Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C[O:16]CC1>[OH-].[Pd+2].[OH-]>[OH:16][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:2][C:3](=[O:12])[O:4]2)=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: O=c1oc2ccccc2cc1O
Agent: [Pd+2]
Agent: [OH-]
Product: O=C1CCc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydroxycoumarin (2.0 g, TCI) in anhydrous THF (50 ml) was added with 10% palladium hydroxide/activated carbon (1.0 g, WAKO), and stirred at room temperature for 2 hours under hydrogen atmosphere. The atmosphere was replaced with nitrogen gas, and then the insoluble matters were removed by filtration through Celite. The solvent was evaporated under reduced pressure to obtain the title compound (2.0 g).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17]([N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[CH:2]1[CH3:1])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1NCCCC1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C(O)CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a solution of 1.4 g (9.232 mmol) 2-methyl-piperidin-3-ol (CAS: 4766-56-7) in 9.8 ml dichloromethane under argon at room temperature, was added 2.57 ml (18.46 mmol) triethylamine. The mixture was stirred for 15 minutes and then cooled to 0° C. 1.37 ml (9.232 mmol) benzyl chloroformate was added dropwise. The reaction mixture was allowed to come to room temperature and the stirring was continued overnight. The mixture was extracted three times with water and the combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 30) to provide 800 mg (34.8%) of the title compound as a colorless oil. MS (m/e): 272.4 (M+Na+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH:11]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCC.[C:33]([O:36][CH2:37]C)(=[O:35])[CH3:34]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)/[CH:11]=[CH:34]/[C:33]([O:36][CH3:37])=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](C=O)OC1CCCCO1
Solvent: CCCCCC
Product: COC(=O)/C=C/[C@H](OC1CCCCO1)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 69 %

Procedure:
Using the procedure of Example 5 with the resultant compound of Example 11 provided, after silica gel chromatography using 6:1 hexane:ethyl acetate, the desired compound (Rf 0.55, 7:3 hexane:ethyl acetate) in 69% yield. 1H NMR spectrum showed a 1:1 mixture of diastereomers. Mass spectrum: (M+H)+ =420.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1/[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]/1)[CH2:14][CH2:13][CH2:12]2)=[O:4]>CO.[Hg]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]\1)[CH2:14][CH2:13][CH2:12]2)=[O:4]
Reactant: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: [Hg]
Solvent: CO
Product: COC(=O)CCC/C=C1/CC2CCCC2C1=O
Yield: 25 %

Procedure:
A solution of 6-[(E)-(mixture of 3α and 3β)-hydroxyoct-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (20 mg), prepared as described in Example 4 and predominantly in the 6β-configuration, otherwise known as (±)-methyl(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxyprosta-5,13-dienoate, in methanol (5 ml) was irradiated for 20 hours with ultra-violet rays of wavelength 254 nm, emitted by a low pressure mercury vapour lamp. The solution was carefully concentrated in vacuo and then subjected to preparative thin layer chromatography on silica gel, using a mixture of ethyl acetate and hexane (1:4 v/v) as eluant, to give 6-[(E)-(mixture of 3α and 3β)-hydroxyoct-1-enyl]-3-[(Z)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (5.0 mg), predominantly in the 6β-configuration, otherwise known as (±)-methyl(5Z,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxyprosta-5,13-dienoate [NMR in deuterochloroform: multiplets at 5.9, 5.5., 4.1, 3.0-1.1, 1.1-0.7 p.p.m., singlet at 3.7 p.p.m.]; and recovered 6-[(E)-(mixture of 3α and 3β)-hydroxyoct-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]-bicyclo[3,3,0]octan-2-one (3.6 mg) [NMR in deuterochloroform: multiplets at 6.5, 5.5, 4.1, 3.0-1.1, 1.1-0.7 p.p.m., singlet at 3.7 p.p.m⟧
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[OH:11][CH2:12]C([C@H]([C@@H](CO)O)O)=O>C(O)C>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:12][OH:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C(CO)[C@@H](O)[C@H](O)CO
Solvent: CCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
fermenting said loaded substrate under anaerobic conditions at a pH range of between about 5.5 to about 6.0 and at a temperature range of between about 30° C. to about 45° C., until any xylose in the mixture is isomerized to xylulose as it is produced, and any xylulose is fermented as it is produced to ethanol, while in the same fermentation, glucose is fermented to ethanol; and
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Reaction time: 8 h

