Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].[CH2:32]([C:36]1[N:37]([CH2:49][CH2:50][CH2:51][CH2:52]O)[C:38]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[CH:40][C:39]=2[N:48]=1)[CH2:33][CH2:34][CH3:35].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:32]([C:36]1[N:37]([CH2:49][CH2:50][CH2:51][CH2:52][O:20][N:21]2[C:22](=[O:31])[C:23]3[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:26])[C:38]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[CH:40][C:39]=2[N:48]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 36.5 %

Procedure:
Triphenylphosphine (21.2 g, 80.7 mmol) and N-hydroxyphthalimide (13.2 g, 80.7 mmol) were added to a solution of 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (16.0 g, 53.8 mmol) in tetrahydrofuran (200 mL). The mixture was stirred for five minutes and then was cooled to approximately 0° C. Diisopropyl azodicarboxylate (19.6 g, 96.8 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for three hours. An analysis by LC/MS indicated the presence of starting material, and the reaction was stirred at 60° C. overnight. An analysis by LC/MS indicated the presence of starting material, and additional triphenylphosphine, N-hydroxyphthalimide, and diisopropyl azodicarboxylate (26.9 mmol of each) were added to the reaction mixture. The reaction was stirred at room temperature for two hours and heated at reflux for three hours. The reaction was concentrated under reduced pressure, and the residue was dissolved in chloroform (200 mL). The resulting solution was washed with brine (3×150 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. An analysis of the crude product mixture by LC/MS indicated that starting material was still present. The mixture was dissolved in tetrahydrofuran (200 mL) and treated with triphenylphosphine (21.2 g, 80.7 mmol), N-hydroxyphthalimide (13.2 g, 80.7 mmol), and diisopropyl azodicarboxylate (19.6 g, 96.8 mmol) as described above. The reaction was stirred overnight at room temperature. The product was present as a white precipitate, which was isolated by filtration and washed with tetrahydrofuran to provide 8.68 g of 2-[4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:26][CH2:25][CH2:24][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Reactant: NCCN1CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)NCCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
A mixture of 3-(tert-Butoxycarbonylamino-methyl)-benzoic acid (500 mg, 1.99 mmol), 2-Pyrrolidin-1-yl-ethylamine (0.28 mL, 2.19 mmol), EDC (459 mg, 2.39 mmol), HOBt (323 mg, 2.39 mmol) and triethylamine (0.40 mL, 2.99 mmol) in DMF (10 mL) was stirred at ambient temperature for 15 h. The mixture was diluted with EtOAc (25 mL) and washed with water (25 mL) and NaHCO3 (25 mL). The aqueous mixture was extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the title compound (403 mg, 58%). m/z (M+1) 348.21.
Reaction SMILES: [Cl-].[Li+].O.[CH:4]([O-:6])=[O:5].[Li+].[Cl:8][C:9]1[CH:14]=[N:13][C:12]2[N:15]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:16]=[C:17](I)[C:11]=2[C:10]=1[CH:29]=[O:30].C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:8][C:9]1[C:10]([CH:29]=[O:30])=[C:11]2[C:17]([C:4]([OH:6])=[O:5])=[CH:16][N:15]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:12]2=[N:13][CH:14]=1
Reactant: O=C[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(C=O)c(Cl)cnc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)c(Cl)cnc32)cc1
Temperature: 52 °C
Yield: 74.9 %

Procedure:
Lithium chloride (1.05 g, 24.7 mmol) and lithium formate monohydrate (1.73 g, 24.7 mmol) were combined in a dry sealable tube under nitrogen. DMF (20 mL), 5-chloro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (3.8 g, 8.25 mmol), acetic anhydride (1.56 mL, 16.5 mmol) and palladium acetate (185 mg, 0.83 mmol) were added. DIPEA (2.87 mL) was added, and the reaction tube was sealed and heated at 52° C. for 3 h. The reaction mixture was taken up in MeOH/DCM (20%) and filtered to remove the insoluble black carbon material. The yellow solution was concentrated in vacuo, dissolved in MeOH/DCM (10%), and washed with aqueous HCl (0.1N). The aqueous layer was extracted with MeOH/DCM (10%, 2×). The organics were combined, dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (10-15% MeOH/DCM) gave the title compound as a light tan solid (2.34 g, 75%). 1H NMR (500 MHz, CD3OD) δ 3.15 (s, 3H), 8.24 (d, J=8.5 Hz, 2H), 8.81 (d, J=8.5 Hz, 2H), 9.17 (s, 1H), 9.38 (s, 1H), 11.81 (s, 1H). [M+H] calc'd for C16H11ClN2O5S, 379, 381; found, 379, 381.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:20][CH3:21])(=[O:19])[CH:15]=[CH:16][CH2:17][CH3:18].CC(C)([O-])C.[K+]>>[CH2:17]([C:16]1[C:15]([C:14]([O:20][CH3:21])=[O:19])=[CH:10][NH:11][CH:12]=1)[CH3:18]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCC=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCc1c[nH]cc1C(=O)OC
Yield: 63.7 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (10.1 g), methyl 2-pentenoate (6.01 g) and potassium tert-butoxide (7.01 g), a procedure as in Reference Example 39 was performed to give the title compound as pale-yellow crystals (yield 5.05 g, 64%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:7]=1.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:3]([CH2:2][NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[S:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: FC(F)(F)c1cccc(-c2csc(CCl)n2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NNCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.9 %

