Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[NH3:3].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3([C:19]#[N:20])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:17]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#CCc1ccc(OCCCN2CCCC2)cc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a suspension of NaH (60%, 0.574 g, 14.35 mmol) in DMF (8 mL) at 0° C. was added dropwise [4-(3-pyrrolidin-1-ylpropoxy)phenyl]acetonitrile (1 g, 4.10 mmol) in DMF (3 mL). The reaction mixture was stirred at 0° C. for 5 min than at room temperature for 30 min. After cooling to 0° C., 1,4-dibromobutane (0.980 mL, 8.2 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature then heated to 50° C. overnight. It was poured into ice-cold water and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography, eluting with a gradient of DCM:MeOH:NH3 (from 99:0:1 to 90:10:1) to give the title compound (0.443 g, 36%). 1H NMR (400 MHz, DMSO-d6) δ7.29 (d, 2H), 6.79 (d, 2H), 4.02 (m, 2H), 3.18 (m, 2H), 2.47-2.28 (m, 4H), 2.19-1.75 (m, 11H), 1.19 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=O)[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>ClCCl.O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([NH:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:20])[NH:15][C:14]=12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reactant: NCc1cccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of ethyl 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Reference Example 3) (634 mg, 1.64 mmol) and 3-(aminomethyl)pyridine (3.8 mL, 37 mmol) was heated neat at 100° C. for 72 h under N2. The mixture was cooled to room temperature and diluted with dichloromethane (150 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient 50-70% ethyl acetate/hexanes) to provide 7-(dibenzylamino)-N-(3-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (364 mg, 49%) as an orange solid: Rf 0.08 (75:25 ethyl acetate/hexanes); mp 105-108° C.; 1H NMR (300 MHz, CDCl3) δ4.60 (2H, d, J=6.0 Hz), 4.89 (4H, s), 6.50 (1H, t, J=5.4 Hz), 6.71 (1H, s), 6.99 (1H, d, J=5.6 Hz), 7.28-7.31 (2H, m), 7.34-7.42 (9H, m), 7.64 (1H, d, J=7.8 Hz), 7.89 (1H, d, J=5.6 Hz), 8.55 (2H, s), 8.97 (1H, s); ESI MS m/z 448 [C28H25N5O+H]+; HPLC (Method A) >99% (AUC), tR=13.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[Br:13][C:14]1[S:15][C:16]([CH2:20]OS(C)(=O)=O)=[C:17]([CH3:19])[N:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[S:15][C:16]([CH2:20][O:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[C:17]([CH3:19])[N:18]=1
Reactant: Cc1nc(Br)sc1COS(C)(=O)=O
Reactant: N#Cc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(Br)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
To a solution of 2-Chloro-4-hydroxy-benzonitrile (1.6 g, 10.1 mmol) in dry dimethylformamide (30 mL) is carefully added sodium hydride (486 mg, 12.1 mmol). The resulting mixture is stirred for 20 minutes at room temperature. A solution of Methanesulfonic acid 2-bromo-4-methyl-thiazol-5-ylmethyl ester (3.0 g, 10.1 mmol) in dry dimethylformamide (5 mL) is added and the reaction mixture is stirred at room temperature. The reaction mixture is diluted with 100 mL of ethyl acetate after 5 h and water (20 mL) is carefully added (Caution: development of H2). The phases are separated and the organic phase is dried over MgSO4. The solvent is removed under reduced pressure and the crude product is purified by reversed phase HPLC to yield 2.2 g of 4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-benzonitrile. C12H8BrClN2OS (343.63), MS (ESI): 343.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:15]2([N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN1CCNCC1
Reactant: c1c[nH]nn1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(C2(n3ccnn3)CCC3(CC2)OCCO3)CC1