Procedure:
To a solution 4-bromobenzoyl chloride (25 g, 114 mmoles) in THF at 0° C. (200 mL) was added triethylamine (63.5 Ml, 456 mmoles) dropwise followed by diisopropylamine (32.5 mL, 228 mmol). The solution was allowed to stir overnight. The next day the reaction mixture was acidified with 1 N HCl and extracted with CH2Cl2. The organic layer was basified with sat. NaHCO3 wash and dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex. to 100% EtOAc provided the desired product as a yellow solid. 1H NMR (600 MHz, CD3OD) δ 7.60 (d, 2H), 7.23 (d, 2H), 3.30 (br s, 1H), 3.29 (br s, 1H), 1.5, (br s, 6H), 1.22 (br s, 6H). LRMS (ESI) calc'd for (C13H19BrNO) [M+H]+, 284.1; found 284.1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].CC(C)=O.CCOC(C)=O>CCOCC.CCOC(C)=O>[Cl:15][C:16]([Cl:20])([Cl:19])[C:17](=[NH:18])[O:14][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(C)C(O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)C(OC(=N)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium Hydride (60%, 0.87 mmol) was suspended in Et2O (9 mL) and a solution of 1-(4-bromophenyl)-2-methylpropan-1-ol of step 1 (8.7 mmol, 2.0 g) in Et2O (6 mL) was added. The mixture was stirred at r.t. for 0.25 h. The mixture was cooled to 0° C. Trichloroacetonitrile (11 mmol) was added. The mixture was allowed to warmed to r.t. over 1 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography (10% Acetone/EtOAc) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCC(F)(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (200 mg) in anhydrous DMF were added 2-(2,2,2-trifluoroethoxy)ethyl 4-methylbenzenesulfonate (intermediate BS) (1.5 eq) and Cs2CO3 (2 eq). The mixture was stirred at room temperature for 12 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative-HPLC to obtain compound BT (117 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.62 (s, 2H), 4.08˜4.12 (m, 3H), 4.02˜4.05 (m, 3H), 4.00˜3.94 (m, 2H), 3.90˜3.87 (m, 1H), 3.72˜3.68 (m, 1H), 3.46˜3.39 (m, 3H), 3.30˜3.27 (m, 1H); MS ESI (m/z) 507 (M+H)+, calc. 506.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.N12CCN(CC1)CC2.[C:20](#[N:23])[CH:21]=[CH2:22]>C(OCC)(=O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:21]([C:20]#[N:23])[CH2:22][O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OCC(C#N)=C2
Yield: 72.3 %

