Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:15]([NH:23][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: C=CCC(O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCNCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (500 mg, 2.38 mmol), phenethylamine (348 mg, 2.862.24 mmol), and K2CO3 (643 mg, 4.76 mmol) in anhydrous CH3CN (10 mL) were stirred at rt under N2. Then the solution was refluxing at 80-90° C. overnight. The solid was filtered, and the filtrate was condensed under reduced pressure to give the residue, which was purified by preparative TLC to afford 1-phenethylamino-3-phenyl-hex-5-en-3-ol (320 mg, 45%). 1H NMR (CDCl3): 2.07-2.15 (m, 1H), 2.28-2.39 (m, 1H), 2.51-2.69 (m, 3H), 2.81 (m, 1H), 2.90-3.01 (m, 3H), 3.09 (m, 1H), 5.04 (m, 2H), 5.47-5.58 (m, 1H), 7.17-7.38 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[C:8](Cl)(=[O:12])[C:9]([Cl:11])=[O:10]>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:12])[C:9]([Cl:11])=[O:10])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCCCO
Solvent: ClCCl
Product: CCOCCCOC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-ethoxypropan-1-ol (404 mg, 3.9 mmol) in DCM (total volume: 0.5 mL) was added to a solution of oxalyl chloride (0.5 mL, 5.8 mmol) in DCM (total volume 1.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the resulting residue was dissolved in DCM (3.9 mL) to yield a 1.0M solution in DCM.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].[Br-]>>[CH2:22]([N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccccc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with benzyl chloride, in 49% overall yield and crystallized from ether/hexane to produce a white solid, mp 83°-85.5° C.; IR (KBr) 3213, 1680, 1505, 1399, 1250, 1050, 753 cm-1 ; 1H NMR (CDCl3) δ 2 .17-2.38 (m, 3H), 3.92 (q, J=5.7 Hz, 2H), 4.84 (dd, J=7.5, 5.6 Hz, 1H), 5.16 (s, 2H), 6.86-7.03 (m, 4H), 7.21-7.37 (m, 5H); MH+ at m/z=284; Anal. Calc'd for C 17H17NO3 : C, 72.07; H, 6.05; N, 4.94. Found: C, 72.08; H, 6.20; N, 4.87.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1cccc(-c2cnc3[nH]cc(-c4ccccc4F)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Crude (3-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from last step was dissolved in methanol (1 mL) and potassium hydroxide (50% w/v, 0.038 mL, 0.136 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 30 minutes before being diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was then dissolved in DMSO and purified by mass triggered reverse phase HPLC to afford pure (3-(3-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (5.6 mg, 21% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo [2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light brown syrup. 1H NMR (500 MHz, DMSO-d6) δ 3.60 (m, br, 8H), 7.33 (m, 3H), 7.39 (m, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.74 (m, 1H), 7.84 (m, 3H), 8.28 (m, 1H), 8.61 (d, J=2.5 Hz, 1H), 12.17 (s, 1H). MS: m/z 402.1 (M+H+).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>O1CCOCC1>[ClH:31].[C:1]1([O:7][C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(Oc4ccccc4)cnc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Oc2cnc3c(N4CCNCC4)cccc3c2)cc1
Yield: 100 %

Procedure:
A stirred solution of 1,1-dimethylethyl 4-[3-(phenyloxy)-8-quinolinyl]-1-piperazinecarboxylate (D8) (0.085 g, 0.21 mmol) in 1,4-dioxan (2 ml) and aqueous 4 M hydrochloric acid (2 ml) was heated at 80° C. for 2 h under argon. The reaction mixture was concentrated in vacuo to a residue which was re-evaporated with toluene (2×50 ml) to yield the title compound as a foam (0.075 g, 0.22 mmol, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: Cc1cc(N2CC=C(C(=O)OC(C)C)CC2)c2cccc(Br)c2n1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CC=C(C(=O)OC(C)C)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Under a nitrogen atmosphere, 8-bromo-4-(4-isopropyloxycarbonyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline (5.9 g), 2,4-dichlorophenylboric acid (3.2 g) and sodium carbonate (4.8 g) were suspended in a mixed solvent of deaerated water (15 mL), toluene (7.5 mL) and ethanol (7.5 mL), followed by adding thereto tetrakis(triphenylphosphine)palladium (0.88 g), and the resulting mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature to be separated. After the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, after which the filtrate was concentrated under reduced pressure and the resultant residue was crystallized from diisopropyl ether. The crystals were collected by filtration and washed with a small amount of diisopropyl ether to obtain the title compound (5.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:36]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:7]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]3[C:5]([C:6]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:16]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(C3CCCN(C(=O)c4ccccc4)C3)c(-c3ccccc3)c2c1

Procedure:
To a dichloromethane (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added benzoyl chloride (0.011 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional dichloromethane were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 453.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.ClCCl.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2)cc1

