Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOC[C@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 29.4 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 249a (407 mg, 1.0 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (800 mg, 2.0 mmol), K3PO4 (424 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (73 mg, 0.1 mmol), sodium acetate (164 mg, 2.0 mmol), acetonitrile (8 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (20 mL). The aqueous layer was separated and extracted with dichloromethane (20 mL×3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 249b (200 mg, 29%) as yellow solid. MS-ESI: [M+H]+ 680.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][NH:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:19]([CH3:20])[CH3:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: CN(C)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 36 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (182 mg, 0.67 mmol) and dimethyl amine using General Procedure G and isolated in 36% yield as a white solid. HPLC Rt=11.27 min; 1H NMR (400 mHz, CDCl3) 7.36-7.34 (m, 2H), 7.06 (dd, J=2.2, 8.4 Hz, 1H), 2.71 (bs, 6H), 2.29 (d, J=12.1 Hz, 2H), 1.68-1.53 (m, 7H), 1.25-1.21 (m, 2H); 13C NMR (100 mHz, CDCl3) 173.9, 146.9, 133.0, 130.9, 130.4, 127.4, 125.2, 51.0, 38.1, 36.7, 25.9, 23.6; GC-MS (SCOUT) 12.8 min, M+ 299.
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[F:16][C@H:17]1[CH2:21][NH:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCO>[C:27]1([CH2:26][O:25][C:24](=[O:33])[NH:23][CH2:22][C@H:18]2[C@@H:17]([F:16])[CH2:21][N:20]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][C:4]=3[F:15])[CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NC[C@@H]1CNC[C@@H]1F)OCc1ccccc1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](F)C3)c2n1
Yield: 34.2 %

Procedure:
To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.26 g, 1.28 mmole) in EtOH (5 mL) was added (±)-phenylmethyl {[cis-4-fluoro-3-pyrrolidinyl]methyl}carbamate (0.32 g, 1.28 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (0.20 g, 34%) as a light yellow foam: LC-MS (ES) m/e 457 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)[CH2:8][CH2:9][CH3:10].Cl.[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[NH2:32])[CH2:29]2.C(N(C(C)C)C(C)C)C>ClCCl>[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[NH:32][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([Cl:20])=[N:19][C:11]=1[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:29]2
Reactant: CCCCc1nc(Cl)ccc1C(=O)O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A solution of oxalyl chloride (0.105 mL, 1.20 mmol) in dichloromethane (2 mL) was added dropwise to a stirred suspension of 2-butyl-6-chloronicotinic acid (214 mg, 1.00 mmol), in dichloromethane (25 mL) over a period of 2 minutes under nitrogen. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was evaporated to dryness and dissolved in DCM (5 mL). This solution was added dropwise to a stirred solution of 2-adamantanamine hydrochloride (188 mg, 1.00 mmol) and N-ethyldiisopropylamine (0.693 mL, 4.01 mmol) in dichloromethane (20 mL) over a period of 2 minutes under nitrogen. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 mL), and washed sequentially with 0.1M HCl (20 mL), saturated NaHCO3 (20 mL), and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford N-adamantan-2-yl-2-butyl-6-chloronicotinamide (290 mg, 83%)
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:28]1(CN)CCCC1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH:6]([N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1CC1CCCC1
Reactant: NCC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C1CCCC1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)nc21
Yield: 36 %

Procedure:
1-Cyclopentylmethyl-6-quinolin-5-yl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one. A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)-pyrazin-2-ylamine (150 mg, 0.29 mmol), cyclopentylmethylamine hydrochloride (268 mg, 2 mmol), and triethylamine in ethanol (4 mL) was reacted and purified according to General Procedure E2 to give 25 mg (36% yield) of white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (dd, J=4.1, 1.6, 1H), 8.54-8.61 (m, 2H), 8.12 (d, J=8.2, 1H), 7.77-7.90 (m, 2H), 7.47-7.59 (m, 2H), 3.11-3.19 (m, 2H), 1.98-2.12 (m, 1H), 1.67-1.77 (m, 2H), 1.49-1.65 (m, 4H), 1.15-1.30 (m, 2H); MS (ESI) m/z 346.4 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:31][CH3:32])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(O)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Yield: 89.5 %

