Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][CH2:10][O:11][C:12]([CH:14](Br)[CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:14]([CH3:15])[C:12]([O:11][CH2:10][CH3:9])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Yield: 25.8 %

Procedure:
A suspension of hydroquinone (12.2 g), ethyl DL-2-bromopropionate (10 g) and potassium carbonate (50 g) in methylethylketone (100 ml) was stirred under reflux for 5 hours. After removal of insoluble materials by filtration, the filtrate was concentrated by distillation. The residue was dissolved in ethyl acetate, washed with 5% aqueous hydrochloric acid and concentrated to remove ethyl acetate. The residue was purified by silica gel chromatography (eluent: 20% ethyl acetate : 80% n-hexane) to give ethyl 2-(4-hydroxyphenoxy)propionate (3.0 g). Yield, 26%.
Reaction SMILES: [NH:1]=[C:2]1[C:15](NC(NC(OC)=O)=S)=[C:14](CC2C=CC=CC=2)[C:13](Cl)=[C:4]([C:5](C2C=CC=CC=2)=O)[CH:3]1Cl.[OH-].[Na+].CI.N=[C:38]1[C:51]([NH:52][C:53](=[N:56][C:57]([O:59][CH3:60])=[O:58])[S:54][CH3:55])=[CH:50][CH:49]=[C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:42])[CH:39]1CC1C=CC=CC=1>CN(C)C=O.O>[NH:1]=[C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([CH2:5][C:43]2([C:41](=[O:42])[C:40]3[CH:49]=[CH:50][C:51]([NH:52][C:53](=[N:56][C:57]([O:59][CH3:60])=[O:58])[S:54][CH3:55])=[CH:38][CH:39]=3)[CH:44]=[CH:45][CH:46]=[CH:47][CH2:48]2)[CH2:3]1
Reactant: COC(=O)NC(=S)NC1=C(Cc2ccccc2)C(Cl)=C(C(=O)c2ccccc2)C(Cl)C1=N
Reactant: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)N=C(Nc1ccc(C(=O)C2(CC3=CC=CC(=N)C3)C=CC=CC2)cc1)SC
Reaction time: 2 h

Procedure:
To a solution of 3-imino(2,6-dichloro)phenylmethyl-4-(3-carbomethoxythioureido)benzophenone (2.43 g.; 0.005 mole) in dimethylformamide (100 ml.) is added water (5.0 ml.) and then sodium hydroxide (50% aqueous; 0.4 g.; 0.005 mole). The solution is stirred for 11/2 hours and then methyl iodide (0.71 g.; 0.005 mole) is added. The solution is stirred for one-half hour. The precipitate which forms is collected by filtration and dried to afford 1.3 g. of 3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p. 63°-68° C. (dec.).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18]Cl)[N:12]=[CH:11][N:10]=[C:9]2[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[CH:22]=1.[C:29]([O-:32])(=[O:31])[CH3:30]>CN(C=O)C>[C:29]([O:32][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:32][C:29](=[O:31])[CH3:30])[N:12]=[CH:11][N:10]=[C:9]2[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[CH:22]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCCl)c(OCCCl)cc23)c1
Agent: Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC(C)=O)c(OCCOC(C)=O)cc23)c1
Yield: 135.2 %

Procedure:
The title product of Example 29 (200 mg, 0.456 mmol) was treated with cesuim acetate (1.75 g, 9.12 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford an oil (277 mg) which was recrystallized from CH2 Cl2 /hexane. (184 mg; 90%; M.P. 137°-138° C.; LC-MS: 450 (MH+); anal. RP18-HPLC RT: 4.64 min.).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:14]([CH:15]([F:17])[F:16])=[CH:13][C:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:11][C:10]=12)=[O:5])C.[OH-].[K+].S(=O)(=O)(O)O>O.CO>[F:17][CH:15]([F:16])[C:14]1[N:9]2[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[N:11]=[C:12]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:13]=1
Reactant: CCOC(=O)c1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A mixture of 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (6.0 g, 15.6 mmol), potassium hydroxide 14 g (0.25 mmol) in water (62.5 ml) and methanol (125 ml) was stirred at room temperature for 2 h and at 60° C. for 1 h, cooled (ice-water), and 3N sulfuric acid (90 ml) was added. The formed precipitate (4.32 g) was collected by filtration, acetic acid (65 ml) was added and the stirred solution was heated under reflux conditions for 1 h. The reaction mixture was evaporated, ethyl acetate (30 ml) was added and the mixture was stirred for 30 min at 0° C. The precipitate was collected by filtration and dried to yield 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (2.15 g, 39%) as a yellow solid. MS (ISN) 356.0 [(M−H)−]; mp 238° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Methyl 5-benzyloxy-2-methoxybenzoate (3.72 g) was dissolved in a mixed solvent of THF (30 ml) and methanol (30 ml), and 1N aqueous sodium hydroxide solution (27.3 ml) was added to the mixed solution. The mixture was stirred at room temperature for 2 days, and 1N aqueous hydrochloric acid solution (40 ml) was added. The precipitate was collected by filtration and washed with water to give 5-benzyloxy-2-methoxybenzoic acid (3.10 g, 88%) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:34])[C:14](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][N:28]=[C:27]2[Cl:31])=[C:22]([O:32][CH3:33])[CH:21]=1)[CH2:15][CH2:16][CH2:17][Cl:18])(C)(C)C>>[Cl:18][CH2:17][CH2:16][CH2:15]/[C:14](=[CH:19]\[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][N:28]=[C:27]2[Cl:31])=[C:22]([O:32][CH3:33])[CH:21]=1)/[C:13]([OH:34])=[O:12]
Reactant: COc1cc(C=C(CCCCl)C(=O)OC(C)(C)C)ccc1-n1ccnc1Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1ccnc1Cl
Yield: 84.9 %

