Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:24]([CH3:30])([CH3:29])[CH2:23][CH2:22][C:21]([CH3:32])([CH3:31])[C:20]=3[CH:19]=2)[C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.O.[OH-].[Na+].Cl>C1COCC1.CCOC(C)=O.O>[CH3:1][C:2]1([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:24]([CH3:30])([CH3:29])[CH2:23][CH2:22][C:21]([CH3:32])([CH3:31])[C:20]=3[CH:19]=2)[C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)C(C)(c1cc3c(cc1C)C(C)(C)CCC3(C)C)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C1(C)COc3ccc(C=CC(=O)O)cc31)C(C)(C)CCC2(C)C

Procedure:
A solution of ethyl 3-[3-methyl-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydrobenzofuran-5-yl]acrylate (320 mg, 0.74 mmol), water (40 μl) and sodium hydroxide (240 mg, 6 mmol) in THF is heated to reflux for 24 h. The reaction mixture is poured onto an AcOEt/water mixture, acidified to pH=1 with a concentrated hydrochloric acid solution, and extracted once with ethyl acetate. After separation the organic phase is washed twice with water, dried over magnesium sulphate and concentrated in vacuo at 40° C. in a rotary evaporator. The solid obtained is crystallized in heptane.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.O[NH:25][C:26]([C:28]1[S:29][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:31][CH:32]=1)=[NH:27]>>[CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[O:13][N:27]=[C:26]([C:28]4[S:29][C:30]([S:33]([NH2:34])(=[O:36])=[O:35])=[CH:31][CH:32]=4)[N:25]=3)=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)O)cnn12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnn12

Procedure:
The title compound was prepared from 7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.25) (161 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane/MeOH) as a light yellow solid (88 mg, 35%). MS (EI) 506.1 [(M+H)+]; mp 276° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.C(O)C.[CH3:15][NH2:16].Cl>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:16][CH3:15])[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNc1nc2ccc(Br)cc2s1
Reaction time: 0.25 h
Yield: 79 %

