Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]2[C:1]([NH:2][C:18]3[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=[CH:16][C:17]=3[S:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[N:12][CH:11]=[N:10][C:4]=2[N:5]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of the product from Example 10B (340 mg, 1.80 mmol), and the product of Example 63A (480 mg, 1.80 mmol) in acetic acid (10 mL) was stirred in an oil bath preheated to 130° C. for 30 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum leaving a brown oil as the title compound (0.65 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:44][C:45]1[CH:46]=[C:47]([N:52]2[CH:56]=[C:55]([CH2:57][NH2:58])[N:54]=[CH:53]2)[CH:48]=[CH:49][C:50]=1[I:51]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:58][CH2:57][C:55]2[N:54]=[CH:53][N:52]([C:47]3[CH:48]=[CH:49][C:50]([I:51])=[C:45]([F:44])[CH:46]=3)[CH:56]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cn(-c2ccc(I)c(F)c2)cn1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cn(-c2ccc(I)c(F)c2)cn1)c1ccc(Cl)s1
Reaction time: 0.08 h
Yield: 21.3 %

Procedure:
To a solution of 5-chloro-2-thiophenecarboxylic acid 1-5 (165 mg, 1.01 mmol) and triethylamine (0.300 mL, 2.16 mmol) in DMF (5 mL), BOP (472 mg, 1.07 mmol) was added. After 5 min of stirring, a solution of (1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanamine (268 mg, 0.845 mmol) in DMF (4 mL) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 5-chloro-N-((1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (83 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]([CH3:23])[CH2:18][C:19]([F:22])([F:21])[F:20])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:34][OH:35]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]4)[C:15]([N:17]([CH3:23])[CH2:18][C:19]([F:20])([F:21])[F:22])=[N:16][C:12]=3[CH:11]=[C:10]([C:32](=[NH:33])[NH:34][OH:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: NO
Reactant: CN(CC(F)(F)F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Solvent: CCO
Product: CN(CC(F)(F)F)c1nc2cc(C(=N)NO)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a reaction vessel containing the residue of 4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (0.027 g, 0.056 mmol) suspended in EtOH (1.0 mL) was added hydroxylamine (0.10 mL, 50% w/w in H2O). The reaction was stirred at ambient temperature for 3 hours. To the reaction was then added benzene (2.0 mL), and the reaction was concentrated in vacuo to afford 4-(5-chloropyridin-3-yl)-N-hydroxy-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide as a crude residue. MS ESI calc'd. for C23H27ClF3N7O [M+H]+ 510. found 510.
Reaction SMILES: [CH2:1]([O:17]CC1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCCCCCCCCCCCCOCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C=CCCCCCCCCCCCCCCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
Into clean flame dried Ar flushed 500 mL RBF was placed 6.3 g (19 mmol) of 27 and 100 mL of dry DCM and the mixture was cooled to −78° C. 95 mL of BCl3 (1.0 M solution in DCM) was then slowly added to the above solution. After complete addition the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued for an additional 30 minutes at room temperature after which the reaction was cooled in an ice-water bath and quenched very cautiously!! (as it turns violent) with 100 mL of water. The organic layer was then separated and washed with water, dried over MgSO4 and the solvents evaporated under vacuum. The crude was then purified with combiflash using hexane/ethylacetate as eluent to furnish 4.3 g of 26 in 94% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH2:14][C:15](=O)[CH2:16][CH2:17][CH3:18])[C:7]([O:9][CH3:10])=[O:8])([O-])=O.C(O)C.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[CH2:16]([C:15]1[NH:1][C:4]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=2)[CH2:17][CH3:18]
Reactant: CCCC(=O)Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Yield: 58.5 %

