Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6].C(N)(=O)C>O.C(OCC)C.[Fe]>[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Agent: CC(N)=O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1ccc(N)c(F)c1
Reaction time: 1 h

Procedure:
A stirred flask containing 350 mL of acetic acid was heated to 80°-85° C. under a nitrogen atmosphere. To this flask was added 39.10 g (0.700 mole) of powdered iron, and this mixture was stirred for one hour. A solution of 4-isopropoxy-2-fluoronitrobenzene in 250 mL was added to the mixture dropwise. Upon completion of addition, the reaction mixture was heated at 80°-85° C. for one hour. After being cooled below 40° C., the mixture was filtered, and the solvent was evaporated under reduced pressure, leaving a residue. This residue was dissolved in a mixture of water and diethyl ether. The organic layer was separated and was washed in succession with saturated aqueous solutions of sodium bicarbonate and sodium chloride. It was then dried over anhydrous magnesium sulfate, filtered through a short column of silica gel, and the solvent was evaporated under reduced pressure, leaving an impure residue which contained significant amounts of acetamide in addition to the desired product. This residue was suspended in 500 mL of 2N hydrochloric acid for one hour. The hydrochloric acid mixture was then extracted with diethyl ether, and the two phases were separated. Aqueous sodium hydroxide solution was added to the aqueous hydrochloride solution until it was basic. This basic solution was extracted with diethyl ether, and the extract was dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent under reduced pressure, the residue was recrystallized from diethyl ether/petroleum ether to yield 16.90 g of 4-isopropoxy-2-fluoroaniline as an oil which darkened on standing. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([NH:11][C:12]1[O:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>CCOCC>[CH2:7]([N:11]([C:12]1[O:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNc1nc(C)co1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCN(C(=O)OCC)c1nc(C)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (10.5 ml, 0.11 mol) was added dropwise over 20 minutes to a stirred solution of 2-butylamino-4-methyl oxazole (15.4 g, 0.10 mol) and triethylamine (15.3 ml, 0.11 mol) in dry ether (100 ml) cooling to 5°-10° C. The mixture was stirred for a further 2 hours at ambient temperature, the white solid was filtered off and the filtrate evaporated under vacuum to a pale oil (22.4 g) NMR (CCl4) 6.3 δ (oxazole 5-H). This 3-acylated compound was dissolved in xylene and the solution was heated under reflux for 2 hours, cooled, washed with dilute HCl, saturated NaCl solution, dilute Na2CO3 and NaCl solution again, dried and evaporated. The residue was distilled under vacuum, b.p. 85°-90° C./0.6 mm NMR (CCl4) 7.12 δ (oxazole 5-H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:21][CH:22]=3)[CH:10]=[C:11]([C:13]([F:14])([F:16])[F:15])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cncc(C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A mixture of 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.4 g (72%) of N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 268-270° C. Anal. Calc'd. for C18H15F3N4O3S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.68; H, 3.47; N, 12.53; S, 7.43.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28]/[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:30]\[O:31][CH3:32]>C(#N)C.O>[CH3:32][O:31]/[N:30]=[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CO/N=C(\CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of ethyl 3-(4′-hydroxybiphenyl-4-yl)propanoate (0.27 g, 0.001 mmol) in acetonitrile was added potassium carbonate (0.27 g, 0.002 mmol) and (1Z)-2-bromo-N-methoxy-1-phenylethanimine (0.23 g, 0.001 mmol) and refluxed at 80° C. for 3 h. RM was diluted with water and extracted with ethyl acetate, Organic layer was washed with water and brine solution, dried over anhydrous Na2SO4 and concentrated to get crude product which was purified by comb flash to get white gummy solid as product (0.25 g, Yield: 60%): MS (ESI, 120 eV): m/z=418 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.59-7.63 (m, 2H), 7.37-7.42 (m, 4H), 7.26-7.28 (m, 3H), 7.15 (d, 2H), 6.88-6.90 (d, 2H), 5.15 (s, 2H), 4.03-4.10 (m, 2H), 3.99 (s, 3H), 2.87-2.93 (t, 2H), 2.54-2.60 (t, 2H), 1.17-1.19 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[CH3:30][C:29]([Si:26]([CH3:28])([CH3:27])[O:25][CH2:24][CH2:23][CH:7]([C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(I)cc1
Temperature: 70 °C
Yield: 70.3 %