Procedure:
A trifluoroacetic acid (15 mL) solution of 5-chloro-2-(4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzylidene)valeric acid tert-butyl ester (1.35 g) was agitated under ice-cooling. The reaction solution was concentrated under reduced pressure after 2 hours. When the residue was purified in LC-MS, 0.99 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([NH:28][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of 5.0 g (22 mmol) 4-chloro-3-nitrobenzotrifluoride in 100 ml dimethylformamide was added 3.4 ml (24 mmol) triethylamine and 2.8 ml (23 mmol) cyclohexylamine. The reaction mixture was stirred at 80° C. for 2 h. After cooling to 25° C. the reaction mixture was evaporated in vacuo. The residue was stirred with 100 ml water and the precipitate was filtered off. Recrystallization (methanol) gave 3.9 g (61%) N-cyclohexyl-2-nitro-4-trifluoromethylaniline. M.p. 80.1° C., 1H-NMR (CDCl3): 8.4 (1H, s), 8.3 (1H, m), 7.5 (1H, dd), 6.9 (1H, d), 3.5 (1H, broad s).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([NH:14][C:15](=O)[CH3:16])[CH3:13])=[N:9][CH:10]=1)(=O)C.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:15]([NH:14][CH:12]([CH3:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][N:9]=1)[CH3:16]
Reactant: CC(=O)NC(C)Cc1ccc(OC(C)=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(C)Cc1ccc(O)cn1

Procedure:
To the solution of 0.39 g of 5-acetoxy-2-(2-acetylaminopropyl)-pyridine in 20 ml of anhydrous tetrahydrofuran, 3.6 ml of a 1 molar solution of alanetriethylamine in toluene are added dropwise while stirring at 0°. After 12 hours 22 ml of 2 N aqueous sodium hydroxide are added at 0°, and the mixture evaporated azeotropically with isopropanol. The residue is taken up in 50 ml of methanol, the pH of the solution adjusted to 8 with 5 N ethereal hydrogen chloride, the resulting salts filtered off, and the filtrate evaporated. The residue is triturated with isopropanol, to yield the 2-(2-ethylaminopropyl)-5-pyridinol melting at 75°-79°.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:22][CH:23]=[CH2:24].C(#N)C>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH2:24][CH:23]=[CH2:22])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCNc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]-piperazine (International Publication 88/08424, 2.78 g), 3-bromopropene (1.87 g), anhydrous potassium carbonate (3.3 g) and acetonitrile (100 ml) is refluxed for 36 hr. The mixture is cooled and then diluted with dichloromethane and aqueous potassium carbonate solution. The phases are separated and the organic phase is washed with saline and than concentrated in vacuo. Purification by flash column chromatography (2% methanol/chloroform) provided of the title compound. Capillary GC analysis (HP1 column, initial temperature at 100° for 1 min, then programmed to rise 20° per minute to 250° ) gave a peak at 6.06 (96%) minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:10]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].Cl[C:35]([O:37][CH3:38])=[O:36]>CC(C)=O>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][N:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:23][CH2:22]2)[C:10]=1[CH3:27]
Reactant: COC(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Cl)c2C)CC1
Temperature: 80 °C