Procedure:
To a solution of methyl 3-nitro-4-(2-oxopentyl)benzoate (114 mg) in a mixture of tetrahydrofuran (1.5 ml), ethanol (1.5 ml) and water (2.1 ml) was added sodium hydrosulfite (3.0 g), and the mixture was stirred under reflux for 30 minutes. The resulting mixture was evaporated in vacuo, and the residue was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by thin layer chromatography with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-propylindole-6-carboxylate (54.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[C:3]([Br:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc2cc(N)ccc2c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(Br)c(N)ccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 6-amino-2-naphthoate (0.5 g) in THF (10 ml) was added pyridinium tribromide (0.87 g). The reaction mixture was stirred at 0° C. for 1 h after which it was then filtered through a pad of SiO2 and washed with hexane. The organic washings were evaporated to dryness and the residue was purified by flash chromatography eluting with hexane to afford the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19]C(=O)C2C=CC=CC=2)=[CH:11][C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][C:10]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OC(=O)c2ccccc2)c2ccccc2c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.9 g (0.032 mol) of 1-benzyloxy-2-methyl-4-benzoyloxynaphthalene was suspended in 120 ml of methanol, and to this was added 20 ml of 2N NaOH, followed by stirring for 2 hours at room temperature. After evaporation of methanol from the reaction mixture under reduced pressure, the residue was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and then with water, and ethyl acetate evaporated under reduced pressure. The residue was dissolved in methanol, decolorized with activated carbon, and following filtering out of the activated carbon, water was added to the filtrate, and precipitated crystals were collected, recrystallized from methanol-water to give 5.2 g of white plates, m.p. 159-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=O)[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12][Cl:13])[O:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[S:19])[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12][Cl:13])[O:10][C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=O
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=S
Yield: 73.2 %

Procedure:
To a solution of 43 g (0.16 mole) of 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 400 ml of dry toluene was added a mixture of 23 g (0.12 mole) of phosphorus pentasulfide and 23 g of potassium sulfide which had been ground together. The reaction mixture was stirred and heated at reflux for 24 hr. The mixture was filtered hot and the filtrate concentrated under reduced pressure to give 25.5 g (55%) of orange oil which solidified on standing at room temperature. The solid was recrystallized from ethanol, m.p. 105°-106° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][CH2:12][CH:11]2[C:14]([O:16]C)=[O:15])[CH2:6][CH2:5]1.O.[OH-].[Li+:22]>>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][CH2:12][CH:11]2[C:14]([O-:16])=[O:15])[CH2:6][CH2:5]1.[Li+:22]
Reactant: COC(=O)C1CCN1C1CCN(CC(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C1CCN1C1CCN(CC(F)(F)F)CC1

Procedure:
The reaction of methyl 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carboxylate 19G and lithium hydroxide monohydrate yielded lithium 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carboxylate as a light brown solid (quant.). MS ISP (m/e): 267.2 (100) [(M+H)]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14]/[C:13](=[CH:16]\[CH:17]=[CH:18]\[C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=[CH:24][C:23]=4[NH:33]C(=O)OC(C)(C)C)=[O:20])/[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)(O)[O-].[Na+].[OH-].[K+]>>[NH2:33][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:27][C:22]=1[NH:21][C:19](=[O:20])/[CH:18]=[CH:17]/[CH:16]=[C:13]1/[CH2:12][N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[CH2:15][CH2:14]/1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)/C=C/C=C1\CCN(Cc2ccc3c(c2)OCO3)C1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Product: Nc1ccc(-c2cccs2)cc1NC(=O)/C=C/C=C1\CCN(Cc2ccc3c(c2)OCO3)C1

Procedure:
Following the same procedure as described in Example 1, step 7 (scheme 1), but substituting compound 8 for compound 277 and sodium bicarbonate with potassium hydroxide, the title compound 278 was obtained in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH3:11].Cl>[Fe].C(O)C>[NH2:8][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([CH3:11])[C:2]=1[NH2:1]
Reactant: Cc1cncc([N+](=O)[O-])c1N
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Cc1cncc(N)c1N
Yield: 60.1 %

Procedure:
A mixture of 4-amino-3-methyl-5-nitropyridine (1.198 g), iron powder (1.748 g), ethanol (52 mL) and hydrochloric acid (13 mL) was heated to reflux for 3 hours. After cooling to room temperature the ethanol was distilled off and the resulting suspension was diluted with water to 50 mL and the pH was adjusted to 13 by addition of 2N NaOH. Extraction with ethyl acetate (3×70 mL), drying of the combined organic phases of anhydrous sodium sulphate and evaporation of the solvent afforded 0.579 g (60%) of 3,4-diamino-5-methylpyridine.
Reaction SMILES: C1C=CC(N)=CC=1.Cl.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:34]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([P:44](=[O:47])([OH:46])[OH:45])[CH3:43])=[O:40])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:23])C)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:34]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([P:44](=[O:45])([OH:47])[OH:46])[CH3:43])=[O:40])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:23])[CH3:17]
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Product: CNCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The aniline salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-tyrosyl-L-alanyl)amino]-ethylphosphonic acid was suspended in acetic acid and 10% palladium-on-carbon was added under argon. Acetic acid was then added. The mixture was stirred overnight at room temperature and then hydrogenated until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate was evaporated. The residual solid was triturated with methanol, filtered off, washed and dried. The solid was purified by reprecipitation from aqueous hydrochloric acid/ethanol with propylene oxide to give (1R)-1-(N-sarcosyl-L-tyrosyl-L-alanylamino)-ethylphosphonic acid of melting point 275°-277° C. (decomposition).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]#[N:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1C=CC=CC=1>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][C:6]1([C:16]#[N:17])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: CN(C)CCCl
Reactant: N#CC1c2ccccc2CCc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: c1ccccc1
Product: CN(C)CCC1(C#N)c2ccccc2CCc2ccccc21

