Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([F:16])[F:15])[CH:8]=[O:9].C([O-])(=O)C.[Na+].CN(C)C=O>>[F:15][CH:14]([F:16])[O:13][C:12]1[C:5]2[O:4][C:3]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:2]=3[C:6]=2[C:7]([CH:8]=[O:9])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Yield: 73.3 %

Procedure:
To a mixture of 3-(2-bromo-4-nitrophenoxy)-4-(difluoromethoxy)benzaldehyde (11.5 g, 0.030 mol) and sodium acetate (3.7 g, 0.045 mol) in dimethylformamide (50 mL) palladium(II) acetate (0.68 g, 0.003 mol) was added in 4 different lots with 1 hour duration at 120-125° C. After the completion of the addition, it was refluxed for 16 hours. The reaction mixture was filtered through hyflo, washed with dimethylformamide (10 mL). The filtrate was poured into the cold water. The solid separated out was filtered. The solid was washed with hexane and dried. Yield—73.3%. HPLC (purity): 84.5%; Rf—0.5 (Ethyl acetate:Hexane (3:7)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[ClH:11]>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:11])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CO)cc1
Reactant: Cl
Solvent: Cc1ccccc1
Product: CSc1ccc(CCl)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Under an atmosphere of nitrogen, 78.7 g (500 mmo)l [sic] of 4-(methylthio)benzyl alcohol were dissolved in 154.5 g of toluene. 131.6 g, (1.3 mol) of conc. HCl were added, and the mixture was stirred at 20-25° C. for 30 min. After 2 h (no starting materialleft according to TLC), the reaction mixture was diluted with 349 g of toluene and the aqueous phase was separated off. The organic phase was neutralized using 14.0 g of NaHCO and, after 15 min, filtered, and the solvent was evaporated. The residue that remained consisted of 107.4 a of a yellow oil with toluene, corresponding to a yield of >95% (according to NMR).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)([CH3:24])[C:17]=2[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:35]=[C:36]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([C:25]4[O:26][CH:27]=[CH:28][CH:29]=4)([CH3:24])[C:17]=3[CH:30]=2)=[CH:10][CH:11]=[C:12]1[C:36]#[N:35])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(c1ccco1)OCC(=O)N2
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccco1)OCC(=O)N2

Procedure:
tert-Butyl-2-cyano-5-[5-(2-furyl)-5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-[5-(2-furyl)-5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate generally according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.17 (s, 1H), 7.71 (d, J=1.46 Hz, 1H), 7.34 (dd, J=1.93, 8.34, Hz, 1H), 7.28 (d, J=3.79 Hz, 1H), 7.21 (d, J=8.42 Hz, 1H), 7.16 (d, J=1.94 Hz, 1H), 6.44-6.41 (m, 2H), 6.24 (d, J=3.18 Hz, 1H), 4.13 (d, J=16.14 Hz, 1H), 4.01 (d, J=16.11 Hz, 1H), 1.89 (s, 3H), 1.38 (s, 9H); MS (ES) m/z 434 ([M+H]+, 100%)
Reaction SMILES: [S:1]([CH3:13])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl[Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.ClCCCl.ClCCl>[Si:15]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([S:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of methyl 1-thio-β-D-galactopyranoside (25) 5 g, 28 mmol), chloro t-butyldiphenylsilane (5.85 g, 21 mmol) and DMAP (2.63 g, 21 mmol) in dry 1,2-dichloroethane (130 mL) was left to stir at reflux for 2.5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (200 mL) and washed with saturated sodium chloride solution (2×250 mL). The organic phase was dried over MgSO4 and subsequently evaporated to dryness to give methyl 6-O-(t-butyldiphenylsilyl)-1-thio-β-D-galactopyranoside (26) (7.5 g, 81%) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11]C)(=O)C.C(O)(=O)C.[Si:17]([O:24][C@@H:25]1[C@@H:29]([CH:30](OC)[OH:31])[O:28][C@@:27](C)([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CO>[Si:17]([O:24][C@@H:25]1[C@@H:29]([CH:30]([CH2:7][O:10][CH3:11])[OH:31])[O:28][C@@H:27]([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COC(O)[C@H]1O[C@@](C)(n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of 3′-O-t-butyldimethylsilyl-5′-(R)-C,O-methylenethymidine (1.84 g, 5 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in methanol was stirred at room temperature for 90 h. Ethyl acetate (70 ml) was added and the mixture neutralized with acetic acid to pH 7. Solvents were evaporated and the residue was dissolved in methylene chloride (30 ml). Precipitates were filtered and the solution concentrated- The residue was purified by chromatography on silica (EtOAc-hexane, 1:1) to give 310 mg of intact starting material and 578 mg of 3′-O-t-butyldimethylsilyl-5′-C-methoxy-methylthymidine as a colorless solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:27]=2)OC1>>[F:34][C:31]1[CH:30]=[C:29]([C:35]#[N:36])[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])=[CH:33][CH:32]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile as described in Example 1 to give 4,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.42-7.48 (2H, m), 7.57 (1H, dd, J 8 and 3), 7.61-7.66 (3H, m), 8.10 (1H, s), 9.02 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:45]=[N+:46]=[N-:47].