70 (dt, J=6.9, 6.7 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 7.0 Hz, 2H), 1.68-1.51 (m, 4H); FDMS 496 (M+1). Anal. (C30H29N3O4.0.1C2H4O2) C, H, N.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:15])[CH2:10][C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]([CH3:15])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H](CC=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a 50 ml round bottom flask was introduced 200 mg (0.86 mmol) of methyl (S)-3-t-butyldimethylsilyloxybutanoate, to which was added 2.5 ml dry CH2Cl2. The reaction was stirred in a dry ice/acetone bath, and 1.72 ml (2 eq.) of 1M diisobutylaluminum hydride in toluene was added dropwise. After stirring for 1 hour at -78° C., the reaction was quenched with 2 ml of MeOH and warmed to room temperature. The reaction was diluted with 25 ml of CH2Cl2 and 8 ml saturated aq. potassium sodium tartrate was added. The organic layer was separated and dried over MgSO4 and the solvent was removed under reduced pressure. Thin layer chromatography using 10% ethyl acetate in hexane showed complete and clean conversion to a lower Rf spot. This afforded 170 mg (98%) of the product, (S)-3-t-butyldimethylsilyloxybutanal, which was used without purification to avoid racemization.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]2O[CH:13]=[N:12][CH:11]2S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][C:3]=1[O:25][CH3:26].[CH3:27][NH2:28].C1COCC1>CO.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([C:10]2[N:28]=[CH:27][N:12]([CH3:13])[CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2OC=NC2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1Br
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cn(C)cn2)cc(OC)c1Br
Temperature: 135 °C
Yield: 21 %

Procedure:
To an oven-dried pressure tube was added 5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl-4,5-dihydrooxazole (0.4 g, 0.91 mmol), methylamine-THF solution (1.8 mL of a 2.0 M solution, 3.6 mmol), and xylenes (5 mL). The tube was sealed under argon then heated at 135° C. for 15 hours. After cooling to room temperature, the reaction mixture was transferred and concentrated in vacuo then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine twice, dried over Na2SO4 and concentrated. Purification by chromatography (50-100% EtOAc-hexanes then 2-5% MeOH-EtOAc) provided 4-(4-bromo-3,5-dimethoxyphenyl)-1-methyl-1H-imidazole as a light yellow solid (0.056 g, 21% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][C:12]#[N:13].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.COCCOCCO>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:11]([C:12]#[N:13])[C:10]1=[O:14]
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1ccc(F)cc1Br
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1Br
Temperature: 130 °C
Reaction time: 5 h
Yield: 29.9 %

Procedure:
A mixture of N-(2-bromo-4-fluorophenyl)-2-cyanoacetamide (5.00 g, 19.4 mmol), (3E)-4-methoxybut-3-en-2-one (2.33 g, 23.3 mmol), 1,4-diazabicyclo[2.2.2]octane (2.18 g, 19.4 mmol) and 2-(2-methoxyethoxy)ethanol (50 mL) was stirred at 130° C. for 5 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water (×2) and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (100 g, ethyl acetate/hexane=2/98→50/50), washed with ethyl acetate-hexane and collected by filtration to give the title compound (1.78 g, 29%) as a pale-brown powder.