Procedure:
To a solution of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (100) (Med. Chem. Res. 1, 401 (1991)) (1.0 g, 4.56 mmol) and N-(2-chloroethyl)-N,N-dimethylamine hydrochloride (0.72 g, 5 mmol) in benzene (20 mL) was added 8.8 mL of a 1.3M solution of lithium hexamethyldisilazide (11.4 mmol). The mixture was heated at reflux under nitrogen for 18 hr and the solvent then removed under vacuum. The residue was treated with water (20 mL) and extracted twice with methylene chloride (20 mL). The organic layers were combined, dried over sodium sulfate, and chromatographed directly on silica gel eluted with methylene chloride followed by 95:5:0.5, then 90:10:1 methylene chloride:methanol:ammonium hydroxide. The product fractions were evaporated to dryness in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1OC1C.C(N(C(C)C)CC)(C)C.[Cl:25]Cl>C(Cl)Cl>[Cl:25][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: ClCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC1CO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1Cl
Reaction time: 24 h

Procedure:
To 150 ml. of dry methylene chloride were added 7.35 g. (0.05 mole) of phthalimide followed by 17.5 ml. (5 equiv.) of propylene oxide and 0.065 g. (0.5 mmoles) of diisopropylethylamine. The mixture was cooled to 0° C. and saturated with chlorine. The mixture was stirred for about 24 hours to provide approximately 50% conversion to N-chlorophthalimide.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH:66]=[CH2:67])[C:56]([O:58]CC)=[O:57]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH:55]([CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:72])[C:68]([F:69])([F:70])[F:71])[C:56]([OH:58])=[O:57])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(7,7,8,8,8-pentafluorooctyl)-8-nonenoate prepared in Example 12, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:4]([Cl:23])[CH:3]=1.[I-].[Na+].[CH3:26][O-:27].[Na+].CO>[Cu]=O.CO>[Cl:23][C:4]1[CH:3]=[C:2]([O:27][CH3:26])[S:6][C:5]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)cc3Cl)c(C)nn12
Reactant: C[O-]
Agent: O=[Cu]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)c1cc(C)nc2c(-c3sc(OC)cc3Cl)c(C)nn12
Yield: 21 %

