Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]4[C:24](=[O:25])[CH2:23][S:22][C:21]4=[O:26])=[CH:13][CH:12]=[CH:11][N:10]3[CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:23]1[S:22][C:21](=[O:26])[N:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[C:9]3[N:10]([CH:27]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:11]=[CH:12][CH:13]=2)[C:24]1=[O:25])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2cc(-c3ccccc3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3cc(-c4ccccc4)nc23)C1=O

Procedure:
To a solution of 1.91 g (5.0 mmol) of 3-[4-(2-phenylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.45 ml (5.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 1.70 g (78.0%, yellow foamy substance) of the desired product.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCC[C@@H](C)CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)CCCC(C)C)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
A solution of 6.5 g (41 mmol) of (R)-3,7-dimethyl-1-octanol and 7.8 g (41 mmol) of p-toluenesulphonyl chloride in 50 ml of absolute chloroform is treated at 0° with 7.9 g (0.1 mol) of absolute pyridine. The mixture is subsequently stirred at 4° for 20 hours. For the working-up the mixture is poured on to 500 g of ice and extracted three times with chloroform. The combined organic phases are washed first with cold 1-N hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and subsequently with saturated aqueous common salt solution. After drying over potassium carbonate and removal of the solvent under reduced pressure, the crude product is chromatographed on 300 g of silicagel with benzene. There are obtained 11.4 g (89%) of (R)-3,7-dimethyl-1-octanol p-toluenesulphonate; [α]D20 =+2.0 (c=4.0, benzene).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][OH:18])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:19])[C:3]=1[C:20]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([N:30]([CH2:35][C:36]([O:38]CC)=[O:37])[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=2[S:22](=[O:42])(=[O:41])[N:21]=1>O1CCCC1.Cl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][OH:18])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:19])[C:3]=1[C:20]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([N:30]([CH2:35][C:36]([OH:38])=[O:37])[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=2[S:22](=[O:41])(=[O:42])[N:21]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(CCC(C)C)(NO)C1=O)N2)S(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCC1(NO)C(=O)C(C2=NS(=O)(=O)c3cc(N(CC(=O)O)S(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A solution of Example 53B (15 mg, 0.024 mmol) in tetrahydrofuran (0.3 mL) and 1 N HCl (0.2 mL) was heated at 65° C. for 4 hours. The solution was cooled to room temperature and concentrated in vacuo. The residue was chromatographed on a reverse phase C18 column eluting with 5%-100% acetonitrile in water containing 0.1% trifluoroacetic acid to afforded the title compound as a yellow solid (4 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.46-0.61 (m, 1H), 0.67 (dd, J=12.50, 6.62 Hz, 6H, 0.93-1.05 (m, 1H), 1.16-1.40 (m, 1H), 1.69-1.90 (m, 1H), 1.96-2.16 (m, 1H), 3.11 (s, 3H), 4.46 (s, 2H), 7.43 (d, J=8.46 Hz, 1H), 7.56 (t, J=6.99 Hz, 1H), 7.61-7.73 (m, 2H), 7.73-7.91 (m, 2H), 8.16 (d, J=8.09 Hz, 1H), 10.45-10.75 (br.s, 1H), 12.91-13.14 (br.s, 1H), 14.50 (s, 1H); MS (ESI) m/z 593.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22]1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH:19]([CH2:18][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[N:21]5[CH:25]=[CH:24][CH:23]=[CH:22]5)=[O:29])[CH2:16]4)[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-n1cccc1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1-n1cccc1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-pyrrol-1-yl-benzoic acid. MS (ESI) mass calcd. for C27H25N5O, 435.53; m/z found, 436.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[NH4+].[Cl-].C[OH:24]>>[OH:1][C:2]1([OH:24])[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:3]1
Reactant: COC(=O)c1cc(C(=O)OC)cc(N2CCC(=O)C2)c1
Reactant: CO
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCC(O)(O)C2)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
Dimethyl 5-(3-oxopyrrolidin-1-yl)isophthalate (0.1114 g, 0.401 mmol, 1 eq) and NH4Cl (0.086 g, 1.61 mmol, 4 eq) in 5 ml anhydrous MeOH were heated to reflux at 80° C. for 22 h. After cooling to room temperature the solvent was removed in vacuo. The residue was stirred in EtOH and filtered through cotton to remove any insoluble material. Purification via flash chromatography yielded 0.082 g, (0.25 mmol, 63% yield) of dimethyl 5-(3,3-dihydroxypyrrolidin-1-yl)isophthalate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1nccc2ccccc12
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1nccc2ccccc12