[Na+].Cl>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]4[NH:47][N:46]=[N:45][N:21]=4)=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C#N)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a solution of 0.17 g (0.34 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-ethoxy}-3,5-dimethyl-benzonitrile in 4 ml o-xylene, were added 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide and the solution was heated at 150° C. (oil bath temperature) for 19.5 h. Another 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide were added and the reaction mixture was heated for an additional 4 h, then stirred for 3 days at room temperature. The reaction mixture was poured onto aqueous 1M hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was suspended in acetonitrile, filtered and washed with acetonitrile. The obtained crude material was purified on a preparative HPLC (Zorbax column) eluting with a gradient of acetonitrile and water containing 0.5% formic acid. White solid (18%). MS (Turbo Spray): m/z=549.199 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].C(Cl)Cl.CO>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1ncc(CO)cc1Cl
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: CCc1ncc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
MnO2 (620 mg, 7.13 mmol) was added to a solution of (5-chloro-6-ethyl-3-pyridinyl)methanol (103 mg, 0.600 mmol) in DCM (4 ml) and the mixture was stirred at room temperature overnight. TLC (10% DCM/MeOH) showed starting material remaining. An excess of MnO2 (261 mg, 3.00 mmol) was added. After stirring for 3 h, the reaction went to completion. The resulting suspension was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give 52 mg of the title compound as colourless oil.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[C:16]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:15]=2)[CH2:9][CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[C:16]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:15]=2)[CH2:9][CH2:8]1
Reactant: COc1ccc2nc(C=Cc3ccccn3)nc(N[C@H]3CC[C@@H](CNC(=O)C(F)(F)F)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(C=Cc3ccccn3)nc(N[C@H]3CC[C@@H](CN)CC3)c2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of cis-4-trifluoroacetylaminomethyl-N-{2-[2-(2-pyridyl)ethenyl]-6-methoxyquinazolin-4-yl}cyclohexylamine in 45 mL of methanol and 5 mL of water was combined with 414 mg of potassium carbonate, and stirred at room temperature for 15 hours. The reaction solution was combined with water, extracted with chloroform, and then dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol:aqueous ammonia=100:10:1) to obtain 120 mg of the desirable compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:3]([Cl:2])[C:4]=3[CH3:17])[CH2:8][CH2:9]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1c(OC2CCNCC2)ccc(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1c(OC2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc(Cl)c1Cl
Temperature: 20 °C
Reaction time: 14 h
Yield: 79.9 %

Procedure:
Acetonitrile (144 mL) and water (336 mL) were added to a mixture of 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine hydrochloride (60 g), 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (74.7 g) and potassium carbonate (57.3 g) and the mixture was heated to reflux for 7 h, then cooled over 30 min to 75° C. and held at 75° C. for 14 h, then heated over 30 min to reflux. Acetonitrile (192 mL) was added and then the mixture was cooled to 20° C. over 2 h to give a suspension. The suspension was filtered under vacuum, the filter cake was washed with water (180 mL) and then with acetonitrile (180 mL) and dried under vacuum at 40° C. to give 4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (73.9 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][NH:1][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reaction time: 12 h
Yield: 56.3 %

Procedure:
A solution of tert-butyl N-(2-aminoethyl)carbamate (1.00 g, 6.24 mmol) and 4-chlorobenzaldehyde (0.90 g, 6.37 mmol) in DCE (10 mL) was stirred for 30 minutes, followed by the addition of NaBH(OAc)3 (1.98 g, 9.36 mmol) in a single portion. After being stirred for 12 hours, the mixture was acidified to pH 2 with 0.2N HCl, and extracted with DCM (3 times, each discarded). The acidic aqueous layer was basified to pH 10 with 2.0 M NaOH, and extracted with DCM. The DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester as an oil (1.0 g). LCMS (APCI+) m/z 285, 287 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:20][C:21]#[N:22].[NH4+]>CO>[OH:19][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][C:11]([S:20][C:21]#[N:22])=[CH:10][C:9]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#C[S-]
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
