Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:9](=[O:18])[N:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O.CN([CH:31]=[O:32])C>>[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([CH:31]=[O:32])[C:9](=[O:18])[N:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: Cn1c(-c2ccncc2)cc(=O)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(-c2ccncc2)c(C=O)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a 25 ml round-bottom flask with stirbar was added N,N-dimethylformamide (10.0 ml, 130 mmol). The flask was cooled in an ice water bath, and phosphorous oxychloride (4.2 ml, 45 mmol) was added. The reaction was warmed to room temperature and stirred under nitrogen. After 50 minutes, this was transferred, first via syringe and then pipette, to a solution of 1-methyl-2-phenyl-5-(pyridin-4-yl)-1,2-dihydropyrazol-3-one (3.31 g, 13 mmol) in DMF (18 ml). The flask was placed in a preheated oil bath (120 C), stirred for 12 minutes, and then cooled to room temperature. The reaction was poured into a aqueous solution of 5 N NaOH (40 ml) and diluted with ice water (˜75 ml). More ice and water were added. The aqueous phase was extracted with chloroform and the organic extracts were dried over sodium sulfate, filtered, and concentrated. DMF present, so the crude material was diluted with chloroform and washed with water. The aqueous extractions were extracted with chloroform, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give the crude product. MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C16H13N3O2: 279. Material taken to next step without further purification.
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][N:16](C([O:21][CH2:22][C:23]3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.O.C([OH:32])C>C(O)(=O)C.[C].[Pd]>[C:22]([OH:32])(=[O:21])[CH3:23].[NH:16]1[CH2:15][CH2:14][CH:13]([C:1]2[N:2]=[N:3][N:4]3[C:9]=2[C:8]2[CH:10]=[CH:11][NH:12][C:7]=2[N:6]=[CH:5]3)[CH2:18][CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: c1cc2c(ncn3nnc(C4CCNCC4)c23)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
5% Palladium-carbon (0.87 g) was added to benzyl 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (4.88 g, 13.0 mmol) obtained in Synthetic Examplea 26 in a mixture of acetic acid (60 mL), water (6 mL) and ethanol (10 mL), and after then the reaction system was flushed with hydrogen, the reaction mixture was stirred at room temperature for one day and then filtered. The filtrate was concentrated, and the resulting yellow solid was washed with ethanol to give the title compound as a colorless solid (3.30 g, yield 84%).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([OH:31])[CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][CH2:40]C)(=O)[CH2:36]O>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([O:31][CH2:36][CH2:35][O:39][CH3:40])[CH:30]=2)=[CH:33][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)c(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CO
Product: COCCOc1cc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Br

Procedure:
The product from example 63F was processed as described in Example 62A substituting 2-methoxyethanol for ethyl glycolate to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C@@H:14]3[C@@H:17]([CH3:18])[C:16](=[O:19])[N:15]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:28]>C1COCC1>[NH2:28][C:16](=[O:19])[C@H:17]([CH3:18])[C@H:14]([NH:15][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]1[N:13]=[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][N:9]2[CH:11]=1
Reactant: C[C@H]1C(=O)N(C(=O)OC(C)(C)C)[C@@H]1c1cn2cc(C(C)(C)C)ccc2n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](C(N)=O)[C@H](NC(=O)OC(C)(C)C)c1cn2cc(C(C)(C)C)ccc2n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(2S,3R)-tert-butyl 2-(6-(tert-butyl)imidazo[1,2-a]pyridin-2-yl)-3-methyl-4-oxoazetidine-1-carboxylate (Preparation 38) was dissolved in THF (10 mL) and excess 28% aqueous ammonium hydroxide solution (ca 3 mL) added. The reaction was stirred in a sealed vial at 50° C. for 18 hours. The solvent was removed in vacuo to afford 311 mg of the title compound.
Reaction SMILES: [N:1]1([C:7]2[S:11][N:10]=[C:9]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[S:11][N:10]=[C:9]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: C1CN(c2nc(C3CCOCC3)ns2)CCN1
Reactant: Cc1ccccc1CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccccc1CN1CCN(c2nc(C3CCOCC3)ns2)CC1
Temperature: 180 °C