Procedure:
In a thoroughly heated flask, a solution of N-methylpiperazine (2.60 g, 2.88 ml, 26 mmol), 1,4-dioxaspiro[4.5]decan-8-one (3.90 g, 25 mmol) and 1,2,3-triazole (1.87 g, 27 mmol) in toluene (25 ml) was heated for 6 h under reflux in a water separator. The reaction solution was then transferred to a closable measuring cylinder and the crude product was used further in.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:16][O:15]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: Ic1ccc2[nH]ncc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Ic1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a mixture of 5-iodo-1H-indazole (0.90 g, 3.69 mmol) and DHP (1.57 g, 18.7 mmol) in dry dichloromethane (20 mL), was added PTSA (0.08 g, 0.41 mmol) at room temperature. The resulting mixture was stirred overnight. Upon completion, saturated aqueous NaHCO3 (30 mL) was added slowly into the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-5% EtOAc in petroleum ether) affording the title compound (1.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 8.08 (s, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 5.85 (dd, 1H), 3.88-3.85 (m, 1H), 3.78-3.72 (m, 1H), 2.41-2.29 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.72 (m, 1H), 1.61-1.56 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[NH2:17][C:18]1[C:25]([O:26][CH2:27][CH3:28])=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:29][CH2:30][CH3:31]>>[NH2:17][C:18]1[C:19]([O:29][CH2:30][CH3:31])=[CH:20][C:21]([CH2:22][N:13]2[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]3[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[CH2:15][CH2:14]2)=[CH:24][C:25]=1[O:26][CH2:27][CH3:28]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1N
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc(OCC)c1N
Yield: 34 %

Procedure:
The title compound (14 mg, 34%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 4-amino-3,5-diethoxybenzaldehyde. MS: 413.5 (MH+)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][CH2:18][O-:19].[Na+].CCO>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:19][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Yield: 54 %

Procedure:
To 1-(5-chloro-2-nitro-phenyl)-piperidine (197 mg, 0.810 mmol, as prepared in Example 3, step (a)) in 1.5 mL of DMF was added 4 mL of 0.5 M NaOEt in EtOH (1.94 mmol). The resultant solution was heated at 90° C. for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative tic (20% EtOAc-hexane) gave 110 mg (54%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C13H18N2O3, 251.1 (M+H), found 251.1.
Reaction SMILES: [ClH:1].[C:2]([N:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@H:8]([C:19](O)=[O:20])[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].[Cl-].[CH:23]1([C:29]2([CH2:37][S:38][CH3:39])[CH2:35][CH:34]3[NH2+:36][CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl>ClCCl.CCOCC>[Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:36]2[CH:34]3[CH2:33][CH2:32][CH:31]2[CH2:30][C:29]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)([CH2:37][S:38][CH3:39])[CH2:35]3)=[O:20])[CH2:7]1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reactant: Cl
Reactant: CSCC1(C2CCCCC2)CC2CCC(C1)[NH2+]2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CSCC1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@H]1C[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (1-10) (0.170 g, 0.601 mmol) in dichloromethane (5.0 mL) was added 3-cyclohexyl-3-[(methylthio)methyl]-8-azoniabicyclo[3.2.1]octane chloride (3-6) (0.174 g, 0.601 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.173 g, 0.901 mmol), 1-hydroxyl-7-azabenzotriazole (HOAT, 0.082 g, 0.603 mmol), and diisopropylethylamine (0.105 mL, 0.601 mmol). The mixture was stirred at room temperature overnight, diluted with methylene chloride, washed with water and a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue by preparative TLC (90% methylene chloride, 9% methanol, 1% of a 40% of NH4OH aqueous soltion as eluent), followed by the addition of one equivalent HCl in ether to afford (3-7) as white solid (m/z (ES) 519 (MH+)).
Reaction SMILES: [CH2:1]([C:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH2:31]([SH:33])[CH3:32].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1.C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:33][CH2:31][CH3:32])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO)C1=O
Reactant: CCS
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CSCC)C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 121, Step L, 100 mg, 0.224 mmol) was azeotroped three times in benzene on a rotary evaporator. The residue was dissolved in toluene and transferred to a reaction vessel. The vessel was flushed with argon. Ethanethiol (33.1 μl, 0.447 mmol) was added followed by cyanomethylenetributylphosphorane (216 μl, 0.894 mmol). The vessel was sealed and the solution was heated to 100° C. for 4 h. The reaction mixture was diluted with DCM (10 ml) and Si-maleimide (Silicycle, 2.1 g; 0.66 mmol/g; 40-63 microns) was added to scavenge excess thiol. After stirring for about 1 h, the mixture was filtered and the silica gel was rinsed with DCM. The filtrate was concentrated on a rotary evaporator. The residue was dissolved in DCM and loaded directly onto a dry 12 g gold-capped Redisep® column (Teledyne Isco, Lincoln, Nebr.). The column was eluted with a gradient of 0 to 5% MeOH:DCM. The fractions containing the desired product were combined and concentrated to afford the title compound as a colorless film.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].Cl.[CH2:23]([OH:25])C>O>[CH3:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([C:23]2[O:25][C:10]3[C:5]([C:3](=[O:4])[C:2]=2[OH:1])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:16][CH:15]=1
Reactant: CC=Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC=Cc1ccc(-c2oc3ccccc3c(=O)c2O)cc1
Reaction time: 12 h
Yield: 35 %