Procedure:
The compound (0.60 g) obtained in Example 103b was dissolved in N,N-dimethylformamide (3 mL), and tert-butyl hydrazinecarboxylate (1.45 g) and triethylamine (0.61 mL) were added. The reaction mixture was stirred at room temperature for 96 hr, and diluted with ethyl acetate and water. The ethyl acetate layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give tert-butyl 2-({4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)hydrazinecarboxylate (0.54 g) as a colorless solid. The solid was dissolved in 10% hydrogen chloride-ethanol (30 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (0.45 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][CH:3]=1.[NH2-].[Na+].ClC1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>C1C=CC=CC=1.C(O)CCC.Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: N#CCc1ccc(F)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCO
Product: Fc1ccc(Cc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 100 g (740 mmol) of 4-fluorophenylacetonitrile in 200 ml of benzene was added to a cooled (0° C.) slurry of 40 g (945 mmol) of sodium amide in 600 ml of the same solvent. After the addition was complete the solution was warmed to ambient temperature and stirred for one-half hour. The reaction mixture was again cooled to 0° C., 73.2 g (370 mmol) of solid 4,7-dichloroquinoline was added in increments, and the mixture was then stirred at ambient temperature overnight. Quenching with NH4Cl followed by workup gave the crude disubstituted acetonitrile, which was dissolved in 500 ml of n-butanol saturated with anhydrous HCl. The acidic solution was heated at reflux for 18 hours. The majority of the solvent was removed via distillation, and the residue was diluted with solvent, and washed with 10% NaOH. The organic layer was dried, and the solvent was removed in vacuo. Purification via HPLC gave 67 g of the title product. Yield: 67%.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)#[N:2].[H][H]>N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(C#N)c1CNc1cccn2c(C)c(C)nc12
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: Cc1cccc(CN)c1CNc1cccn2c(C)c(C)nc12
Yield: 12.3 %