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate (150 mg, 0.37 mmol), potassium carbonate (360 mg, 2.60 mmol) and methyl chloroformate (0.11 mL, 1.50 mmol) were added to acetone (3.0 mL). The slurry was heated in a microwave reactor at 80° C. for 3 h. The reaction mixture was concentrated and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×30 mL) and dried over MgSO4 to give methyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate. Mass Spectrum (ESI) m/e=356.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](C(O)=O)=[CH:8]2.C[N:17](C=O)C.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH2:17])=[CH:8]2
Reactant: CN(C)C=O
Reactant: COc1cccc2cc(C(=O)O)ccc12
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
5-Methoxy-2-naphthoic acid (3.17 g, 15.7 mmol), CH2Cl2 (38 mL) and DMF (3.04 mL, 39.2 mmol) were combined in a 50-mL flask under a N2 atmosphere. Oxalyl chloride (2.73 mL, 31.3 mmol) was added dropwise over 30 minutes at 20 to 23° C. The resulting yellow solution was stirred at room temperature for 15 minutes. The solution was then concentrated in vacuo to 6.48 g of yellow solid which was slightly wet with DMF. The solid was dissolved in CH3CN (157 mL) and added dropwise over 35 minutes to a solution of sodium azide (2.55 g, 39.2 mmol) in 24 mL of water, and rinsed in with an additional 25 mL of CH3CN. Analysis of the resulting yellow mixture by HPLC after 5 minutes showed 15% acyl chloride remaining. Water (15 mL) was added to give an orange mixture and to promote acyl azide formation. The mixture was heated at reflux for 1 hour and 40 minutes. The mixture was cooled to room temperature. Sodium hydroxide (50 mL, 2N solution) was added and the resulting yellow mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to 102.0 g of brown gum plus liquid. The mixture was extracted with 50 mL of CH2Cl2. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated in vacuo to provide 1.83 g of the intermediate title compound as a brown oil (HPLC: 91%, 61% yield).
Reaction SMILES: [I-].[Na+].[NH2:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[N:40][O:41][CH2:42][CH:43]=[CH2:44])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:17]([CH2:20]Cl)[CH2:18][S:19][C@H:14]23)=[O:11])[N:5]=1.[Cl-].[Na+].C(O[CH2:51][CH3:52])(=O)C>C(#N)C.[Ag]>[NH2:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[N:40][O:41][CH2:42][CH:43]=[CH2:44])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:17]([CH2:20][S:19]/[CH:18]=[CH:17]\[C:52]4[CH:51]=[CH:10][CH:9]=[CH:6][N:5]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:5]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reactant: CCOC(C)=O
Agent: [Ag]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3ccccn3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h

Procedure:
To a suspension of [(Z and E)-2-(2-pyridyl)vinylthio]silver (1.9 g) in acetonitrile (80 ml) was added sodium iodide (6.9 g) at ambient temperature. The mixture was stirred for 30 minutes at the same temperature. To this mixture was added a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (2.88 g) in acetonitrile (30 ml) under ice-cooling. The mixture was stirred for 1 hour at the same temperature. The insoluble material was filtered off. The filtrate was concentrated in vacuo to give a residue. The residue was dissolved in a mixture of ethyl acetate and a saturated aqueous solution of sodium chloride, and the mixture was stirred for 1 hour at ambient temperature. Sellaite was added to the mixture and the insoluble material was filtered off. The separated organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was subjected to a column chromatography on silica gel (175 g) and eluted with a mixture of ethyl acetate and n-hexane (3:1, V/V). The fraction containing the material having a larger Rf value in thin layer chromatography was combined and concentrated in vacuo to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(2-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1.58 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCO)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCCCCc1ccc(O)cc1
Yield: 42 %

Procedure:
To a stirred solution of 4-(4-methoxyphenyl)butanol (1 equiv.) in dry dichloromethane at −10° C. under an argon atmosphere was added boron tribromide (2.7 equiv., using a 1 M solution of boron tribromide in CH2Cl2). Stirring was continued at that temperature until completion of the reaction (4 hours). Unreacted boron tribromide was destroyed by addition of aqueous saturated NaHCO3 solution at 0° C. The resulting mixture diluted with CH2Cl2 and water, the organic phase was separated, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (30% diethyl ether-hexane) afforded the title compound in 42% yield.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:6]1[C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=1[O:39][CH3:40].[OH-].[Na+]>O1CCOCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:7]3[N:6]([C:29]4[CH:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:32]=[CH:31][C:30]=4[O:39][CH3:40])[CH:5]([CH2:4][C:3]([OH:41])=[O:2])[C:14]4[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=4)[N:8]=3)=[CH:21][CH:20]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3ccc(F)cc3)cc2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(c2ccc(-c3ccc(F)cc3)cc2)=Nc2c(F)cccc2C1CC(=O)O