Procedure:
A solution of 4.92 g (36.1 mmol) of 2-hydroxyacetophenone, 3.30 g (34.2 mmol) of β-methyl styrene, 4-carboxaldehyde (mixture of cis and trans isomers) and 8.15 g NaOH (in 15 ml of water) in 125 ml of ethanol was stirred for 12 hours before the solution was poured into 600 ml of water. The resulting mixture was neutralized with dilute HCl. The yellow precipitate obtained was filtered and dried. The chalcone was purified by recrystallized from methylene chloride. Further oxidation of above chalcone was carried out with excess of H2O2 (30%) in ethanol under basic conditions for 12 hours. The resulting solution was poured into 300 ml water and acidified with dilute HCl. Yellow precipitate obtained was filtered and dried. 3-hydroxy-4'-(β-ethenyl) flavone was recrystallized from THF/hexane mixture. Yield: 35%. Quantum Yield: (1.75 relative to 3HF in methyl cyclohexane), Extinction coefficient: εmax (M-1 cm-1)=24000. λmax (abs)=355 nm and λmax (em)=551 nm.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)C1C=CC=CC=1.[ClH:18].[H][H]>[C].[Pd].C(O)C>[ClH:18].[CH3:17][S:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixed solution obtained by mixing 2.3 g of 100% pure (S)-1-benzyl-3-methanesulfonyloxypyrrolidine with 3.0 ml of ethanol and adding dropwise 1.00 ml of 35% aqueous hydrochloric acid thereto with cooling on an ice-water bath was charged, together with 300 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed for 4 hours. Hydrogen absorption came to an end in 3.2 hours after the start of hydrogen introduction. After completion of the reaction, the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, and the filtrate obtained was concentrated under reduced pressure and further dried under vacuum to give 2.4 g (yield: 84 mole percent) of (S)-3-methanesulfonyloxypyrrolidine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33]C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:75])([C:65]([F:74])([F:73])[C:66]([F:72])([F:71])[C:67]([F:70])([F:69])[F:68])[CH2:49]CCC(CCCCCC=C)C(OCC)=O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33][CH2:49][C:48]([F:47])([F:75])[C:65]([F:73])([F:74])[C:66]([F:71])([F:72])[C:67]([F:70])([F:69])[F:68])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 8 and the ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared in Example 4, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[C:12]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[N:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:20]=1OS(C(F)(F)F)(=O)=O)([O-:10])=[O:9].[NH2:37][CH2:38][C:39]([CH3:42])([CH3:41])[OH:40]>C(Cl)Cl>[F:36][C:33]([F:34])([F:35])[S:30]([O:29][C:12]1[C:11]([N+:8]([O-:10])=[O:9])=[C:20]([NH:37][CH2:38][C:39]([OH:40])([CH3:42])[CH3:41])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1)(=[O:32])=[O:31]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)nc2c(c1OS(=O)(=O)C(F)(F)F)CCCC2
Reactant: CC(C)(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c2c(nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Triethylamine (1.36 mL, 9.8 mmole) was added to a solution of 5,6,7,8-tetrahydro-3-nitro-2,4-bis[(trifluoromethyl)sulfonyloxy]quinoline (4.2 g, 9.4 mmole) in methylene chloride (180 mL). 2-Amino-α,α-dimethylethanol (0.88 g, 9.8 mmole) was added to the reaction mixture which was then stirred at ambient temperature overnight. The reaction mixture was evaporated to provide a residue which was purified by silica gel chromatography eluting with hexane:ethyl acetate 40:60 to provide 3.8 g of the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH:12]=[CH2:13].Cl[Sn]Cl.O.CC(=O)OCC>O>[C:1]1([CH2:7][CH:8]([OH:9])[CH2:13][CH:12]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: C=CCBr
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(O)Cc1ccccc1
Yield: 54.3 %