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and isoquinoline-1-carboxylic acid were combined to provide N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-1-isoquinolinecarboxamide as a yellow crystalline solid, m.p. 61.0-63.0° C. 1H NMR (300 MHz, DMSO-d6) δ8.94 (t, J=5.9 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.05-7.96 (m, 3H), 7.84-7.96 (m, 1H), 7.70-7.65 (m, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.37 (dt, J=7.7, 1.0 Hz, 1H), 7.19 (dt, J=7.6, 1.2 Hz, 1H), 6.53 (broad s, 2H), 4.60 (t, J=7.2 Hz, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.41 (m, 2H), 3.28-3.12 (m, 5H), 1.92-1.76 (m, 4H); MS (EI) m/e 468.2261 (468.2274 calcd for C27H28N6O2).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[NH:4][N:3]=1.[I:11](O)(=O)=O.II>C(O)C>[I:11][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cc(C)n[nH]1
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]nc(C)c1I
Temperature: 50 °C
Yield: 231.4 %

Procedure:
A suspension of N-(3-methyl-1H-pyrazol-5-yl)acetamide (29.6 g, 0.213 mol), iodic acid (9.3 g, 0.053 mol) and iodine (32.5 g, 0.128 mol) in ethanol (300 mL) was heated at 50° C. for 3 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and taken up in ethyl acetate. The solution was washed twice with 2 M Na2S2O3 followed by brine solution. The organic layer was dried (magnesium sulphate), filtered and concentrated in vacuo. The residue was triturated from diethyl ether, filtered and dried to provide the title compound as a white solid (32.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](Cl)=[O:32].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:21][C:31](=[O:32])[CH2:30][C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To the solution of 3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]aniline (0.28 g) in THF (15 mL) was added 2-thienylacetyl chloride (0.16 g). The reaction was kept stirring at RT for 0.5 h and worked up with sat. NaHCO3 solution (8 mL). After extraction with EtOAc (2×10 mL), drying with Na2SO4, and concentration, the crude mixture was purified through silica gel column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide as a yellow solid (0.36 g, 95%). ES-LC/MS m/z=464 [M+H]+.
Reaction SMILES: [OH-].[Li+].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:9]([CH:22]=1)[C:10]([O:12]CC1C=CC(F)=CC=1F)=[O:11]>O1CCCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:9]([CH:22]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccc(F)cc1F)c1cc(Br)ccc1OCc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1F

Procedure:
Lithium hydroxide (0.83 g, 34.5 mmol) and water (50 ml) were added to a solution of (2,4-difluorophenyl)methyl 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}benzoate (may be prepared by Description 102; 5.39 g, 11.49 mmol) in tetrahydrofuran (200 ml). The mixture was heated to reflux for 2 hrs. The tetrahydrofuran was then removed on a buchi and the aqueous mixture was acidified to pH=1 using 2M aqueous HCl. The solid formed was filtered off, washed with water (2×50 ml) and dried in air under vacuum. The solid was triturated with diethyl ether to give a white solid. 3.1 g.
Reaction SMILES: CON=[C:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([O:13][CH3:14])[CH:7]([N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C(=O)C)[CH:6]=[C:5]1[CH3:26].C(O)(=O)C(C)=[O:29].Cl>C(O)C>[CH2:19]([NH:15][CH:7]1[CH:8]([O:13][CH3:14])[C:9]([CH3:12])([CH3:11])[CH2:10][C:4](=[O:29])[C:5]([CH3:26])=[CH:6]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON=C1CC(C)(C)C(OC)C(N(Cc2ccccc2)C(C)=O)C=C1C
Reactant: CC(=O)C(=O)O
Agent: Cl
Solvent: CCO
Product: COC1C(NCc2ccccc2)C=C(C)C(=O)CC1(C)C
Temperature: 75 °C
Yield: 69.3 %