Procedure:
A solution of 5-(4-iodo-phenyl)-3-oxo-pentanoic acid tert-butyl ester (10.0 g, 26.7 mmol) in dimethylformamide (25 mL) was added dropwise over 20 min to a stirred suspension of sodium hydride (60% mineral oil suspension; 1.12 g, 28.0 mmol) in dimethylformamide (25 mL) at 0° C. under nitrogen. After stirring for 20 min (2-bromoethoxy)-t-butyldimethylsilane (7.03 g, 6.31 mL, 29.4 mmol) was added dropwise over 20 min at 0° C. then the reaction heated to 70° C. for 3.5 h. On cooling to room temperature the reaction was quenched by careful addition of water (2 mL) then the volatiles evaporated. The residue was partitioned between saturated aqueous ammonium chloride solution (150 mL) and dichloromethane (150 mL) and the phases separated. The aqueous phase was washed with dichloromethane (3×150 mL) then the organic phases combined, washed with brine (150 mL), dried (sodium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (25% diethyl ether: cyclohexane) to give the title compound (10.0 g, 70%) as colourless oil which was a mixture of diastereomers. LC/MS: 4.55 min; z/e 533, calcd (M+1) 533. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 6.90 (2H), 3.55 (3H), 2.85 (4H), 2.15 (2H minor), 1.95 (2H major), 1.40 (9H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[C:14]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([CH:26]4[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[O:18])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[C:14]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([C@H:26]4[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]4)=[CH:24][CH:25]=3)=[O:18])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)Nc2ccc(C3CCC(=O)CC3)nc2)cnn1-c1ccc(C(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)Nc2ccc([C@H]3CC[C@H](O)CC3)nc2)cnn1-c1ccc(C(C)(C)C)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-tert-butylphenyl)-5-methyl-N-[6-(4-oxocyclohexyl)pyridin-3-yl]-1H-pyrazole-4-carboxamide (136 mg) in ethanol (5 ml) was cooled in ice water, sodium borohydride (48 mg) was added and stirred at the same temperature for an hour. After the reaction, water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel column chromatography (n-hexane/ethyl acetate), washed with ethanol, the resulting solid was filtered and dried at 60° C. in vacuo to give the titled compound (29 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl>Cl>[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)nc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To 0.5 g (3.9 mmol) of 6-chloro-pyridin-3-ylamine in 6 mL of 12M HCl at −20° C. were added a solution of 0.36 g (5.2 mmol, 1.3 eq) of sodium nitrite dissolved in 2 mL of H20. The reaction mixture was stirred for 15 min, and 4.4 g (19.5 mmol, 5 eq) of tin chloride dihydrate dissolved in 2 mL of 12M HCl were added. The reaction mixture was allowed to reach 0° C. within 40 min, and the white precipitate was recovered by filtration and washed with Et2O to yield 0.35 g (62%) of (6-chloro-pyridin-3-yl)-hydrazine hydrochloride as a white solid, MS: 144 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]CC2C=CC=CC=2)=[C:4]([Br:16])[CH:3]=1.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Br:16])[CH:3]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Br)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Nc1ccc(O)c(Br)c1
Yield: 56 %

Procedure:
To a solution of 4-amino-1-benzyloxy-2-bromobenzene in 2 mL of dichloromethane at −78 C was added boron trichloride (0.4 mL, 1 M in DCM) dropwise. The reaction was quenched with water at 0 C, concentrated and dried under vacuum to afford 4-amino-2-bromo-1-hydroxybenzene (17 mg, 56% two steps)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[OH-].[Na+].[BH4-].[Na+].Cl>O.C1COCC1>[OH:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC1CCc2cc(Cl)ccc21
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 2.5 g of 5-chloroindan-1-one and 30 ml of THF is cooled to 0-5° C., 2.5 ml of concentrated NaOH solution and then, in portions, 0.88 g of sodium borohydride are added and the reaction mixture is stirred overnight at RT. It is poured into 100 ml of water, the mixture is acidified to pH 2 by the addition of concentrated HCl solution, extracted with AcOEt, the organic phase is washed with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a cyclohexane/AcOEt mixture (80/20; v/v) to give 2.1 g of the expected product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Yield: 33 %