Procedure:
To a mixture of phenylacetaldehyde 30a (7.84 g, 65.3 mmol) and 3-bromoprop-1-ene (11.1 g, 91.5 mmol) in water (50 mL), KI (3.25 g, 19.6 mmol) and NiCl2.6H2O (3.1 g, 13 mmol) were added. After the mixture was stirred for several minutes, SnCl2.H2O (29.5 g, 13 mmol) was added. The mixture was vigorously stirred at rt overnight and then extracted with EA. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, evaporated in vacuo. The residue was purified by CC using PE:EA=5:1 as mobile phase to give the desired product (5.75 g, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:31])[CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:14]=[N:13]2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:42]([CH2:50][C:51]([F:54])([F:53])[F:52])S(C(F)(F)F)(=O)=O>CN(C=O)C>[F:52][C:51]([F:54])([F:53])[C:50]([OH:29])=[O:42].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:50][C:51]([F:54])([F:53])[F:52])[C:10](=[O:31])[CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:14]=[N:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(-c2cn(CC(=O)Nc3ccc(F)c(Cl)c3)nn2)ccc1-n1cnc(C)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cn(CC(=O)N(CC(F)(F)F)c3ccc(F)c(Cl)c3)nn2)ccc1-n1cnc(C)c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
N-(3-chloro-4-fluorophenyl)-2-{-4-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-1,2,3-triazol-1-yl}acetamide (50 mg, 0.113 mmol) and KHMDS (27.1 mg, 0.136 mmol) were added to a 25-mL flask under nitrogen and DMF (3 ml) was added. Trifluoroethyl triflate (0.023 ml, 0.159 mmol) was added and the suspension stirred at room temperature for 16 h. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA, to give the product (25 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:18])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.[C:19]([N:27]=C=O)(=[O:26])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[OH:18][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19]([NH2:27])=[O:26])[CH:7]=1)([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: Cc1ccccc1CC(C)(O)c1ccnc(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1CC(C)(O)c1ccnc(NC(N)=O)c1
Temperature: 50 °C
Yield: 19.2 %

Procedure:
2-(2-Amino-pyridin-4-yl)-1-o-tolyl-propan-2-ol (37 mg, 0.15 mmol) is dissolved in DCM (1 mL) and benzoyl isocynate (27 mg, 0.18 mmol) is added. The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (1 mL) and potassium carbonate (32 mg, 0.23 mmol). The mixture is heated at 80° C. for 55 min. The solvent is removed and the residue is partitioned between water (25 mL) and EtOAc (35 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 8.2 mg of the titled product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][CH:10]=[O:11])=[CH:7][CH:6]=[N:5]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][CH:10]=[O:11])=[CH:7][CH:6]=[N:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=CNc1ccnn1CCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1nccc1NC=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-hydroxyethyl)-5-formamidopyrazole (10 g) and triethylamine (18 ml) in methylene chloride (100 ml) was added dropwise methanesulfonyl chloride (8.5 ml) under ice-cooling. The mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was poured into water (20 ml) and the methylene chloride layer was separated. The aqueous layer was reextracted with tetrahydrofuran twice. The organic layers were combined and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel (200 g) using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-(2-methylsulfonyloxyethyl)-5-formamidopyrazole (3.2 g) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1.[CH2:15]([C@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@H:17]([OH:19])[CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: ClC[C@@H]1CO1
Reactant: CCC(CC)COc1cccc(Br)c1
Product: CCC(CC)COc1cccc(C[C@@H](O)CCl)c1

Procedure:
Metallation of 1-bromo-3-(2-ethylbutoxy)benzene followed by addition to (S)-(+)-epichlorohydrin gave (R)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol. Yield (1.55 g, 59%): 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m, 3H), 5.13 (d, J=4.8 Hz, 1H), 3.88-3.82 (m, 1H), 3.78 (d, J=5.6 Hz, 2H), 3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=10.8, 5.6 Hz, 1H), 2.74 (dd, J=13.6, 5.2 Hz, 1H), 2.61 (dd, J=13.2, 7.4 Hz, 1H), 1.74-1.69 (m, 1H), 1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).