Procedure:
6-bromo-2-chlorobenzo[d]thiazole (1.100 g, 4.4 mmol) and ethanol (20 ml, 343 mmol) was added to a microwave vial equipped with a stirbar. Then methylamine solution, 40% (2.3 ml, 66 mmol) was added to the mixture with stirring. Then HCl (0.34 ml, 11 mmol) was added to the mixture. The vial was capped then placed into the CEM Voyager Microwave (large-scale unit) for 15 minutes at 100° C., while 60 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed mostly desired material in the mixture. The mixture was transferred to a round-bottom flask, then made the mixture basic with sat. Na2HCO3. The precipitate was collected by filtration and washed with Hexanes. The solid was allowed dry in a reduced pressure oven overnight. This gave 6-bromo-N-methylbenzo[d]thiazol-2-amine (0.850 g, 79% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 244 (MH+). Calc'd exact mass for C8H7BrN2S: 243. 1H NMR (400 MHz, DMSO-d6): 2.93 (d, J=4.52 Hz, 3H), 7.33 (q, J=8.53 Hz, 2H), 7.90 (s, 1H), 8.06 (d, J=4.52 Hz, 1H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=[O:9].N1C=CC=CC=1.[SH:17][C:18]([CH3:24])([CH3:23])[CH2:19][CH:20](O)[CH3:21]>C(OCC)C>[CH:8]([O:10][CH:20]([CH2:19][C:18]([SH:17])([CH3:24])[CH3:23])[CH3:21])=[O:9]
Reactant: CC(O)CC(C)(C)S
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(CC(C)(C)S)OC=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of 12.3 g of acetic anhydride and 6.2 g of formic acid was heated at 40°C for 1 hour. After cooling to 20°C 1 g of pyridine was added and subsequently, with stirring, 15 g of 4-mercapto-4-methylpentan-2-ol in the course of 10 minutes. The temperature of the reaction mixture slowly rose to 28°C. After standing overnight it was dissolved in diethylether, washed five times with 3% aqueous NaHCO3 solution and then with aqueous NaCl solution to neutral. The ethereal solution was dried over Na2SO4 and concentrated. Distillation of the residue yielded 10.5 g (58%) of 4-mercapto-4-methylpent-2-yl formate, b.p. 30°-32°C/1 mm, nD20 1.4564.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:10][CH2:11][CH3:12])[C:8]=1[NH2:9].[OH:15][C:16]12[CH2:23][CH2:22][C:19]([C:24](O)=O)([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.O.[OH-].[Na+].Cl>CN(C=O)C>[OH:15][C:16]12[CH2:23][CH2:22][C:19]([C:24]3[NH:2][C:3]4[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:10][CH2:11][CH3:12])[C:8]=4[N:9]=3)([CH2:20][CH2:21]1)[CH2:18][CH2:17]2
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: O=C(O)C12CCC(O)(CC1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
5,6-Diamino-1-propyl-1H-pyrimidine-2,4-dione hydrochloride salt (3.4 g) was dissolved in 80 mL of DMF along with 4-hydroxy-bicyclo[2.2.2]octane-1-carboxylic acid (2.5 g, 15 mmol). HATU (5.9 g, 1.05 eq) was added, followed by Et3N (8.30 mL, 4.05 eq). The resulting reaction mixture was stirred at rt overnight. The reaction mixture was filtered to remove some of the precipitate. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 60 mL of H2O containing 10 eq of NaOH (5.9 g). The reaction mixture was stirred under reflux for 1 h, cooled to rt and acidified to pH2 with concentrated HCl. The resulting precipitate was collected by filtration and dried to afford 1.85 g of the xanthine derivative.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)[CH2:9]1)(C)(C)C>C(Cl)Cl.C(C(O)=O)(F)(F)F>[F:19][C:17]([F:18])([F:20])[CH2:16][N:13]1[CH2:14][CH2:15][C:10]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:8]([CH2:7][C:6]([OH:27])=[O:5])[CH2:9]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CC2(CCN(CC(F)(F)F)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CC2(CCN(CC(F)(F)F)CC2)c2ccccc21

Procedure:
A solution of tert-butyl[1′-(2,2,2-trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2H)-yl]acetate (91.0 mg, 0.237 mmol) from Step B in CH2Cl2 (2 mL) and CF3CO2H (1 mL) was stirred at ambient temperature for 6 h. Added CF3CO2H (1 mL) and stirred 1 additional hour. The mixture was concentrated in vacuo. The crude product was partitioned between CH2Cl2 (20 mL) and saturated NaHCO3 (20 mL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=329 (M+1).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:13](=S)=[S:14]>C(O)C>[C:2]1([C:1]2[O:8][C:13]([SH:14])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(-c2ccccc2)o1