Procedure:
To a solution of 8-(2-cyano-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.42 g, 1.44 mmol) in ammonia saturated ethanol/methanol (10/2.5)(30 ml) was added Raney nickel (50% in water)(0.45 g) The mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Following filtration through celite, the solvents were evaporated under reduced pressure and the residue was purified by by column chromatography on silica gel using methylene chloride:methanol (10:2) as eluent. Recrystallization from methylene chloride/ diethyl ether gave 0.052 g (12%) of the desired product.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:4][CH2:3][CH2:2]1.Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH2:18][CH3:19])[CH:9]=1>C1COCC1.[Zn+2].[Br-].[Br-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH2:18][CH3:19])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CCC1
Reactant: CCc1cc(Br)ccc1C(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1cc(C2CCC2)ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred mixture of ZnBr2 (33.5 g, 149 mmol, 4.00 equiv) in THF (350 mL) under nitrogen at 0° C. was added dropwise a solution of cyclobutylmagnesium bromide (148 mmol in 50 mL THF). After stirring at 0° C. for 0.5 h, the temperature was lowered to −78° C. and Pd(dppf)Cl2 (2.00 g, 2.73 mmol, 0.07 equiv) was added followed by the addition of a solution of methyl 4-bromo-2-ethylbenzoate (compound 181.2, 9.00 g, 37.0 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise at the same temperature. The reaction mixture was slowly allowed to reach ambient temperature and then stirred overnight. The reaction was carefully quenched with a saturated NH4Cl aqueous solution (100 mL). The resulting mixture was extracted with 500 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50) to furnish 8.00 g (99%) of the desired product as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](I)[CH2:26][CH3:27].[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH2:25][CH2:26][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To 110 mg (0.32 mmol) 4-benzyloxycarbonylamino-1-t-butoxycarbonylpiperidine from Step C and 0.16 mL (1.6 mmol) of n-propyl iodide in 2 mL of DMF under nitrogen was added 26 mg (0.65 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 16 h and was then poured into water and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 20% ethyl acetate in hexanes to afford 90 mg of title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=[C:6]([C:21]([NH:23][NH2:24])=[O:22])[CH:5]=1)[CH3:2].O.[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=O.C1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=[N:24][NH:23][C:21](=[O:22])[C:6]1[CH:5]=[C:4]([NH:3][CH2:1][CH3:2])[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[N:7]=1
Reactant: O=CC(F)(F)C(F)(F)F
Reactant: CCNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CC(F)(F)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
4-ethylamino-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.30 g, 0.00088 mol) was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.29 g, 0.00088×2.0 mol) and benzene, and further with a small amount of concentrated hydrochloric acid. The obtained mixture was refluxed and dehydrated for about 8 hours using a water separator. The obtained reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:36][CH2:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][C:6]=1[C:7]([NH:36][CH2:37][C:38](=[O:39])[NH:40][CH:41]([CH3:43])[CH3:42])=[O:9]
Reactant: CC(C)NC(=O)CN
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)CNC(=O)c1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-hydroxyanthranilic acid (7.6 g, 49.3 mmol) in DMF (100 mL) was added 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (EDC) (10.4 g, 54.2 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (7.3 g, 54.2 mmol), 2-amino-N-isopropyl-acetamide hydrochloride (INTERMEDIATE I.1) (7.5 g, 49.3 mmol) and N,N-diisopropylethylamine (DIEA) (9.50 mL, 7.0 g, 54.2 mmol). The reaction mixture was stirred at room temperature for 24 h, concentrated in vacuo to half of its volume and partitioned between diethyl ether (100 mL) and 1N HCl (aq.) (400 mL). The aqueous layer was extracted with diethyl ether (5×100 mL), and ethyl acetate (5×100 mL). The aqueous layer was then concentrated under high vacuum to dryness. The red residue was dissolved in ethanol (20 mL) followed by addition of dichloromethane (1 L). The resulting brown precipitate was filtered under vacuum and washed with a minimum amount of methanol to give the desired product 2-amino-5-hydroxy-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE I.1) hydrochloride salt as a white solid (5.7 g, 19.8 mmol, 40%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:24][C@H:25]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:26]([N:28]1[CH2:33][CH2:32][C:31]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:40][C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29][N:28]([C:26]([C@H:25]([NH:24][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=2)=[O:14])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:27])[CH2:33][CH2:32]1
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A round-bottomed flask was charged with 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.12 g, 0.36 mmol), (R)-2-amino-1-(4-hydroxy-4-phenylpiperidin-1-yl)-3,3-dimethylbutan-1-one (191 mg, 0.49 mmol), HOBT (61 mg, 0.40 mmol) and EDC (76 mg, 0.40 mmol). Then added DMF (1.6 mL) followed by N,N-diisopropylethylamine (0.12 mL, 0.68 mmol). The reaction mixture was stirred at room temperature over the weekend the quenched with water and extracted with diethyl ether (2×). The organic layers were combined and washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 12 g SiO2 with 0-60% EtOAc/heptane to afford 0.21 g (94%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]12([NH:35][C:27]([C:24]3[CH:25]=[CH:26][C:21]([S:18]([N:8]4[C:7]5[CH:32]=[CH:33][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:10]([CH:11]5[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]5)[C:9]4=[O:17])(=[O:19])=[O:20])=[C:22]([O:30][CH3:31])[CH:23]=3)=[O:29])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC23CC4CC(CC(C4)C2)C3)cc1OC
Yield: 42.2 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.5 g of the compound obtained in EXAMPLE 13, 0.3 g of 1-aminoada- mantane hydrochloride, 0.5 g of BOP, 2 ml of DIPEA and 25 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.27 g of the expected product after crystallization from an EtOH/iso ether mixture (80/20; v/v). M.p.=228° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 83.6 %

Procedure:
To 600 mg of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 15 mL of absolute ethanol was added 500 mg of 3-chloro-4-fluoroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 765 mg (83%) of 4-(3-chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile as yellow needles: melting point 108-111° C.; mass spectrum (m/e): M+H 316.8.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(F)c2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(F)c2)n1
Yield: 49.2 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-amine (1.24 mg, 5.32 mmol) and phenyl chloroformate (2.0 mL, 16.0 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-ylcarbamate (926 mg, 2.62 mmol, 49%). 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 7.79-7.23 (m, 8H), 6.38 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH3:45])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:44]([O:43][C:37]1[CH:36]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH3:42])[CH3:45]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OC
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Temperature: 85 °C
Reaction time: 10 h
Yield: 38.3 %

Procedure:
After adding 230 mg of 2-hydrazinopyrimidine and 293 μl of triethylamine to a 50 ml DMF solution containing 983 mg of {2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, the mixture was stirred at 85° C. for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of a methanol:THF=1:1 mixed solvent. After adding 420 μl of acetic acid and 657 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture which was then filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (400 mg) as a light yellow solid.