Procedure:
A mixture of 5-(piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1,2,4-thiadiazole (19.1 mg, 75.0 μmol), 1-(chloromethyl)-2-methylbenzene (31.6 mg, 225 μmol) and DIPEA (96.9 mg, 131 μL, 750 μmol) in N-methyl-2-pyrrolidinone (1 mL) was heated under microwave irradiation for 10 min at 180° C. The resulting reaction solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield, after evaporation of the product containing fractions 13 mg (48%) of the title compound. MS (m/e): 359.2 (MH+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Mg].[CH3:9][O:10][C:11](=O)[O:12]C>C1COCC1>[CH3:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:11]([O:10][CH3:9])=[O:12]
Reactant: Cc1ccsc1Br
Reactant: COC(=O)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
2-Bromo-3-methylthiophene (10.0 g, 0.0565 mol) was slowly added dropwise over a 60 minute period to a slurry of magnesium turnings (1.72 g, 0.0706) in THF. During the course of the addition, the exotherm was controlled to <40° C. by external cooling with a water bath. After the addition was completed, the resulting mixture was stirred at ambient temperature for 60 minutes. Dimethylcarbonate (7.63 g, 0.0847 mol) was then added dropwise over a 5-minute period, and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was quenched by the addition of 6 M HCl (50 mL), and extracted with ethylacetate (100 mL). The organic phase was washed with water (25 mL), followed by saturated aqueous NaHCO3. Concentration of the organic phase then gave 7.38 g (84%) of methyl 3-methyl-2-thiophenecarboxylate as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:25])=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[N:7]=1
Reactant: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1-c1ccnc(Cl)n1
Reactant: NCCc1ccc(O)cc1
Product: COc1ccc(CN2CCNC[C@@H]2C)cc1-c1ccnc(NCCc2ccc(O)cc2)n1

Procedure:
Intermediate 146 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 434. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H) 7.8 (s, 1H) 7.3 (d, 1H) 7.1 (m, 3H), 6.6 (m, 3H), 3.9 (s, 3H) 3.6 (m, 4H) 3.5 (d, 2H) 3.43-3.37 (m, 2H) 3.2 (m, 2H) 2.8 (t, 2H), 1.5 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:10]([F:21])[CH:9]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([F:21])[CH:9]=2)=[N:6][C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4][N:3]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]
Reactant: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)O)c(F)c2)n1

Procedure:
To a solution of ethyl 5-amino-6-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyrazine-2-carboxylate (0.253 g, 0.7 mmol) in DCM (4 mL) at RT was added TFA (2.157 mL, 28.0 mmol). The resultant solution was stirred at RT for 2 hours. The reaction solution was concentrated and further dried to afford the crude desired product as a TFA salt. This product was directly used at the next step. 0.214 g (100% yield) of light sticky liquid was obtained. LC-MS (m/z): 306.1 (MH+), 0.563 min.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>CN(C)C=O>[CH2:4]([O:5][C:6]([C:8]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[O:14])=[O:7])[CH3:3]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CCOC(=O)C(C)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(CC2(C(=O)OCC)CCCCC2=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a mixture of 9.6 g of 50% sodium hydride and 200 ml of dimethyl formamide was added dropwise 34 g of ethyl 2-cyclohexanone carboxylate under ice-cooling, the mixture was stirred at 50° C. for 30 minutes, thereafter again under ice-cooling 45.3 g of ethyl 2-(p-chloromethylphenyl)propionate was added dropwise, and the mixture was heated at 50°-60° C. with stirring for 1 hour. After the reaction was completed, the reaction mixture was poured into an ice-water, extracted with ether, the extract washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 69.5 g of an oily substance, which was subjected to a vacuum distillation affording 57 g of the dsired compound as a colorless oily substance, b.p. 200°-205° C. at 0.4 mm Hg.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14](Cl)=O.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:14]([C:13]3[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:12]=3[F:11])[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1c(F)ccc(F)c1F
Agent: N
Product: Fc1ccc(F)c(-c2nc(-c3ccnnc3)no2)c1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 2,3,6-trifluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.28-7.37 (m, J=9.5, 9.5, 3.7, 2.4 Hz, 1H), 7.67-7.79 (m, J=9.6, 9.6, 8.7, 4.9 Hz, 1H), 8.39 (dd, J=5.3, 2.2 Hz, 1H), 9.46 (dd, J=5.3, 1.2 Hz, 1H), 9.88 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z=279 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: NC1CCCCC1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 108.7 %