Procedure:
By essentially following the procedure detailed in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part A) in 33% yield as an oil following radial chromatography (SiO2; gradient of 2-10% MeOH in CH2Cl2).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([F:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(F)ccc2[nH]1

Procedure:
(S)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.5 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (0.5 mmol) were coupled according to Procedure A. The crude product was triturated once with 1:1 ether-hexanes and once with hexanes. The resulting solid was boiled in ethyl acetate, the resulting suspension filtered, and the collected solid dried. Yield 103 mg, 48%; HPLC (60/40) 3.69 minutes (95%); PBMS 428 (MH+, 100%);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12])#[N:2].[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]([O:12][CH3:13])=[C:3]([CH:8]=1)[C:1]#[N:2])([O-:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1C#N

Procedure:
A mixture of 2-cyano-4-nitrophenol (3.5 g, 21 mmol), K2CO3 (5.9 g, 42 mmol), and MeI (9.08 g, 64 mmol) in acetone (50 mL) was heated at reflux overnight. The mixture was cooled and concentrated, taken up in H2O, stirred, filtered the yellow solid, dried by air (3.0 g, 79%). 1H NMR (400 MHz, CDCl3): d 4.08 (s, 3H), 7.12 (d, J=9.2 Hz, 1H), 8.5 (m, 2H).
Reaction SMILES: C(OC([O:6][CH:7]1[CH2:19][CH2:18][C:17]([O:21]C(OCC)C)([CH3:20])[CH:16]([O:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:29])[CH:15]=[CH:14][CH:13]([CH3:41])[CH:12](/[C:42](/[CH3:69])=[CH:43]/[CH:44]=[CH:45]/[C:46]([O:63]C(OCC)C)([CH3:62])[CH2:47][CH:48]2[O:61][CH:49]2[CH:50]([CH3:60])[CH:51]([O:54]C(OCC)C)[CH2:52][CH3:53])[O:11][C:9](=[O:10])[CH2:8]1)C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(O)(C)C>O1CCCC1>[OH:6][CH:7]1[CH2:19][CH2:18][C:17]([OH:21])([CH3:20])[CH:16]([O:27][C:28]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:34][CH2:35]2)=[O:29])[CH:15]=[CH:14][CH:13]([CH3:41])[CH:12](/[C:42](/[CH3:69])=[CH:43]/[CH:44]=[CH:45]/[C:46]([OH:63])([CH3:62])[CH2:47][CH:48]2[O:61][CH:49]2[CH:50]([CH3:60])[CH:51]([OH:54])[CH2:52][CH3:53])[O:11][C:9](=[O:10])[CH2:8]1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)N2CCC(N3CCCC3)CC2)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)N2CCC(N3CCCC3)CC2)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)N2CCC(N3CCCC3)CC2)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)N2CCC(N3CCCC3)CC2)C=CC1C
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
To the crude product of (8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide (11 mg, 11 μmol) was added a solution of pyridinium p-toluenesulfonate (11.4 mg, 45 μmol) in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (1 mL) at room temperature. To the mixture was added molecular sieves 4 Å (10 mg), followed by stirring at room temperature for 18.5 hours. Additional pyridinium p-toluenesulfonate (11.4 mg, 45 μmol) was added, followed by stirring at room temperature for 72 hours. The reaction mixture was evaporated, and the resulting residue was diluted with ethyl acetate, and then washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtrated and evaporated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel Plate, methanol:dichloromethane=1:19) to give the title compound (2.88 mg, 35%, two steps) as a colorless oil.
Reaction SMILES: O=S(Cl)Cl.C([N:12]1[CH2:19][C@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:17][C@@:13]1([CH3:29])[C:14]([OH:16])=[O:15])(OC(C)(C)C)=O.[CH3:30]O>>[CH3:30][O:16][C:14](=[O:15])[C@:13]1([CH3:29])[CH2:17][C@@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:19][NH:12]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@@]1(C)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@]1(C)C[C@@H](OCc2ccc(Br)cc2)CN1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
SOCl2 (0.27 mL) was carefully added dropwise to 2.7 mL of MeOH at −5° C. To this mixture was added (2S,4R)-N-Boc-4-(4-Bromobenzyloxy)-2-methyl-proline (0.25 g) in 2.7 mL of MeOH. The reaction mixture was allowed to warm to 20° C. and stirred overnight. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated in vacuo to afford the titled compound (85 mg).
Reaction SMILES: S(=O)(=O)=[O:2].[F:5][C:6]1([F:15])[S:10][C:9](F)(F)[C:8]([F:13])=[C:7]1[F:14].[F-].FC1(F)SC(F)(F)C=C1>>[F:5][C:6]1([F:15])[S:10][C:9](=[O:2])[C:8]([F:13])=[C:7]1[F:14]
Reactant: O=S(=O)=O
Reactant: FC1=C(F)C(F)(F)SC1(F)F
Agent: FC1(F)C=CC(F)(F)S1
Agent: [F-]
Product: O=C1SC(F)(F)C(F)=C1F
Yield: 24.5 %