Procedure:
To 2-hydroxy-4-methoxy-benzaldehyde (10.0 g, 65.72 mmol) and DABCO (1,4-diazabicyclo[2.2.2]octane) (1.84 g, 16.43 mmol) was added acrylonitrile (17.44 g, 328.62 mmol). The reaction mixture was refluxed for 20 h. The reaction mixture was diluted with ethyl acetate and the resulting rheum was separated. The organic phase was washed with a 1 molar solution of NaOH and then with a 1 molar solution of HCl. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the crude product (8.89 g, 72% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39]([NH:41][C@H:42]([CH2:51]O)[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].S([O-])([O-])(=O)=O.[Mg+2]>O.C(OCC)(=O)C.O1CCCC1>[C:47]([O:46][C:44](=[O:45])[CH2:43][CH:42]1[CH2:51][N@@:41]1[C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])([CH3:48])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
2.90 g of triphenylphosphine and 15 mL of tetrahydrofuran were added to 100 mL flask and the resulting reaction solution was cooled to 0° C. 2.17 mL of diisopropylazodicarboxylate was dropped while the reaction solution was stirred. After 30 minutes, 10 mL of tetrahydrofuran solution with 1.52 g of (S)-t-butyl 3-(t-butoxycarbonylamino)-4-hydroxybutanoate was dropped and stirred for 16 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, 40 mL of ethyl acetate and 40 mL of water were added to the reaction solution and then stirred for 10 minutes. An organic layer was isolated, dehydrated with magnesium sulfate, and then concentrated under reduced pressure. A concentrated residue was isolated with column chromatography (n-hexane:ethyl acetate=15:1) and then concentrated under reduced pressure to obtain 1.04 g of a title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2,6-dichloropyrazine (10.0 g, 67.1 mmol), tert-butyl piperazine-1-carboxylate (12.5 g, 67.1 mmol) and cesium carbonate (43.7 g, 134 mmol) were added to a round bottom flask and flushed with nitrogen. DMF (300 ml) was then added and the reaction was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (600 mL) and washed with brine (600 mL). The aqueous layer was washed with additional EtOAc (600 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to a crude residue that was purified by silica gel chromatography to afford tert-butyl 4-(6-chloropyrazin-2-yl)piperazine-1-carboxylate as an off-white solid. LRMS calculated for C13H19ClN4O2[M+H]+, 299.1; found 299.1.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH3:12][O:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1.[OH-].[NH4+:42].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClC(Cl)C.ClCCl.[Cl-].[Na+].O>[NH2:42][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][CH2:14][O:13][CH3:12])[N:17]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C:18]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: COCCc1nc2cnc3cccnc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: COCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Chloroperoxybenzoic acid (7.8 g of 77%) was added in a single portion to a solution of tert-butyl N-{4-[2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butyl}carbamate (7 g) in dichloroethane (100 mL). The reaction mixture was stirred at ambient temperature for 3 hours, Concentrated ammonium hydroxide (100 mL) was added and the reaction mixture was stirred until a suspension formed. Para-toluenesulfonyl chloride (3.6 g) was added in a single portion. The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with dichloromethane and brine. The organic layer was separated, washed with brine (×2), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 8.83 g of crude tert-butyl N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butyl}carbamate as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH:7]=[C:8]([P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:25]/[C:26](/[CH3:37])=[CH:27]\[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[O:29]>C(O)(C)C>[CH3:37][C:26]1[NH:25][C:9]([CH3:11])=[C:8]([P:12]([O:17][CH:18]([CH3:20])[CH3:19])([O:13][CH:14]([CH3:16])[CH3:15])=[O:21])[CH:7]([C:6]2[CH:22]=[CH:23][CH:24]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:27]=1[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[O:29]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)P(=O)(OC(C)C)OC(C)C
Reactant: CCCOCCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCCOCCOC(=O)C1=C(C)NC(C)=C(P(=O)(OC(C)C)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 71.5 %

Procedure:
A mixture of 5.1 grams of diisopropyl 1-(3-nitrobenzylidene)-acetonylphosphonate and 2.69 grams of 2-n-propoxyethyl 3-aminocrotonate was added to 20 ml of isopropanol and the mixture was heated to reflux for eight hours with stirring. The reaction mixture was evaporated in vacuo, to the residue was added ether to crystallize, the crystals were collected by filtration, and recrystallized from a mixture of ethyl acetate and ether to afford 5.38 grams of 2-n-propoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-diisopropoxyphosphinyl-1,4-dihydropyridine-3-carboxylate, pale yellow crystals, melting point 125°-6° C. Yield 72%.
Reaction SMILES: C=CCCCC.[CH3:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC/C=C\CCCC
Solvent: C=CCCCC
Product: CCCCC=CCCCC