Procedure:
Starting from 38.90 (0.07 mmol) of the ester from Example 20A, reaction in analogy to general method [E] with 8.24 mg (0.21 mmol) of sodium hydroxide in 10 ml of dioxane results in 29 mg (76% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].N1C=CC=CC=1.[N+:17]([C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:26](=[O:27])[CH:25]([O:24][C:23]1[CH:31]=[CH:32][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[CH2:29][CH3:30]
Reactant: CCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reactant: COc1ccccc1CN
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)NCc1ccccc1OC
Yield: 58.1 %

Procedure:
In 50 ml of toluene were dissolved 1.9 g (0.014 mole) of 2-methoxybenzylamine and 1.2 g (0.015 mole) of pyridine. Then, was added dropwise thereto a solution of 2.8 g (0.012 mole) of 2-(4-nitrophenoxy)-butyroyl chloride in 30 ml of toluene and the mixture was treated according to the same procedure as in Synthesis Example 7. The resultant crude crystals were recrystallized from ethanol to give 2.4 g of N-(2-methoxybenzyl)-2-(4-nitrophenoxy)-butyramide melting at 109°~112° C. as colorless needles.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.N1CCCCC1.CCOCC>C(O)C>[Br-:1].[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N+:14]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:25][CH:24]=1
Reactant: CCCCCCCCCCCC[n+]1ccccc1C
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC[n+]1ccccc1C=Cc1ccc(N(C)C)cc1
Yield: 50.7 %

Procedure:
1-Dodecyl-2-methylpyridinium bromide (3.42 g, 0.01 mole) and 4-dimethylaminobenzaldehyde (1.6 g, 0.011 mole) were refluxed in ethanol (15 ml) in the presence of piperidine (0.2 ml) under nitrogen for two hours. The solution was cooled and ether was added when an orange solid crystallised which was collected giving 2-[4-(dimethylamino)styryl]-1-dodecylpyridinium bromide quarter hydrate (2.4 g), melting point 197°-198° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[N:10]1.[C:16]([Cu])#[N:17]>CN1C(=O)CCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([N:9]2[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[N:10]2)[CH:4]=1
Reactant: Cn1cnn(-c2cc(F)ccc2Br)c1=O
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cn1cnn(-c2cc(F)ccc2C#N)c1=O
Yield: 78.5 %

Procedure:
A mixture of 1-(2-bromo-5-fluorophenyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (0.484 g, 1.78 mmol), CuCN (0.319 g, 3.56 mmol), and 8 mL of NMP was subjected to microwave irradiation at 120° C. for 3 h. The brown mixture was filtered over Celite® and washed with DMF. This solution was treated with 10% aqueous NH4OH (28-30% solution) and extracted with EtOAc. The combined organic fractions were successively washed with 10% aqueous NH4OH (28-30% solution), saturated aqueous NH4Cl, water, brine and dried over Na2SO4. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage column chromatography system on silica gel with hexanes:ethyl acetate (3:7 to 2:8) gradient as the eluent to afford the title compound as a pink solid (0.305 g, 79% yield): 1H NMR (400 MHz, CDCl3) δ 7.76 (1H, dd, J=8.8, 5.8 Hz), 7.72 (1H, dd, J=9.6, 2.5 Hz), 7.64 (1H, s), 7.10 (1H, ddd, J=8.7, 7.4, 2.7 Hz), 3.40 (3H, s); LCMS (+ESI, M+H+) m/z 219.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.ClC[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCCCl
Reactant: COc1nc(-c2ccccc2)nc2ccccc12
Product: CCOC(=O)CCCOc1nc(-c2ccccc2)nc2ccccc12
Yield: 88.6 %

Procedure:
According to the preparation of 69, ethyl 4-chlorobutyrate (1.36 g, 9.00 mmol) was used to yield 72 (1.34 g, 88.6%) as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]5([CH3:37])C[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[ClH:38]>O1CCOCC1>[ClH:38].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]5([CH3:37])[CH2:25][CH2:26][NH:27][CH2:28]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCNC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
tert-Butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpiperidine-1-carboxylate (103 mg, 0.20 mmol) was dissolved in 20 mL of a saturated solution of HCl (g) in dioxane and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 20% acetonitrile/80% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(3-methylpyrrolidin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride (30 mg, 36.5%) as a pale yellow solid. MS: (M+H)+=408; 1H NMR (300 MHz, DMSO): δ 9.16 (s, 1H), 8.57-8.41 (m, 4H), 7.92 (s, 1H), 7.75 (d, 1H, J=10.5 Hz), 7.32-7.26 (m, 1H), 6.98-6.93 (m, 1H), 5.75 (d, 2H, J=6.9 Hz), 4.19 (s, 3H), 3.16 (brs, 5H), 1.96 (brs, 3H), 1.61 (s, 3H).