Procedure:
To a 100 ml flask were added 2.7 g of benzoyl hydrazine, a solution of 1.2 g potassium hydroxide in ethanol (20 ml) and 3 g of carbon disulfide. The mixture was heated under reflux for 6 hours with stirring. After the reaction was completed, the solvent was distilled under reduced pressure and water was added to dissolve the solid. The pH was adjusted to 6-7 with 10% hydrochloric acid and a lot of solid was precipitated, which was filtrated, and recrystallized with anhydrous ethanol to give 5-phenyl-2-mercapto-1,3,4-oxadiazole. MP: 212-214° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C=O.[CH3:10][CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19].N[CH2:21]C(OC)=O>C(O)(=O)C.O>[CH3:18][C:13]1([CH2:21][NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:12]([CH3:19])=[C:11]([CH3:10])[C:15]([CH3:16])=[C:14]1[CH3:17]
Reactant: CC1=C(C)C(C)C(C)=C1C
Reactant: COC(=O)CN
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CNCC1(C)C(C)=C(C)C(C)=C1C
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a stirred mixture of methyl glycinate hydrochloride (6.28 g, 0.05 mole) in 30 mL of glacial acetic acid and 37% aqueous formaldehyde (4.1 g, 1.5 g real, 0.05 mole) is added pentamethylcyclopentadiene (6.81 g, 0.05 mole) after all of the solid methyl glycinate has dissolved. A light brown solution is initially obtained. The temperature is kept at 35° C. for five minutes with ice-bath cooling to control the exotherm. The color of the solution changes to light purple and the temperature is then kept at 33° C. for about 6 hours. This reaction mixture is combined with 100 mL of water and the aqueous phase is extracted with two×20 mL portions of methylene chloride. The clear aqueous phase is then treated with 50% sodium hydroxide, with cooling to maintain a temperature of 35° C., to pH 12. The basic aqueous phase is extracted with two×30 mL portions of methylene chloride. The organic layer is concentrated in vacuo to give approximately 5.0 g of the title compound. Yield is 40%, about 80% purity, of the product which is identified by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance and electron impact mass spectral analyses.
Reaction SMILES: C([O:8][C:9]1[C:32]([O:33][CH3:34])=[CH:31][C:12]2[C:13](=[O:30])[N:14]3[CH2:28][C:27](=[O:29])[CH2:26][C@H:15]3[C@H:16]([OH:25])[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CCOC(C)=O.CCCCCC>[C:21]([O:20][C:18]([N:17]1[C:11]2[CH:10]=[C:9]([OH:8])[C:32]([O:33][CH3:34])=[CH:31][C:12]=2[C:13](=[O:30])[N:14]2[CH2:28][C:27](=[O:29])[CH2:26][C@H:15]2[C@@H:16]1[OH:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1cc2c(cc1OCc1ccccc1)N(C(=O)OC(C)(C)C)[C@@H](O)[C@@H]1CC(=O)CN1C2=O
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1O)N(C(=O)OC(C)(C)C)[C@@H](O)[C@@H]1CC(=O)CN1C2=O
Yield: 53.9 %