Procedure:
To a solution of ethanol (40 ml) containing the 4-(N-acetylbenzylamino)-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime obtained in step 3 (8.5 g, 23.7 millimoles) there were added pyruvic acid (4.18 g, 47.4 millimoles) and 6N hydrochloric acid (40 ml), and the mixture was heated at 75° C. for 4 hours. The reaction solution was concentrated and the resulting residue was dissolved in methanol (50 ml) and then neutralized with a 10% aqueous sodium hydroxide solution while stirring on ice. Water (100 ml) was added, extraction was performed with benzene, and after washing the benzene solution with water it was dried over anhydrous magnesium sulfate. The benzene was distilled off and the resulting residue was subjected to silica gel column chromatography with benzene-ethyl acetate (19:1) as the eluent, to obtain 4.72 g (69%) of 4-benzylamino-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.Cl.O([NH2:18])C.N1C=CC=CC=1>CO.Cl.[Pd]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH2:18])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)c2ccc(F)cc2O1
Reactant: CON
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC1(C)CC(N)c2ccc(F)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 65A (415 mg, 2.14 mmol) in methanol (12 mL) was added methoxylamine hydrochloride (0.179 g, 2.14 mmol) and pyridine (0.87 mL, 10.8 mmol). The mixture was stirred overnight at room temperature and was then evaporated in vacuo. The residue was partitioned between ethyl acetate and H2O, and the organic layer was dried over Na2SO4 and was evaporated in vacuo. The residue thus obtained was dissolved in methanol (8 mL) and was hydrogenated (balloon) over 10% Pd-C in the presence of 4 drops of concentrated HCl overnight at room temperature. The catalyst was filtered off (Celite), and the filtrate was evaporated in vacuo. The residue was taken up in ether (20 mL) and was extracted with 1N HCl (3×10 mL). These acidic extracts were then basified to pH 10 with 2N NaOH and were extracted with ethyl acetate (3×10 mL). Drying over Na2SO4, followed by evaporation in vacuo, yielded Example 65B, 158 mg (48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.56 (m, 1H), 6.66 (m, 1H), 6.48 (m, 1H), 3.81 (m, 1H), 2.02 (m, 2H), 1.35 (s, 3H), 1.20 (s, 3H). MS (ESI) m/z 196 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:26])[CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[N:27]([Si](C)(C)C)=[N+:28]=[N-:29].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:26])[CH2:10][CH2:11][CH:12]2[N:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[N:27]=[N:28][NH:29][N:25]=3)[C:14](=[O:17])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1cccc(F)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C1CCC(CCC(O)Cc2cccc(F)c2)N1CCCCCCc1nn[nH]n1
Yield: 64.2 %

Procedure:
Following the procedure described for Example 6, Step C, 7-{2-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (141.3 mg, 0.392 mmol) was reacted with azidotrimethylsilane (0.210 mL, 1.57 mmol) and dibutyltin oxide (29 mg, 0.116 mmol) in toluene (8 mL) heated under reflux for 72 h. Purification by medium pressure chromatography (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2) provided the title compound of Example 5C (101.5 mg). 1H NMR (CDCl3) δ7.26 (m, 1H), 6.94 (m, 3H), 3.87 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H), 2.98 (m, 3H), 2.78 (m, 2H), 2.48 (m, 2H), 2.20 (m, 1H), 1.89-1.24 (m, 14H); MS 404.2 (M+1), 401.9 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.[Br:11]Br>C(Cl)Cl>[Br:11][CH:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: BrBr
Reactant: CC1(C)CC(=O)C(C)(C)O1
Solvent: ClCCl
Product: CC1(C)OC(C)(C)C(Br)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of commercially available 2,2,5,5-tetramethyldihydrofuran-3(2H)-one (Aldrich, 10.0 g, 0.07 mol) in CH2Cl2 (100 mL) was added bromine (Aldrich, 3.6 mL, 0.07 mol,) dropwise at room temperature. The reaction mixture was stirred for 2 hours over which time the reaction mixture became clear. Then, the reaction mixture was cooled to 0° C., quenched with NaHCO3 powder in small portions, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.26 (s, 3H), 1.27 (s, 3H), 1.30 (s, 3H), 1.39 (s, 3H), 5.22 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:27]([OH:29])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH:38]([OH:41])[CH2:39][NH2:40])([CH3:33])([CH3:32])[CH3:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:27]([NH:40][CH2:39][CH:38]([OH:41])[CH2:37][NH:36][C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:42])=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.20 g (0.50 mmol) of N2,N5-bis[(benzyloxy)carbonyl]-L-ornithine and 0.124 g (0.65 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.124 g (0.65 mmol) of EDC and 0.02 g (0.15 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.Br[CH2:25][CH2:26][O:27][CH3:28]>>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][N:20]([CH2:25][CH2:26][O:27][CH3:28])[C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1
Reactant: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1
Reactant: COCCBr
Product: COCCn1ccc(-n2c(C)nc(C#Cc3cccc(C)c3)c2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=362.3 (M+H+), was prepared in accordance with the general method of example 3 from 4-[2,5-dimethyl-4-m-tolylethynyl-imidazol-1-yl]-1H-pyridin-2-one and 2-bromoethyl-methylether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].[CH2:15]([N:33]=[C:34]=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:15]([NH:33][C:34]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:9][CH3:10])[O:11][CH3:12])=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CO[Si](CCCNCCN)(OC)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCNCCC[Si](OC)(OC)OC
Temperature: 25 °C

