Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C(C(C)C)=NN2C=CC=CC=12.N1C=CC(B(O)O)=CC=1.[CH:23]([C:26]1[C:34]([C:35]2[CH:36]=[C:37]([NH2:41])C=[CH:39][CH:40]=2)=[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1)([CH3:25])[CH3:24]>>[CH:23]([C:26]1[C:34]([C:35]2[CH:40]=[CH:39][N:41]=[CH:37][CH:36]=2)=[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1)([CH3:24])[CH3:25]
Reactant: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Agent: CC(C)c1nn2ccccc2c1I
Agent: OB(O)c1ccncc1
Product: CC(C)c1nn2ccccc2c1-c1ccncc1

Procedure:
2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 4-pyridineboronic acid following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example 59) (1584 mg, 34%). 1H-NMR (250 MHz, DMSO-d6) δ 8.87-8.82 (m, 3H), 8.09 (d, J=6.5 Hz, 2H), 7.95 (d, J=9.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.11 (t, J=6.8 Hz, 1H), 3.48 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H); LC/MS 238.3 m/z (M+H+). Compound 1103.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:15])[CH2:10][CH2:11][N:12]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 75 %

Procedure:
A solution of 4-(4-chlorophenyl)piperidin-4-yl amine hydrochloride (0.030 g, 0.1058 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.016 g, 0.1058 mmol) and triethylamine (0.074 ml, 0.5289 mmol) in n-butanol (1.0 ml) was heated to 100° C. for 2 days. Concentration and purification by SCX-2 Isolute column (2 g), eluting with 1M NH3/MeOH, followed by silica column chromatography (20% methanol in DCM) gave a white solid (0.026 g, 74%). LC-MS (LCT2) m/z 328 [M+H+], Rt 2.59 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COCC1.O=[C:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:19]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:18]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:11]=[C:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:19]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:18]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)[C@H]1CCC(=O)C[C@@H]1C(=O)OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: C=C1CC[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)C1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Methyl triphenylphosphonium bromide (1.9 g, 5.32 mmole) and sodium bis(trimethylsilyl)amide (1.0 M in THF, 5.32 ml, 5.32 mmole) in toluene (15 ml)/THF (5 mL) solution was combined with a solution of (1S,2S)-1-tert-butyl 2-benzyl 4-oxocyclohexane-1,2-dicarboxylate (1.0 g, 4.09 mmole) in toluene (15 mL) at −10° C. The resulting mixture was stirred at r.t. for 2 hours at −10° C. and at r.t for 2 hours. TLC showed starting material was consumed. The mixture was diluted with EtOAc, and the resulting solution was washed with water (×1); brine (×2); and dried over MgSO4. After filtration, the filtrate was concentrated. The crude product was purified with combi-flash to afford (1S,2S)-1-tert-butyl 2-benzyl 4-methylenecyclohexane-1,2-dicarboxylate (0.65 g; 1.97 mmole).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1Cl)CC1C=C(C(N)C(C)C)C=C[N:18]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH2:18])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CC(C)C(N)c1ccnc(Cc2ccc(Cl)c(Cl)c2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(NC(N)=O)c1
Reaction time: 1 h

Procedure:
3-methoxyphenyl isocyanate (37 μl, 0.28 mmol) was added to a solution of provide 1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropylamine (88 mg, 0.28 mmol) in methylene chloride solution (2 ml) at room temperature. After 1 h, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution (5 ml). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated to provide 1-{1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-2-methylpropyl)}-3-(3-methoxyphenyl)urea. (104 mg) as a white solid. mp 161.4-161.8° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22].C(=O)([O-])O.[Na+]>>[CH2:20]([NH:23][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:21]=[CH2:22]
Reactant: C=CCN
Reactant: CCCCCCCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCCCCC)c2scc(C)c2n1
Yield: 68.3 %