Procedure:
A catalytic amount of 10% palladium on carbon (0.23 g) was added to a solution of cyclized compound 23 (2.3 g, 4.9 mmol) in absolute alcohol (50 mL). The reaction mixture was hydrogenated for 4 h at 30 Psi. When the reaction was complete as indicated by TLC (SiO2, 50% EtOAc-hexane) the reaction mixture was filtered through Celite, and removal of excess solvent under reduced pressure afforded the phenol 24 (4.7 g, 2.64 mmol, 53%) as a white solid: [α]25D=+115° (c=0.10, MeOH); 1H NMR (CDCl3, 400 MHz): δ 1.39 (s, 9H, Boc), 2.68-2.80 (m, 1H, 1-H), 2.87-3.02 (m, 1H, 1-H), 3.84-4.06 (m, 6H, 3-H, 11a-H, OH, 7-OMe), 4.22-4.35 (m, 1H, 3-H), 5.53-5.71 (m, 1H, 11-H), 6.02 (s, 1H, OH), 6.73 (s, 1H, 9-H), 7.20 (s, 1H, 6-H); 13C NMR (CDCl3, 100 MHz): δ 28.1, 40.4, 52.6, 56.2, 56.7, 85.9, 110.1, 115.9, 123.1, 129.9, 145.9, 148.2, 167.8, 208.1; IR (neat): 3355, 2977, 1760, 1685, 1606, 1515, 1469, 1415, 1369, 1332, 1297, 1212, 1162, 1132, 1042, 767 cm−1; MS (ES+) m/z (relative intensity) 379 (M+., 93), 380 ([M+2H]+., 25), 364 (100), 396 (75), 420 (45).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.O>[F:25][C:11]1[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13][N:14]([S:46]([C:42]2[S:41][CH:45]=[CH:44][CH:43]=2)(=[O:48])=[O:47])[C:10]=1[C:9]1[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccs1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccs2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (60% in oil, 37 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (1 mL), 15-crown-5 (205 mg) and 2-thiophenesulfonyl chloride (136 mg) at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a colorless oil (yield 276 mg, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][C@H:8]1[O:37][C@@H:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][O:29]CC3C=CC=CC=3)=[CH:23][CH:22]=2)[C@H:11]([OH:38])[C@@H:10]([OH:39])[C@@H:9]1[OH:40])=[O:5])[CH3:2]>C(OCC)(=O)C.C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([O:6][CH2:7][C@H:8]1[O:37][C@@H:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][OH:29])=[CH:25][CH:26]=2)[C@H:11]([OH:38])[C@@H:10]([OH:39])[C@@H:9]1[OH:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CCOCc3ccccc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CCO)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of 2-[4-(2-benzyloxyethyl)benzyl]phenyl 6-O-ethoxycarbonyl-β-D-glucopyranoside (0.18 g) in ethyl acetate (4 mL) and ethanol (1 mL) was added 10% palladium-carbon powder (0.072 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 2-[4-(2-hydroxyethyl)benzyl]phenyl 6-O-ethoxycarbonyl-β-D-glucopyranoside (0.11 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:13]=[CH2:14])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCOCC1.O>[O:12]=[C:9]1[CH2:8][CH2:7][C:6]([CH:13]=[CH2:14])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: C=CC1(C(=O)OCC)CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CC1(C(=O)O)CCC(=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of the commercially available 4-oxo-1-vinyl-cyclohexanecarboxylic acid ethyl ester (provided by Small Molecules Inc.), (1.20 g, 6.11 mmol) in 1,4-dioxane (20 mL) was treated with a solution of lithium hydroxide monohydrate (734 mg, 30.6 mmol) in water (10 mL). After stirring at 50° C. for 2 h, the volatiles were removed in vacuo. The residue was partitioned between water and diethyl ether. The aqueous layer was acidified to pH 1 by addition of saturated potassium hydrogen sulfate solution and was extracted with ethyl acetate (3×). The organic layer was dried over anhydrous magnesium sulfate, filtered and the volatiles were removed in vacuo to afford the title compound (1.00 g, 97%) as a clear gum. 1H NMR (300 MHz, CDCl3) δ 1.92-2.08 (m, 2H), 2.36-2.59 (m, 6H), 5.34 (d, J=17.5 Hz, 1H), 5.35 (d, J=10.5 Hz, 1H), 5.97 (dd, J=17.5, 10.5 Hz, 1H), 11.30 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[C:37]([Si](C)(C)C)#[N:38]>ClCCl.O.[Zn+2].[I-].[I-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([CH:33]([OH:34])[C:37]#[N:38])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: N#CC(O)c1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Reaction time: 70 h

Procedure:
To a stirred solution of 4-(7-(4-chlorophenyl)-3-oxo-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)benzaldehyde (38.0 mg, 0.075 mmol) in dichloromethane (1 mL) at room temperature under argon was added cyanotrimethylsilane (9.3 mg, 0.093 mmol) and then ZnI2 (2.4 mg, 0.0075 mmol). After 70 h, the reaction mixture was diluted with water and extracted twice with dichloromethane. The organic extracts were combined, dried (MgSO4), filtered and evaporated. Purification by preparative reverse phase HPLC (methanol-water-trifluoroacetic acid), pooling the fractions, evaporating, redissolving the residuum in dichloromethane, washing with saturated aq. NaHCO3 solution, drying (MgSO4), filtering and evaporating provided the title compound as a light yellow solid, 10.4 mg, 26%. HPLC/MS: retention time=3.56 min, [M+H]+=536. 1H NMR (CDCl3): δ 8.71 (d, J=1.7 Hz, 1H), 7.85 (dd, J=1.6 Hz, 7.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.24 (d, J=6.5 Hz, 1H), 7.17 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H), 6.95 (d, J=6.6 Hz, 2H), 6.60 (d, J=7.2 Hz, 1H), 5.37 (s, 1H), 5.18 (s, 1H), 3.30 (br s, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([CH:32]([CH3:34])[CH3:33])=[CH:26][C:27]=2[C:29](=O)[CH3:30])[C:22]([CH3:36])([CH3:35])[CH2:21][CH2:20]1)[CH2:17][CH3:18]>>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[C:29](\[C:27]1[CH:26]=[C:25]([CH:32]([CH3:34])[CH3:33])[CH:24]=[C:23]2[C:28]=1[N:19]([CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][C:22]2([CH3:35])[CH3:36])/[CH3:30])[CH3:1]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)=O)c21
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C(=O)OCC)c21