Procedure:
To 22.2 g (0.10 mole) of 3-(2-aminoethylamino)propyltrimethoxysilane under nitrogen was added 29.5 g (0.10 mole) of octadecylisocyanate over a 45 min. period. The reaction temperature rose to ca. 70° C. Upon cooling to ambient temperature, the product solidified to a white wax. IR (neat film) 3300, 2900, 1620, 1570, 1470, 1090 cm-1. NMR (CDCl3) 0.4-1.0 (m; 5H), 1.1-2.0 (m; 34H), 2.4-2.8 (m; 2H), 2.9-3.4 (m; 7H), 3.55 (s; 9H), 5.5 (br s; 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.[Br:22][CH2:23][CH2:24]Br>CN(C=O)C.O>[Br:22][CH2:23][CH2:24][N:17]1[C:16](=[O:19])[N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]2=[N:18]1
Reactant: BrCCBr
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCBr)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Temperature: 95 °C

Procedure:
6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (synthesized according to Example 1, 500 mg, 1.69 mmol) was dissolved in 5 ml DMF and 1,2 dibromoethane (1.0 mL, 11.8 mmol) was added. The reaction was heated to 95° C. overnight. The reaction was cooled, diluted with water/EtOAC and the layers were separated. The organic layer was washed with NaHCO3. The organics were dried (MgSO4), filtered, concentrated and purified by flash chromatography (Rf=0.46, 1:1 hexanes:EtOAc) to afford 2-(2-bromoethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. To a solution of 2-(2-bromoethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.124 mmol) in 1 mL DMF was added K2CO3 (51 mg, 0.372 mmol) and 4-phenyl-1H-imidazole (36 mg, 0.249 mmol) and the reaction was heated to 85° C. for 24-72 hours until the SM was consumed. The reaction was concentrated and purified by reverse phase HPLC to afford compound 100 (24 mg, 41%). GS-490257. C24H18F3N5O2, m/z (ESI)=466.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:40][Mg]Br>O1CCCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:28][CH2:29][CH2:30]1)([OH:26])[CH3:40])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCC2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(cyclobutyl)methanone (Preparation 29, 28 mg; 0.050 mmol) in tetrahydrofuran (0.5 mL) was added methylmagnesium bromide (50 uL; 0.15 mmol; 3.0M in diethyl ether). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with 2 drops water and 1 drop aqueous 2N hydrochloric acid. The mixture was diluted with ethyl acetate and filtered over a column containing silica gel and sodium sulfate. The crude was purified over 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-50% ethyl acetate in heptane) to give 22 mg (76% yield) of the title compound as a colorless gum. MS (ES−): Calc: 581.4, Found: 580.6 (M−H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.74 (s, 2H), 7.42 (d, 1H), 7.41 (s, 1H), 7.33 (d, J=9.13 Hz, 1H), 5.27(d, J=16.60 Hz, 1H), 5.15 (d, J=16.18 Hz, 1H), 4.85 (s, 2H), 4.18 (s, 3H), 2.97 (m, 1H), 2.12-1.69 (m, 6H), 1.43 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.[N:12]1([CH2:21][C:22]2[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=2)[C:25](OCC)=[O:26])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1>>[CH:1]1([NH:7][C:25](=[O:26])[C:24]2[CH:30]=[CH:31][CH:32]=[C:22]([CH2:21][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(Cn2cnc3ccccc32)c1
Reactant: NC1CCCCC1
Agent: C[Al](C)C
Product: O=C(NC1CCCCC1)c1cccc(Cn2cnc3ccccc32)c1

Procedure:
N-Cyclohexyl 3-(1H-benzimidazylmethyl)benzamide was prepared by the method of example 9 starting with cyclohexylamine and reacting with trimethylaluminium and ethyl 3-(1H-benzimidazylmethyl)benzoate.