Procedure:
In a sealed tube were heated 82 mg (1.2 mmol) of 2-chloro-4-heptylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 261 mg (yield: 68.3%) of the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1.[I:19]I.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[I:19][C:13]1[CH:12]=[C:11]([O:10][CH3:9])[N:16]=[CH:15][C:14]=1[C:17]#[N:18]
Reactant: COc1ccc(C#N)cn1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(I)c(C#N)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., 19.4 ml of lithium diisopropylamide (2 molar in THF/heptane/ethylbenzene, 1.3 eq.) were added to a solution of 4.0 g (29.8 mmol) of 6-methoxypyridine-3-carbonitrile in 120 ml of THF, and the mixture was stirred at −78° C. for 1 h. At −78° C., a solution of 9.1 g (35.8 mmol) of iodine in 20 ml of THF was then added, and the reaction mixture was stirred at −78° C. for 1 h and then carefully added to saturated aqueous ammonium chloride solution. After addition of ethyl acetate, the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried (magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 4.0 g (purity 92%, 48% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:9])[F:20])[N:16]=2)=[O:18])[CH:7]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Reactant: Nc1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)ncn1)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-6-chloropyrimidine (230 mg, 1.78 mmol) in DCM (15 mL) is added 6-(trifluoromethyl)picolinoyl chloride (276 mg, 1.78 mmol) and DIPEA (0.912 ml, 5.33 mmol). The mixture is stirred overnight at RT. The mixture is diluted with DCM (10 mL), washed with saturated NaHCO3 solution (25 mL). The organic layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by prep HPLC E, delivering the title compound as a yellowish solid (102 mg, 19%); LC-MS A: tR=0.89 min; [M+H]+=302.92.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: Cc1cccc(C(O)CN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(C)c2)cc1
Yield: 54.1 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methylphenyl)ethanol (prepared as described in Preparation 44), 4.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 4.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.2 g of the title compound were obtained having an Rf=0.24 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][S:8][C:9]1(C([O-])=O)OC[N:11]=[N:10]1.[K+]>C1C=CC=CC=1.[Hg]>[CH3:7][S:8][C:9]1[O:3][C:2]([C:1]([Cl:6])=[O:5])=[N:11][N:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSC1(C(=O)[O-])N=NCO1
Agent: [Hg]
Agent: [K+]
Solvent: c1ccccc1
Product: CSc1nnc(C(=O)Cl)o1

Procedure:
A solution of oxalyl chloride (2.57 ml., 0.03 mole) in benzene (15 ml.) was added dropwise to a refluxing suspension of potassium 5-methylthio-1,3,4-oxadiazole-5-carboxylate (3.96 g., 0.02 mole) in benzene (50 ml.). After the addition, the mixture was stirred at reflux for one hour. Filtration and evaporation left the acid chloride; distillation gave 1.86 g. (52%); B.P. 65°-69° C. at 0.05 mm. of mercury.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:27]([O-])=O)(=[O:3])[CH3:2].[H][H]>CO.COCCO.[Ni]>[C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)(=[O:15])=[O:16])=[CH:9][C:8]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: COCCO
Solvent: CO
Product: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N