Procedure:
To a suspension of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (3.05 g, 10.71 mmol) in CH2Cl2 (50 mL) at room temperature was added Hunig's base (2.70 mL, 15.43 mmol, 1.3 equiv) and cyclohexylamine (1.60 mL, 14.2 mmol, 1.2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (4.96 g, 13.1 mmol, 1.1 equiv) in one portion, and the resulting suspension was stirred in the ice bath for 30 minutes. LCMS showed conversion complete. The mixture was diluted with CH2Cl2 (50 mL) and filtered through celite. The filtrate was washed water (2×25 mL) and then brine. The organic was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 50% EtOAc in CHCl3 afforded the title compound (4.26 g) as a foam. LC-MS (ES) m/z=366 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:3][CH2:4][C:5]2[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=c1[nH]cccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccc[nH]c1=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 14.94 %

Procedure:
In Example 2, 0.0725 g of 60% sodium hydride (NaH) was dispersed in mineral oil (1.60 mmol) and was suspended in 40 mL of THF in a 100 mL RBF under the presence of argon gas. Then, 0.2003 g (1.60 mmol) of 3-(hydroxymethyl)pyridine-2(1H)-one was added slowly and the solution stirred for 30 min with gentle heating before 0.250 mL (2.08 mmol) of 4-fluorobenzoyl chloride was added dropwise. The reaction was allowed to stir with gentle heating and for 48 hours. The reaction was quenched with the addition of 20 mL of water. The reaction was washed with ethyl acetate (4×20 mL) and the organic layers combined. The organic layer was washed with brine (3×20 mL) and dried over MgSO4. The solvent was evaporated in vacuo to produce a white solid. The product was purified by crystallization from toluene. The yield of the reaction was 0.0590 g (14.94% yield). MP: 170-173° C. IR (cm−1): 3415.21 (m, broad), υ (O—H), 3125.47 (m, broad), υ (N—H), 1716.90 (m), υ (C═O), 1614.44 (m), (C═C aromatic). 1H NMR (DMSO-d6, 500 MHz) δ: 5.13 (s, 2H), 6.23 (t, J=6.6 Hz, 1H), 7.37 (t, J=8.9 Hz, 2H), 7.41 (dd, J=4.5, 2.1 Hz, 1H), 7.59 (dd, J=4.7, 2.1 Hz, 1H), 8.06 (t, J=7.7 Hz, 2H), 11.78 (s, 1H).
Reaction SMILES: [Li]CCCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].FC1C([O:20][C:21](=O)[C@@H:22]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=C(F)C(F)=C(F)C=1F.[NH4+].[Cl-]>C1COCC1>[C:31]([O:30][C:28](=[O:29])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21](=[O:20])[CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Cc1ccccn1)C(C)(C)C
Temperature: -40 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
The reaction was carried out under argon in flame dried apparatus. n-BuLi (1.6 M in hexanes, 11.3 mL, 18.1 mmol) was added dropwise to a cooled (−40° C.) solution of 2-picoline (1.64 mL, 16.6 mmol) in THF (30 mL). When addition was complete the solution was stirred at −40° C. for 1 hour before cooling to −78° C. A solution of 2(S)-tert-butoxycarbonylamino-3,3-dimethyl-butyric acid pentafluorophenyl ester (3.00 g, 7.6 mmol) in THF (30 mL) was added via a cannula, maintaining the reaction temperature below −65° C. After stirring for 1 hour at −78° C. saturated NH4Cl solution (10 mL) was added and the reaction mixture was allowed to warm to room temperature before it was partitioned between EtOAc (200 mL) and saturated NH4Cl solution (200 mL). The organic extract was washed with water (200 mL) and brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 25% Et2O in hexanes) to give the title product as a bright yellow solid (1.01 g, 44%).
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]1
Reactant: CCOC(=O)c1cn(CO)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCl)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
The obtained 1-hydroxymethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole was dissolved to 3 ml of chloroform, and 4 ml of thionyl chloride was added, followed by refluxing for 30 minutes. After the reaction mixture was cooled to 0° C., it was poured into ice-water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 225 mg of 1-chloromethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:35][CH2:36][O:37]C)[N:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]3[N:26]=[CH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl.C(#N)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:35][CH2:36][OH:37])[N:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]3[N:26]=[CH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1cc2ccccc2cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC#N
Product: Nc1nc2ccccc2c2c1nc(CCO)n2CCCNC(=O)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Boron tribromide (5.50 mL of 1 M in dichloromethane) was added dropwise to a chilled (0° C.) suspension of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}isoquinoline-3-carboxamide (1.0 g, 2.2 mmol; U.S. Pat. No. 6,756,382, Example 192) in dichloromethane (20 mL). The reaction mixture was stirred at 0° C. for 45 minutes and then allowed to warm to ambient temperature. After 5 hours the reaction mixture was concentrated under reduced pressure and the residue was allowed to stand over the weekend. The residue was diluted with methanol (20 mL) and then heated to 50° C. Hydrochloric acid (about 10 mL of 6 N) was added and the mixture was stirred for about 2.5 hours. The mixture was made basic with aqueous sodium hydroxide and then extracted with ethyl acetate (×2). The combined extracts were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide a white solid. This material was suspended in hot acetonitrile, allowed to cool, and then the solvent was decanted. The resulting material was dried under vacuum to provide about 400 mg of N-{3-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}isoquinoline-3-carboxamide as a white solid, mp 245-246° C. Anal calcd for C25H24N6O2: % C, 67.73; % H, 5.59; % N, 18.80. Found: % C, 67.38; % H, 5.54; % N, 18.84.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[CH3:7][N:6]1[C:2]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Product: Cn1ncc([N+](=O)[O-])c1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 97 %