2,6,-Diphenylphenol (100.0 g, 0.406 mole) and ammonium thiocyanate (67.99 g, 0.893 mole) were suspended in methanol (150 ml) in a three-necked round bottom flask equipped with magnetic stirrer, thermometer and bubbler. The reaction mixture was cooled to -5° C. in an acetone/ice bath and chlorine gas bubbled through the solution for three hours. Maintaining the temperature below 10° C., ammonia gas was bubbled through the reaction for 2 hours. The contents of the flask were then poured into iced distilled water (250 ml) and allowed to stand for 12 hours in the refrigerator. After filtering, the solid was dried in vacuo at 45° C. for 12 hours. The title compound was purified by chromatography on silica and recrystallized from hexane, m.p. about 104°-106.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[S:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1Sc1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of ethyl 4-amino-3-(2,4-difluorophenylthio)benzoate (1.1 g) and methanesulfonyl chloride (0.93 g) in pyridine (5 ml) was stirred at 60° C. for 2 hours. The reaction mixture was evaporated. The residue was dissolved in methanol and treated with potassium hydroxide (2 g). The mixture was concentrated and the residue was dissolved in water and washed with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The solid residue was recrystallized from ethanol to give 3-(2,4-difluorophenylthio)-4-(methanesulfonamido)benzoic acid (0.66 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: BrCC1CCCCC1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCC1CCCCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chlorothiophene-2-carboxylic acid (3.01 g, 19.0 mmol), cyclohexylmethyl bromide (3.51 g, 19.8 mmol) and potassium carbonate (2.81 g, 20.33 mmol) was stirred under Ar at +85° C. for 3 days and cooled to room temperature. Reaction mixture was diluted with water and extracted with hexanes three times. Combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (2%-15% EtOAc—hexanes gradient) gave cyclohexylmethyl 5-chlorothiophene-2-carboxylate as a colorless oil. Yield (4.76 g, 97%); 1H NMR (400 MHz, CDCl3) δ 7.56-7.60 (m, 1H), 6.90-6.94 (m, 1H), 4.08 (d, J=6.10 Hz, 2H), 1.64-1.82 (m, 6H), 1.10-1.34 (m, 3H), 0.97-1.10 (m, 2H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.641 g (5.0 mmol) of 1-octanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.54 g (71.4%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14](O)[CH2:15][CH:16]=[CH2:17].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:14]([C:4]1[C:5]([CH3:13])=[C:6]([O:11][CH3:12])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCC(O)c1c(C)c(OC)c(C)c(C)c1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Crude 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol (9.8 g) in 10 mL CH2Cl2 was added slowly, dropwise to a rapidly stirred, biphasic solution of TFA (10.5 mL, 153 mmol, 5 equiv.) and Et3SiH (6.3 mL, 1.3 equiv). The exothermic reaction was cooled in a room temperature water bath until addition was complete and the reaction stirred for and additional 2 h at room temperature. The brown solution was concentrated via rotovap, azeotroped 3×50 mL MeOH and 3×50 mL heptane and remainder taken up into 100 mL 5% EtOAc/heptane. The organic layer was washed 1×100 mL water, 1×50 mL saturated aqueous NaCl, filtered to remove particulates and dried over Na2SO4. Flash chromatography yielded 5.08 g of 1-(but-3-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene as a pale yellow oil which solidified upon standing to an off white wax. 1H NMR (400 MHz, CDCl3) δ=5.93 (m, 1H), 5.08 (m, 1H), 4.99 (m, 1H), 3.68 (s, 3H), 3.65 (s, 3H), 2.70 (m, 2H), 2.24 (m, 5H), 2.18 (s, 6H) ppm.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.C([C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44]([CH:48]=1)[C:45]([NH2:47])=[O:46])(=O)C.[OH-].[K+]>C(O)C>[C:45]([C:44]1[CH:48]=[C:40]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:41]=[CH:42][C:43]=1[OH:49])(=[O:46])[NH2:47]
Reactant: CC(=O)c1ccc(O)c(C(N)=O)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)ccc1O
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 5-acetyl-2-hydroxy-benzamide (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (13 mg, 10% yield). MS: 507.24 (M+H+); HPLC Procedure A, retention time=10.36 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.O.[OH:40]OS([O-])=O.[K+]>C1COCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[O:40])[CH:7]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: Oc1ccc(C2COc3cc(O)ccc3C2CCCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(CCCCCCCCCC1c2ccc(O)cc2OCC1c1ccc(O)cc1)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
To a solution of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]chroman (140 mg, 0.250 mmol) and H2O (0.05 ml) in THF (1.2 ml) at 0° C. was added Oxone® (monopersulfate compound; DuPont product) (77 mg, 0.125 mmol). The resulting solution was stirred at 0° C. for 3.5 hr, and then poured into H2O. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel, 60% AcOEt/hexane) to afford (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman (105 mg, 73%).