Procedure:
59 g of 2-(3-acetylureido)-5-(3-trifluoromethylphenylsulfonyloxy)nitrobenzene in 200 ml of methanol and 200 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After hydrogen uptake is complete, the catalyst is filtered off with suction, washed with warm 2-methoxyethanol and the solution is evaporated under reduced pressure. Water is added to the residue and it is then filtered off with suction, washed with water and dried over sodium hydroxide, melting point 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:64]1[C:69](=[O:70])[CH2:68][NH:67][CH2:66][C:65]1=[O:71]>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:67]4[CH2:68][C:69](=[O:70])[NH:64][C:65](=[O:71])[CH2:66]4)=[O:20])=[C:16]([C:23]([F:26])([F:24])[F:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CNCC(=O)N1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC(=O)N1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (300 mg, 0.64 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), HATU (483 mg, 1.27 mmol, 2.00 equiv), DIEA (164 mg, 1.27 mmol, 2.00 equiv), piperazine-2,6-dione (145 mg, 1.27 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 20° C. The resulting solution was diluted with 50 mL of brine. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (10:1). This resulted in 330 mg (91%) of 4-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)piperazine-2,6-dione as a white solid.
Reaction SMILES: [F:1][C:2]([C:4]([OH:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])=[CH2:3].N1C=CN=C1.CN(C)C=O.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>O>[F:1][C:2]([C:4]([O:12][Si:24]([CH3:27])([CH3:26])[CH3:25])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])=[CH2:3]
Reactant: C#CCC(O)(CCCC)C(=C)F
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C(=C)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred 0° C. solution of 13.7 g. of 4-(1-fluorovinyl)-4-hydroxy-1-octyne and 16.1 g. of imidazole in 60 ml. of anhydrous dimethylformamide is added, via a syringe over a 3 minute period, 11.6 ml. of chlorotrimethylsilane. The resulting solution is stirred at room temperature for 18 hours, cooled to 0° C., diluted with 350 ml. of petroleum ether and shaken with 150 ml. of water. The organic phase is separated, washed with six 50 ml. portions of water, then 50 ml. of brine, dried over magnesium sulfate and concentrated in vacuo giving 18.9 g. of the desired product as a colorless liquid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25]CC)=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].Cl>CN(C=O)C.O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:21]2[CH:22]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[C:18](=[O:28])[C:19]([C:23]([OH:25])=[O:24])=[CH:20]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cn(Cc2ccc(F)cc2)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(Bromomethyl)-4-fluorobenzene (122 μl) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (200 mg) and cesium carbonate (499 mg) in DMF (4 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. A 1 N aqueous sodium hydroxide solution (4 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for two hours. A 1 N aqueous hydrochloric acid solution and water were added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and then dried to give 250 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([O:8][C:9](=[O:19])[CH2:10][O:11]CC2C=CC=CC=2)[CH:7]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([O:8][C:9](=[O:19])[CH2:10][OH:11])[CH:7]=1
Reactant: O=C(COCc1ccccc1)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CO
Product: O=C(CO)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
Benzyloxy-acetic acid 5-chloro-2-(2,4-dichloro-phenoxy)-phenyl ester 4 (5 grams) was dissolved in methanol (50 mL) in a pressure vessel, palladium on carbon (5%, 5 grams) was added and the mixture was stirred under an atmosphere of hydrogen (4 Kg) for 4 hours. The catalyst was removed by filtration and the methanol was distilled off to yield crude 5.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:29][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([N:16]([CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C:14]=3[S:15][C:7]=2[C:6]=1[O:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:4]>C(OCC)(=O)C>[C:32]([CH2:31][O:30][C:6]1[C:7]2[S:15][C:14]3[C:13]([N:16]([CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]=2[S:29][C:5]=1[C:3]([OH:4])=[O:2])([OH:34])=[O:33]
Reactant: CCNC(=O)N(CC1CCCCC1)c1cccc2c1sc1c(OCC(=O)OCC)c(C(=O)OC)sc12
Solvent: CCOC(C)=O
Product: CCNC(=O)N(CC1CCCCC1)c1cccc2c1sc1c(OCC(=O)O)c(C(=O)O)sc12

Procedure:
Step C Hydrolysis: Hydrolysis of 7-(1-Cyclohexylmethyl-3-ethyl-ureido)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (30 mg, 0.056 mmol) was carried out following a procedure similar to that delineated in Step C, Example 26, with the exception of an ethyl acetate wash (3×, 5 mL) before precipitation of the desired diacid, to remove a minor impurity associated with the isocyanate. (8.6 mg yellow solid, 28% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[NH:16][CH:17]=[CH:18][N:19]=3)=[CH:10][C:8]=2[CH:9]=1)=O.[NH3:20]>C(O)C>[NH:19]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([C:3]([NH2:20])=[O:2])=[CH:9][C:8]=2[CH:10]=1
Reactant: N
Reactant: COC(=O)c1cc2cc(Cc3ncc[nH]3)ccc2o1
Solvent: CCO
Product: NC(=O)c1cc2cc(Cc3ncc[nH]3)ccc2o1