Procedure:
To a solution of 105 mg of 1-(4-tert-butoxycarbonylpiperazin-1-yl)-7-hydroxyisoquinoline in 10 ml of acetone, 93 mg of potassium carbonate and 55 mg of ethyl iodide were added and heated under reflux for 2 hours. Further adding 55 mg of ethyl iodide, the solution was heated under reflux for 2 hours, followed by addition of 48 mg of potassium carbonate and 55 mg of ethyl iodide, and an overnight's refluxing. Cooling the system off, the residue was extracted with ethyl acetate after addition of water, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:n-hexane=1:4) to provide 102 mg (90%) of 1-(4-tert-butoxycarbonylpiperazin-1-yl)-7-ethoxyisoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: CC(NC(=O)c1coc(Oc2ccc(C(F)(F)F)cc2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 68.5 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-trifluoromethyl phenol (43 mg, 0.26 mmol) to give the title compound (45 mg, 67%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:36]=[CH:35][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[C:29]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:65][C@H:63]([OH:64])[CH2:62][O:61][C:58]4[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=4)=[CH:36][CH:35]=3)[CH2:13][CH2:14]2)=[O:19])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: O=C(NCC(c1ccccc1)c1ccccc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 19.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,2-diphenylethyl)-1-piperidinecarboxamide formate (0.60 g, 1.2 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.496 g, 1.2 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.20 g, 0.236 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].P(Br)(Br)[Br:15]>C(Cl)Cl.O.[Cl-].[Na+].O>[Br:15][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COc1ccc(CO)cc1[N+](=O)[O-]
Reactant: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 191.1 %

Procedure:
(4-methoxy-3-nitrophenyl)methanol (215 mg, 1.174 mmol) was dissolved, under N2 atmosphere, in dry DCM and cooled to 0° C. PBr3 (55.4 μl, 0.587 mmol) was added, and the reaction was stirred RT for 1 hour. Ice and DCM were added to the reaction mixture. The mixture was diluted with WATER and brine and extracted twice with DCM. The organic layers were dried and evaporated to dryness to give 4-(bromomethyl)-1-methoxy-2-nitrobenzene (276 mg, 1.122 mmol, 96% yield) that was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](OC(C)=C)(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([O:8][N:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:11])[CH3:10]
Reactant: C=C(C)OC(C)=O
Reactant: ON=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)ON=C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 2.3 g (20 mmole) of cyclohexanone oxime, 2.0 g (20 mmole) of isopropenyl acetate, 0.9 g (2 mmole) of di(η5 -pentamethylcyclopentadienyl)samarium [Cp*2Sm(THF)2 ], and 20 ml of toluene was stirred at room temperature for one hour, and the precipitated crystals were filtered. 3.1 g of acetyloxyiminocyclohexane (O-acetylcyclohexanone oxime) (yield: 100%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][C:3]=1[CH2:14]O.P(Br)(Br)[Br:17]>ClCCl>[Br:17][CH2:14][C:3]1[CH:4]=[C:5]([CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CCN(CC)Cc1ccc(Cl)c(CO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {2-chloro-5-[(diethylamino)methyl]phenyl}methanol (3.0 g, 13.2 mmol) in anhydrous dichloromethane (80 mL) was added dropwise phosphorus tribromide (2.5 mL, 26.4 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was dried in vacuo, affording {[3-(bromomethyl)-4-chlorophenyl]methyl}diethylamine. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[OH:9][CH2:10][C:11]([C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])=[O:12].[OH-:21].[Na+]>[Ni]>[CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[O:21]=[C:19]([OH:20])[C@@H:17]([C@@H:15]([C@H:13]([C@@H:11]([CH2:10][OH:9])[OH:12])[OH:14])[OH:16])[OH:18]
Reactant: O=C(CO)[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)CC(C)(C)O
Product: O=C(O)[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO
Temperature: 0 °C
Yield: 84.8 %