Procedure:
Following the procedure for Example 230, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate gave (S)-tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate as a pale yellow oil (0.35 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.15-4.85 (m, 1H), 3.84-3.72 (m, 2H), 3.69 (s, 3H), 3.41 (d, J=14.2 Hz, 1H), 3.30-3.13 (m, 1H), 2.11-2.02 (m, 1H), 1.94-1.82 (m, 2H), 1.63-1.52 (m, 1H), 1.42 (s, 9H)
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14]2)[C@H:10]([CH2:24][OH:25])[CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[C:20]([O:19][C:17]([NH:16][C:13]1([C@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[CH2:24][OH:25])[CH2:14][CH2:15]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2CO)CC1
Reaction time: 24 h
Yield: 95 %

Procedure:
cis-1-Benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-hydroxymethylpyrrolidine (820.1 mg, 2.376 mmol) was dissolved in methanol (50 ml). After adding a 5% palladium-carbon catalyst (moisture content: 55.6%, 750 mg), the mixture was stirred under elevated hydrogen pressure (4.5 kg/cm2) over a period of one day and night. After filtering off the catalyst through celite (washed with methanol), the filtrate was concentrated under reduced pressure to obtain 578.8 mg (91.0%) of the titlle compound as a white amorphous substance.
Reaction SMILES: [CH:1]1([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:1]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2]1)=[O:31]
Reactant: COC(=O)CC1CNCCc2ccccc21
Reactant: O=C(O)CCCCCCNc1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(C(=O)CCCCCCNc2ccccn2)CCc2ccccc21
Reaction time: 4 h

Procedure:
To a stirring solution of methyl 2-(1H,2H,3H,4H,5H-benzo[d]azepin-1-yl)acetate in dichloromethane (0.2 M) was added 7-(2-pyridylamino)heptanoic acid (1.2 eq), triethylamine (1.5 eq), and EDAC (2 eq). After 4 hrs, the reaction was washed with water, 10% sodium carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica; EtOAc) afforded a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[S:40][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][CH:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(OCC(=O)CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(OCc2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)s2)cc1OC
Temperature: 110 °C
Yield: 35 %

Procedure:
To a toluene (5 ml) solution of the compound (0.287 g) obtained in Example 19-(4), Lawesson's reagent (0.275 g) was added and the mixture was stirred at 110° C. for an hour. After reversion to room temperature, the reaction mixture was concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (0.100 g, colorless amorphous.)