Procedure:
Sulfur trioxide (128.0 g, 1.60 mol) was added rapidly to 77.6 g (0.40 mol) of hexafluoro-2,5-dihydrothiophene. After an initial exotherm, the mixture was refluxed for 30 min. and fractionated to give 121.9 g, bp 42°-55° C., shown to be mainly pyrosulfuryl fluoride by 19F NMR, and 29.5 g of crude tetrafluoro-2,5-dihydrothiophene, bp 77°-85° C. Redistillation of this product afforded 16.9 g (25%) of tetrafluoro-2,5-dihydrothiophene-2-one, bp 83° C. IR (CCl4): 1755 (C=O) and 1740 cm-1 (C=C). NMR (CCl4): 19F.0. -92.0 (d of d, JFF 14.7, 5.5 Hz, 2F, CF2), -133.5 (q, JFF 14.3 Hz, 1F, CF), -144.3 (d of t, JFF 13.9, 5.5 Hz, 1F, CF). MS: m/e 171.9615 (M+ ; calcd for C4F4OS, 171.9606), 3.9664 (M+ -CO; cald, 143,9657), 121.9641 (M+ -CF2 ; calcd, 121.9638). Anal. Calcd for C4F4OS: C, 27.91; S, 18.63 Found: C, 28.27; S, 19.16.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:25])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:19][C:14]=3[S:13][C:12]=2[CH:24]=1)C>C(O)C>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]2[S:13][C:12]3[CH:24]=[C:8]([CH2:7][C:6]([OH:25])=[O:5])[CH:9]=[CH:10][C:11]=3[C:15]=2[CH:16]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1ccc(CC(C)C)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc2sc3cc(CC(=O)O)ccc3c2c1

Procedure:
To a 500 ml. flask, fitted with a condenser and containing a solution of 0.81 g. of potassium hydroxide in 125 ml. of ethanol was added 4.7 g. of 8-i-butyldibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and the aqueous solution acidified with dilute hydrochloric acid. The product was removed by filtration, washed with water and dried at 60° in a vacuum oven overnight. The yield of 8-i-butyl-dibenzothiophene-3-acetic acid after crystallization from i-propanol was 1.5 g., mp 133°-135° (heptane).
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[C:1]([N:8]1[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@@:9]1([CH3:24])[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-BOC-4-(S)-phenyl-(L)-proline, methyl ester from Step A (2.0 g, 6.56 mmol) in anhydrous THF (20 mL) at −78° C. was added over a 30 min period 1M LiHMDS in hexanes (9.83 mL, 9.83 mmol) and allowed to stir for 30 mins at −78° C. The reaction was then allowed to stir for 1 hr at 0° C. The reaction was then cooled to −78° C. and MeI (4.65 g, 32.79 mmol) was added dropwise. The reaction was allowed to warm to rt overnight. The reaction was quenched with NH4Cl. The organic layer was collected and washed with 1M HCl, NaHCO3, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluted with 75% Et2O/hexanes to give 1.85 g of desired product.