Procedure:
A cylindrical vessel (diameter 12 cm., height 19 cm. with a stirrer, provided with a cylindrically-shaped stainless steel net as cathode surrounded at a distance of 7 mm. by an anode of sintered nickel plate (surface area 0.05 m.2), is filled with 1500 ml. of an aqueous solution of 130 g. (0.5 mole) of diacetone-sorbose and 60 g. (1.5 mole) of sodium hydroxide. At a temperature of 40° C. and a terminal voltage of 2.4 V, it is electrolyzed until 80 Ah have flowed through the reaction mixture. Thereafter, the reaction mixture is cooled to 0° C., mixed with 140 -145 ml. of 32% hydrochloric acid and the resulting precipitate is filtered with suction. After washing with 200 ml. of ice water and drying at room temperature, 124 g. of diacetone-ketogulonic acid, corresponding to a yield of 84.8%, is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][Al](C)C.CCCCCC.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Ag+2].[Cu]Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([CH3:54])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[C:34]([C:42]([F:43])([F:45])[F:44])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: C[Al](C)C
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: Cl[Cu]
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)N1c2ccc(C)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (250 mg) is dissolved in 1,4-dioxane (3 ml), and thereto are added a catalytic amount of tetrakis(triphenylphosphine)palladium, a catalytic amount of silver carbonate and a catalytic amount of copper (I) chloride under nitrogen flow. After adding dropwise trimethylaluminum-hexane solution (1M, 480 μl), the mixture is stirred at 60° C. for 30 minutes. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (153 mg). MS (m/z): 653 [M+H]+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g) and triphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was added diethyl azodicarboxylate (40% toluene solution, 2.88 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.69 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([OH:20])=[CH:10][N:9]=1.Br[CH2:22][CH:23]([F:25])[F:24]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([O:20][CH2:22][CH:23]([F:25])[F:24])=[CH:10][N:9]=1
Reactant: COc1ccc2c(Cl)ncc(O)c2c1
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c(Cl)ncc(OCC(F)F)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Potassium carbonate (659 mg, 4.77 mmol) was added to a solution of 1-chloro-6-methoxyisoquinolin-4-ol (500 mg, 2.385 mmol) and 2-bromo-1,1-difluoroethane (346 mg, 2.385 mmol) and stirred for 3 hrs at 50° C. After 3 hrs, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (2×) followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product 1-chloro-4-(2,2-difluoroethoxy)-6-methoxyisoquinoline (538 mg, 82%) as an orange solid. Crude material used as is in next step. MS: MS m/z 274.1(M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.CO.C(Cl)Cl>[C:20]1([CH2:26][CH2:27][CH2:28][C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12]3)=[O:10])=[CH:6][CH:7]=2)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C(CCCc1ccccc1)Nc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reaction time: 8 h

Procedure:
A solution of N-(4-aminophenyl)isoindoline-2-carboxamide (100 mg, 0.395 mmol), 4-phenylbutanoic acid (78 mg, 0.474 mmol), 1-hydroxybenzotriazole hydrate (66.5 mg, 0.434 mmol) and N-methylmorpholine (0.109 ml, 0.987 mmol) in dimethylformamide (1.771 ml) at room temperature was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (136 mg, 0.711 mmol). The mixture was stirred overnight and diluted with water (10 ml); the resulting suspension was filtered with water washes to give product with an impurity. This solid was suspended in 2% methanol/methylene chloride and filtered to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.78-2.00 (m, 2H), 2.30 (t, J=7.3 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 4.75 (s, 4H), 7.08-7.41 (m, 9H), 7.46 (s, 4H), 8.26 (s, 1H), 9.73 (s, 1H); (ESI(+)) m/e 400 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:23])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid (115 mg, 0.30 mmol), 1-methyl-piperazine (50.0 μL, 0.45 mmol), EDC (104 mg, 0.54 mmol) and HOBt (73.0 mg, 0.54 mmol) in DMF (5 ml) was stirred at ambient temperature for 14 h. The residue was reduced in vacuo, taken up in EtOAc and washed with water and brine, dried (MgSO4) and reduced in vacuo to give 2,6-difluoro-N-{3-[5-(4-methyl-piperazine-1-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (37 mg, 26%) as a pale yellow solid. (LC/MS: Rt 1.78, [M+H]+ 466.09).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([OH:18])=[CH:12][CH:11]=3)=[O:4].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1)=[CH:12][CH:11]=3)=[O:4]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccc(O)cc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc([N+](=O)[O-])cn3)cc12

Procedure:
In analogy to Example 8 from 6-hydroxy-β-carboline-3-carboxylic acid methyl ester and 2-chloro-5-nitropyridine, mp 150°-155° C.