Procedure:
After the reaction was cooled to room temperature, the mixture was filtered through a 100 mL silica gel plug with hexanes to remove the metal complex. The filtrate was dried via rotavap to remove the solvent and also the substrate, 1-hexene, affording the product as colorless liquid. The scale of a typical reaction was 5 mL of the substrate, 1-hexene. (Z)-5-decene: 1H NMR (500 MHz, CDCl3) δ 5.38 (m, 2, CH), 2.06 (m, 4, CH2), 1.35 (m, 8, CH2), 0.93 (m, 6, CH3); 13C NMR (125 MHz, CDCl3) δ 130.06, 32.31, 27.21, 22.66, 14.33.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:32][C:26]1[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=1[S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (52 mg, 0.099 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (42.4 mg, 1.0 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. After this time, the reaction mixture was diluted with water (˜20 mL) and then acidified with 1.0 N aqueous HCl (2 mL). The resulting mixture was extracted with ethyl acetate (2×25 mL), then the combined extracts were washed with brine (30 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated to provide {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (47 mg, 93%) as a yellow film. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([O-:28])=[O:27].O>C(Cl)Cl>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([O:1][CH2:2][C@H:3]2[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)(=[O:37])=[O:36])=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)OC(C)(C)O1
Reaction time: 22 h
Yield: 110.5 %

Procedure:
To a stirring 20°-25° C. solution of the (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl-1,3- dioxane-4-acetate (European Patent Application 0319,847) (10 g, 0.038 mol) in methylene chloride (250 mL) containing triethylamine (7 mL, 0.05 mol) is added 4-nitrobenzenesulfonyl chloride (10.5 g, 43 mmol). Stirring is continued at 20°-25° C. for 22 hours, the solution is poured onto 200 mL of water and the layers separated. The upper aqueous layer is extracted with 250 mL of methylene chloride and the combined organic layers are washed with 100 mL each of saturated sodium bicarbonate solution to ensure complete removal of 4-nitrobenzenesulfonyl chloride and then saturated sodium chloride solution. Drying the solution with magnesium sulfate and concentration in vacuo gives 18.7 g of the product as a brown oil which solidifies immediately.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH:28]C(=O)C)=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl>C(O)C>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:12]3[CH:32]=[CH:33][C:9]([C:3]([OH:8])([C:2]([F:35])([F:1])[F:34])[C:4]([F:5])([F:6])[F:7])=[CH:10][CH:11]=3)[CH2:15][CH2:16]2)=[O:21])=[CH:23][CH:24]=1
Reactant: CC(=O)Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 100 °C
Yield: 65.1 %

Procedure:
N-(4-(1-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidine-4-carbonyl)phenyl)acetamide (1.128 mmol, 567 mg) was dissolved in ethanol (20 mL) and 2M hydrochloric acid (56.4 mmol, 28.2 mL) added. The mixture was heated to 100° C. overnight and cooled. The mixture was purified by strong cation exchange column chromatography and concentrated under reduced pressure to afford the title compound (338 mg). MS (ESI) m/z 461.2 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2)#[N:11].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:15]2)#[N:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C#N)ccc21
Yield: 98.5 %

Procedure:
tert-butyl bromoacetate (0.88 mL; 5.99 mmol) was added to a suspension of 5-cyanoindole (0.71 g; 4.99 mmol) and K2CO3 (1.38 g; 9.99 mmol) in CH3CN (20 mL) and the resulting mixture was stirred at reflux for 16 hours. Filtration and concentration in vacuo gave a light yellow oil which crystallized upon standing. The solid was triturated in a mixture of Et2O and hexane to give the title compound as an off-white solid (1.26 g, 98%). HPLC (Method A), Rt: 4.43 min (Purity: 96.8%). LC/MS (Method B): 256.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH:2]=[CH2:3].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:4]1[C:16]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OCC(=O)OCC)cccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCc1c(OCC(=O)O)cccc1C(F)(F)F
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
8.1 g of the product of Step C in 50 ml of ethanol was stirred for one hour at ambient temperature in the presence of 14 ml of 2N sodium hydroxide and 14 ml of 2N hydrochloric acid were then added with stirring for 15 minutes, followed by concentration to obtain 10.19 g of crude product which was taken up in water. After extracting with methylene chloride and drying, the solvent was evaporated to obtain 7.26 g of the expected product.