Procedure:
Charge an oven dried flask with 3-(5-bromo-3-chloro-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.46 g, 1.1 mmol), copper oxide (0.045 g, 0.56 mmol), sodium iodide (0.020 g, 0.11 mmol), 25% sodium methoxide/methanol solution (10 mL) and anhydrous methanol (10 mL). Reflux the reaction in an oil bath (90° C.) over the weekend under an inert atmosphere. Quench the reaction with ice water and extract with ether (3×100 mL). Combine the organic portions, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (35% ethyl acetate/hexane) to 0% hexane/100% (35% ethyl acetate/hexane) in a step gradient of 10% increments to give a white foam (0.086 g, 21%). ES/MS m/z (35Cl) 363.7 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[Br:24]NC(=O)CCC(N)=O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][C:3]=1[Br:24]
Reactant: NC(=O)CCC(=O)NBr
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1Br
Temperature: 23 °C
Reaction time: 24 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250 mg, 0.822 mmol), N-bromosuccinamide (146 mg, 0.822 mmol), and DMF (4 mL) were allowed to stir at 23° C. After 24 h, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate:hexane 1:1) to afford 6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (27): Mass Spectrum (CI) 385 (MH+Br81).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH3:11][O:12][C:13]([N:15]1[CH:20]=[CH:19][CH2:18][C:17]([CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])=[CH:16]1)=[O:14].CC([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:11][O:12][C:13]([N:15]1[CH:16]=[C:17]([C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH2:18][C:19]([CH:4]=[O:5])=[CH:20]1)=[O:14]
Reactant: COC(=O)N1C=CCC(C2CCCN2C)=C1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1C=C(C=O)CC([C@@H]2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of DMF (0.04 mL, 0.54 mmol) in 4 mL of CH2Cl2 cooled at 0° C. was slowly added POCl3 (0.025 mL, 0.27 mmol). The ice bath was removed and the mixture was stirred at RT for 30 min. It was then transferred via a double tipped needle to a solution of 3-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester II (0.0404 g, 0.18 mmol) in 4 mL of CH2Cl2 cooled at 0° C. The reaction mixture was stirred at RT for 1 day. A solution of NaOAc (0.024 g, 0.29 mmol) in 0.5 mL of water was added and the reaction mixture was stirred at RT for 20 min. A saturated aqueous solution of NaHCO3 was slowly added until pH was basic (about 10 mL). The aqueous layer was extracted with CH2Cl2 (4 times), and the combined organic layers were dried over MgSO4. After evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (15% EtOAc/hexanes) to afford 0.0241 g (54%) of (S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester III as white crystals, mp 78-80° C. IR (thin film, neat, NaCl): 2955, 2767, 1731, 1667, 1620, 1437, 1394, 1203, 991 cm−1; 1H NMR (CDCl3, 300 MHz) δ 9.45 (s, 1H), 7.65 (m, 1H), 6.81 (s, 1H), 3.91 (s, 3H), 3.12-3.07 (m, 1H), 2.93 (s, 2H), 2.59 (m, 1H), 2.20-2.12 (m, 3H), 1.81-1.62 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 191.13, 141.44, 122.61, 120.52, 118.42, 69.75, 56.98, 54.47, 40.61, 29.45, 22.91, 19.86. HRMS Calcd for C13H18N2O3: 251.1396 [M+H]+. Found: 251.1390 [M+H]+. [α]25D −51.7 (c=0.8, CH2Cl2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][N:23]1[CH2:28][C:27]([CH3:29])=[N:26][NH:25][C:24]1=[O:30].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:29][C:27]1[CH2:28][N:23]([NH:22][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:15])[C:24](=[O:30])[NH:25][N:26]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Reactant: CC1=NNC(=O)N(N)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=NNC(=O)N(NC(=O)c2cnc(-c3ccccn3)nc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.152 g, 0.75 mmol), in dry DCM (3 mL) and DMF (0.9 μL) in a dry flask under N2 is added oxalyl chloride (74 μL, 0.86 mmol). The reaction mixture is stirred at rt for 1 h. The solvent is evaporated and toluene is added and evaporated three times. The residue is dissolved in dry DCM (3 mL), and a solution of 4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.77 g, 0.6 mmol) in DCM (5 mL) is added followed by the addition of DIPEA (0.14 mL, 0.79 mmol). The mixture is stirred at rt overnight, and then concentrated in vacuo. The residue is diluted with water and adjusted to pH ˜8.5 with saturated aqueous NaHCO3 solution. The resulting precipitate is filtered to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide (0.043 g, 23%). MS: 312 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.95 (s, 1H), 9.31 (s, 2H), 8.78 (d, 1H), 8.45 (d, 1H), 8.01 (tr, 1H), 7.58 (dd, 1H), 4.22 (2, 2H), 1.91 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2cc1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
3-(1-benzylpiperidin-4-yl)quinolin-2(1H)-one (5.40 mmol, 1.72 g) was suspended in methanol (70 mL). A catalytic amount of 20% palladium hydroxide on carbon was added to the mixture. The reaction vessel was placed on a Parr apparatus and charged with 55 psi of hydrogen gas. Reaction shook at room temperature for 5 hours. Mixture was removed from the apparatus and filtered. Filtrate was concentrated. Title compound was obtained as white solid in 90% yield. 1H NMR (300 MHz, DMSO-d6): δ=7.65 (s, 1H), 7.64 (d, J=10.61, 1H), 7.41 (t, J=7.50, 1H), 7.26 (d, J=8.05, 1H), 7.13 (t, J=7.32, 1H), 3.02 (d, J=11.71, 2H), 2.82 (t, J=11.89, 2H), 2.58 (t, J=11.71, 2H), 1.73 (t, J=11.71, 2H), 1.42 (m, 2H). MS m/e (M+H)+=229.4.