Procedure:
4-Nitrobenzophenone (5.0 g, 0.022 mol) is dissolved in ethanol-dichloromethane (40 ml:30 ml) and hydrogenated at room temperature with 10% palladium on carbon (0.5 g) as a catalyst. The catalyst is filtered off and the filtrate is evaporated to dryness. The product is used in the next reaction step without further purification. Yield 5.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][OH:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH2:20][CH2:19]1.O>ClCCl>[O:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][S:26]([O:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)(=[O:27])=[O:28])[CH2:22][CH2:23]1
Reactant: O=S(=O)(Cl)CCN1CCOCC1
Reactant: OCCOc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(CCN1CCOCC1)OCCOc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 39.4 %

Procedure:
To a solution of 2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethanol (154 mg, 0.53 mmol) and tryethylamine (0.22 ml, 1.58 mmol) in dichlorometane (9 ml) was added a solution of 2-morpholinoethanesulfonyl chloride (prepared from 0.69 mmol of 2-morpholinoethanesulfonic acid and 1.14 ml of oxalyl dichloride in dichlorometane at 0° C.) and the final mixture was stirred at room temperature overnight. Water was added, the organic phase separated and the aqueous phase extracted with more dichlorometane. The combined organic phases were washed with saturated aqueous solution of NaHCO3 and water, and after drying over sodium sulphate, filtered and evaporated to dryness yielding 222 mg of crude compound. After column chromatography purification (silica gel, eluent: petroleum ether/ethyl acetate 8:2), 94 mg of 2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl 2-morpholinoethanesulfonate as a solid was obtained, with a m.p.=120-122° C. after crystallization in acetone-petroleum ether.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13](Cl)=[O:14].Cl>ClCCl>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([C:6]1[NH:5][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc[nH]1)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
200 mL of dichloromethane was poured into a 1 L three-necked flask equipped with a stirrer, thermometer, dropping funnel, and nitrogen inlet tube, cooled to 0° C. using a salt-ice bath, and then 80.4 g (0.6 mol) of aluminum chloride and 40.3 g (0.6 mol) of pyrrole were added. Next, 104.7 g (0.50 mol) of 2,5-dichlorobenzoyl chloride dissolved in 100 mL of dichloromethane was slowly added dropwise using a dropping funnel. After completing the addition, the reactant was stirred for 3 hours while maintained at 5° C. to 10° C. using the salt-ice bath. After confirming the disappearance of raw materials by way of thin-layer chromatography, the reaction liquid was gradually added to 1 L of 2 N HCl, and excessive aluminum chloride was dissolved and removed. The organic layer was washed using 5% sodium bicarbonate water, water, and a sodium chloride solution, and the organic layer was dried using magnesium sulfate, and then the solvent was removed by an evaporator. The approximate yield amount was 120 g. The crude product was recrystallized from hexane/ethyl acetate to obtain the intended product in an amount of 95 g and at a yield of 79% as a milky white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16]S(C1C=CC(C)=CC=1)(=O)=O.C(O)(=O)C>C(O)C.O>[CH3:31][O:30][C:28]1[CH:27]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[CH:29]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: COc1cc(COc2ccccc2OS(=O)(=O)c2ccc(C)cc2)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(COc2ccccc2O)cc(OC)c1
Yield: 75 %

Procedure:
A solution of potassium hydroxide (1.75 g, 31.26 mmol) in ethanol (30 cm3, absolute) and water (30 cm3) was added in portions 15 minutes apart to 1-[3,5-dimethoxy-benzyloxy]-2-[toluene-4-sulfonyloxy]benzene (0.68 g, 1.64 mmol). After heating to reflux for 1 hour, the cooled solution was neutralized with glacial acetic acid and evaporated under reduced pressure. The residue was extracted with diethyl ether (3×20 cm3), and the extracts were washed with sodium bicarbonate (40 cm3) and sodium hydroxide (3×20 cm3, 3% aqueous solution). The sodium hydroxide portion was saturated with solid carbon dioxide pellets, and the precipitate was removed by filtration to give the phenol (0.32 g, 74%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C[N-]OC.[CH2:15]([Li])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2](=[O:9])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:4]=1
Reactant: [Li]CCCCCC
Reactant: O=C(Cl)c1cccnc1
Agent: C[N-]OC
Agent: Cl
Product: CCCCCCC(=O)c1cccnc1