Procedure:
A solution of 5-(1-imidazolylmethyl)benzofuran-2-carboxylic acid methyl ester in a concentrated solution of ammonia in ethanol (25 ml.) was stirred for 18 hours and then evaporated. The residue was crystallized from isopropanol to give 5-(1-imidazolylmethyl)benzofuran-2-carboxamide (0.60 g.), m.p. 174°-176° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:19]2[O:23][C:22]([Si](C(C)C)(C(C)C)C(C)C)=[N:21][CH:20]=2)O1>>[O:23]1[C:19]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)=[CH:20][N:21]=[CH:22]1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(Br)nc1
Product: O=C(O)c1ccc(-c2cnco2)nc1

Procedure:
The title compound is prepared from 6-bromo-nicotinic acid and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[tris(isopropyl)silyl]-oxazole and following a procedure analogous to that described in Intermediate 45. Mass spectrum (ESI+): m/z=189 [M−H]−.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+].FC(F)(F)C(O)=O.[OH-].[NH4+]>C(Cl)Cl.O.C(OCC)(=O)C.CCCCCCC>[CH:1]([C:4]1[CH:5]=[C:6]([C:10]2([N:17]=[N+:18]=[N-:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C2(O)CCCCC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cccc(C2(N=[N+]=[N-])CCCCC2)c1
Temperature: -5 °C
Yield: 100 %

Procedure:
To 3.20 g (14.7 mmol) of compound 1 in 60 mL of CH2Cl2 under nitrogen is added 2.10 g (32.3 mmol) of sodium azide. The stirred suspension is cooled to −5° C. and a solution of trifluoroacetic acid (9.0 mL, 120 mmol) in 35 mL of dichloromethane is added dropwise over 1 h. The resulting suspension is stirred at 0° C. for an additional hour. To the cold, vigorously stirred mixture is added, dropwise, 10 mL of water, followed by dropwise addition of a mixture of 10 mL of water and 10 mL of concentrated ammonium hydroxide. After 30 min the mixture is poured into a separatory funnel containing 350 mL of a 1:1 mixture of heptane and ethyl acetate, and 100 mL of water. The organic phase is washed with an additional portion of water, followed successively by 1 N KH2PO4, water, and brine. It is then dried over anhydrous Na2SO4, filtered and concentrated to afford 3.6 g (14.7 mmol, 100%) of 2 as a pale yellow oil: 1H NMR (CDCl3) δ 7.3 (m, 2H), 7.25 (m, 1H), 7.16 (m, 1H), 2.92 (m, 1H), 2.01 (m, 2H), 1.83 (m, 2H), 1.73–1.64 (m, 5H), 1.3 (m, 1H), 1.26 (d, J=7 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][C:29]([F:32])([F:31])[F:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][C:29]([F:32])([F:31])[F:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: FC(F)(F)CI
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC(F)(F)F)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 27.4 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (53 mg, 0.38 mmol) and 2-iodo-1,1,1-trifluoroethane (28 μL, 0.28 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150° C. for 5 minutes hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) afforded 9 mg (27%) of 3-(2-pyridyl)-5-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.27 (s, 1H), 8.24 (d, 1H), 8.08 (s,1H), 7.92 (t, 1H), 7.50 (m, 2H), 4.53 (q, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[ClH:31].CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(F)cc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(6-fluoroindolin-1-yl)piperidine-1-carboxylate prepared as in STEP 1 above (16.64 g, 52 mmol) in CH2Cl2 (45 mL) was added TFA (30 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 3 h (monitor by HPLC). The resulting mixture was then concentrated to remove most of the solvent and TFA. The resulting residue was partitioned in CH2Cl2/H2O (100 mL/50 mL) and stirred. 3N NaOH(aq) was then added slowly until the pH value of aqueous layer was >11. The aqueous layer was then extracted with CH2Cl2 (100 mL×10). The combined CH2Cl2 layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was dissolved in Et2O (100 mL) and then 1N HCl (1M in Et2O, 60 mL, 60 mmol) was added slowly at 0° C. The resulting mixture was allowed to warm to room temperature for another 30 min. Hexane (100 mL) was added and the resulting mixture was stirred for 15 min. The resulting white solid was filtered and washed with 50% Et2O/hexane (30 mL×3), then dried to yield 6-fluoro-1-(piperidin-4-yl)indoline as a white HCl salt.