Procedure:
Following General Procedure E, triethyl-2-fluoro-2-phosphonoacetate (8.36 g, 34.5 mmol) and 1-(1-n-propyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-ethanone (Intermediate 14, 2.78 g, 9.86 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (SiO2, 2:98 ethyl acetate:hexane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].O.[Cl:10][C:11]([Cl:15])([Cl:14])[CH:12]=[O:13].C(N(CC)CC)C>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH:12]([OH:13])[C:11]([Cl:15])([Cl:14])[Cl:10])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1O
Reactant: O=CC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To the solution of 440 g of 1,2-dihydroxybenzene dissolved in 1 L of methylene dichloride was added 1036 g of trichloroacetaldehyde monohydrate and then the reaction solution was cooled down to 0° C. 102 g of triethylamine was slowly added dropwise thereto. The reaction solution was warmed to room temperature, stirred for about 20 minutes, heated to 50° C. and then stirred for further 3 hours while maintaining the same temperature. After the reaction is completed, the reaction mixture was distilled under reduced pressure to remove methylene dichloride. The residue was dissolved in 4 L of ethylacetate, washed successively with 2400 ml of 0.5N-aqueous hydrochloric acid solution and 2 L of saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent and to obtain 540 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH:11]([CH3:13])[CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:20]1([CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1)[OH:21]>CN(C=O)C>[CH:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:21][C:20]1[CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1)([CH3:13])[CH3:12]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)N(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(CCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 38.5 %

Procedure:
A mixture of compound 4c (400 mg, 2 mmol), K2CO3 (558 mg, 4 mmol), and KI (720 mg, 4 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (440 mg, 4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide compound 4 (210 mg, 0.77 mmol, 38.3% yield) as a brown oil. HRMS (ESI, positive) m/z calcd. for C17H22N1O2 [M+H]+: 272.16451, found: 272.16455. 1H NMR (400 MHz, CDCl3) δ 7.16-7.05 (m, 2H), 6.75-6.56 (m, 7H), 4.08-3.83 (m, 4H), 3.50-3.42 (t, J=7.1 Hz, 1H), 1.19-1.06 (m, 6H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[CH:7][S:6]1(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([Cl:34])[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[S:6](=[O:11])(=[O:12])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:9](=[O:10])[CH:8]=2)=[C:29]([Cl:34])[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](Cc1ccc(I)c(Cl)c1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)N1C(=O)C=CS1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
2-tert-Butylisothiazol-3(2H)-one 1,1-dioxide (284 mg, 1.50 mmol), palladium acetate (48 mg, 0.21 mmol) and tetra-N-butylammonium chloride (238 mg, 0.858 mmol) were combined. To this mixture was added methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-chloro-4-iodophenyl)propanoate (377.2 mg, 0.8579 mmol) in DMF (4.00 mL). The reaction was treated with triethylamine (0.598 mL, 4.29 mmol). The reaction was then degassed and then allowed to stir under an atmosphere of nitrogen at 65° C. for 2 h. The reaction was quenched with water (50 mL), diluted with ethyl acetate (100 mL) and washed with aqueous hydrochloric acid solution (1.0 N, 100 mL). The organic was dried over sodium sulfate, filtered and was concentrated in vacuo. The crude material was purified by silica gel chromatography (5–25% ethyl acetate/hexanes) to afford the product as a white solid (100 mg, 23%). 1H NMR (400 MHz, CD3OD): δ 7.80 (d, J=8.2 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 4.44–4.40 (m, 1H), 3.73 (s, 3H), 3.25–3.20 (m, 1H), 2.95 (dd, J1=10.0 Hz, J2=13.7 Hz, 1H), 1.70 (s, 9H), 1.37 (s, 9H); LCMS found for C17H22ClN2O5S (M+H)+: m/z=401.