Procedure:
In an example of the general procedure (scheme 1), nicotinoyl chloride hydrochloride (1) is converted to the N-methyl-N-methoxyamide (2) in the presence of a base and reacted with hexyl-lithium (J. Med. Chem., 35, 1992, 2392-2406) to produce 1-pyridin-3-yl-heptan-1-one (3).
Reaction SMILES: [CH:1]1([S:6]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:26].[K+]>CO.O>[CH:1]1([S:6]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])(=[O:26])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nccs1)C(c1ccc(Cl)c(Cl)c1)S(=O)C1CCCC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1nccs1)C(c1ccc(Cl)c(Cl)c1)S(=O)(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A solution of rac-2-cyclopentanesulfinyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (20 mg, 0.05 mmol) in methanol (2 mL) was stirred at 25° C. as a solution of potassium permanganate (9 mg, 0.06 mmol) in water (0.5 mL) was added. The mixture was stirred at 25° C. for 30 min and then was filtered. The filter cake was washed with dichloromethane and the combined filtrates were washed with sodium bicarbonate solution (10 mL) and brine (10 mL), then were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 12M column, 50/50 hexanes/ethyl acetate) to provide rac-2-cyclopentanesulfonyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide(10 mg, 48% yield) as a colorless oil: EI-HRMS m/e calculated for C16H16N2O3S2Cl2 (M+) 417.9979, found 417.9977.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.P(Br)(Br)[Br:11].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:11])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
(5-Bromopyridin-3-yl)methanol (1.41 g; 7.5 mmol) is dissolved in 20 mL DCM and the flask is flushed with argon and cooled to 0° C. Phosphorus tribromide (0.70 mL; 7.5 mmol) is added dropwise via a syringe and reaction mixture is stirred at RT for 2 h. NEt3 (1 mL) is added by syringe and the reaction mixture is stirred for 1 h. The mixture is cooled to 0° C. and quenched with the slow addition of 5 mL water, followed by the addition of 2M K2CO3 until mixture is neutral (pH=˜7). The mixture is partitioned between water and EtOAc, the aqueous phase is washed three times with EtOAc and the organic layers are combined, dried over anhydrous sodium sulfate, filtered and deposited on silica. Purification by column chromatography on silica gel (pre-washed with 1% NEt3) using a solvent gradient of hexanes to EtOAc led to the isolation of the desired product as white crystals (1.29 g, 69% yield).
Reaction SMILES: S(Cl)(Cl)=O.C(C1C=CC(C(O)=O)=CC=1)CCCCCCC.C(C1C=CC(C(Cl)=O)=CC=1)CCCCCCC.[CH3:39][O:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][C:50]=1[O:51][CH3:52])[N:47]=[CH:46][CH:45]=[C:44]2[O:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1.[CH2:61]([C:69]1[CH:74]=[CH:73][C:72]([C:75]([N:77]=[C:78]=[S:79])=[O:76])=[CH:71][CH:70]=1)[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68]>C1(C)C=CC=CC=1.C(O)C>[CH3:39][O:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][C:50]=1[O:51][CH3:52])[N:47]=[CH:46][CH:45]=[C:44]2[O:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:78]([NH:77][C:75](=[O:76])[C:72]2[CH:73]=[CH:74][C:69]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])=[CH:70][CH:71]=2)=[S:79])=[CH:56][CH:55]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCCCCCc1ccc(C(=O)N=C=S)cc1
Agent: CCCCCCCCc1ccc(C(=O)Cl)cc1
Agent: CCCCCCCCc1ccc(C(=O)O)cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-octylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-octyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-octyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-octyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 54%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[C:43]2[CH:42]=[C:41]([C:44](=[O:47])[CH2:45][CH3:46])[S:40][C:39]=2[CH:38]=[CH:37][C:36]=1[Cl:48]>O1CCCC1>[Br:1][CH:45]([CH3:46])[C:44]([C:41]1[S:40][C:39]2[CH:38]=[CH:37][C:36]([Cl:48])=[C:35]([Cl:34])[C:43]=2[CH:42]=1)=[O:47]
Reactant: CCC(=O)c1cc2c(Cl)c(Cl)ccc2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1cc2c(Cl)c(Cl)ccc2s1
Temperature: 0 °C
Reaction time: 18 h
Yield: 193 %

Procedure:
Phenyltrimethylammonium tribromide (1.58 g) was added in portions under nitrogen at 0° C. over 30 minutes to a stirred solution of 1-(4,5-dichlorobenzo[b]thiophen-2-yl)propan-1-one (1.09 g) in tetrahydrofuran (80 ml), then the mixture was stirred at 0° C. for 30 minutes, at ambient temperature for 18 hours and at reflux temperature for 5 hours. Further phenyltrimethylammonium tribromide (0.79 g) was added, the mixture was heated under reflux for 2 hours, then it was cooled to ambient temperature and filtered. The solvent was removed in vacuo to give a brown oil which was purified by flash chromatography over silica using a 3:1 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-bromo-1-(4,5-dichlorobenzo[b]thiophen-2-yl)propan-1-one (1.59 g) as an oil which was used without further purification.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27]C(C)(C)C)=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)C(=O)O)C1=O
Reaction time: 3 h

Procedure:
To a solution of 320 mg (0.64 mmol) of tert-butyl (2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (Example 1, Step G) in DCM (3184 μL) was added trifluoroacetic acid (2453 μL, 31.8 mmol) at 0° C. After being stirred at 25 C for 3 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure 3-times to provide the title compound as a pale yellow foam which was used in the subsequent reaction without further purification.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]=[CH:10]2>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11][CH2:10]2
Reactant: COc1ccc2c(=O)occc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1OCCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1M solution of boron tribromide in methylene chloride (101 mL) was added at 0° C. to a solution of 6-methoxy-isochromen-1-one (8.9 g) in methylene chloride (178 mL). Then the ice bath was removed and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled to 0° C., water was added and the aqueous phase was extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 162.03 (C9H6O3); MS (ESI): 163 (M+H+).