Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:17])[C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[CH3:5][O:6][C:7](=[O:17])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][Cl:18])=[CH:14][CH:15]=1)([CH3:9])[CH3:16]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 110.9 %

Procedure:
MDC (600 ml) and aluminum chloride (347 gms) were charged to a reactor and chilled to −10° C. Methyl-2-methyl-2 phenyl-propanoate (Intermediate 4) (500 gms) was dissolved in MDC (650 ml) and added slowly through a dropper at −10 to 0° C. to obtain mixture A. MDC (600 ml) and aluminum chloride (520 gms) were charged to a different reactor, and chilled to −10° C. 4-chloro butyryl chloride (550 gms) was dissolved in MDC (650 ml) and added slowly through a dropper at −10 to 0° C. to obtain mixture B. Both mixtures A and B were stirred for 45 minutes at −10 to 0° C. separately. Mixture A was added to mixture B slowly at −10 to 0° C. and the reaction monitored by GC for completion (24 hours). The mass was quenched slowly in conc. HCl (1 ltr) at 10-20° C. and stirred for 30 minutes. The MDC layer was separated and the aqueous layer extracted with MDC (500 ml). The combined MDC layer was dried over sodium sulfate and concentrated under vacuum to obtain 880 gms of the title compound as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:15][C:14]([CH2:16][NH2:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[NH:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:23]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH3:24].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:15][C:14]([CH2:16][NH:17][C:25](=[O:26])[C@@H:23]([NH:22][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH3:24])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:18]([F:20])([F:21])[F:19])[CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: NCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a stirred solution of 23 (crude) (0.588 mmol) in CH2Cl2 (2.9 mL) at 0 degrees were added Boc-Ala-OSu (185 mg, 0.647 mmol) and triethylamine (0.18 mL, 1.3 mmol). The mixture was allowed to reach 21° C. slowly, stirring for 16 h at room temperature. The solvent was then evaporated. The mixture was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 24 (140 mg, 49%) as a white solid. LRMS (ESI): calc. 484.1; found 507.2 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35]>CN(C=O)C.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: COc1ccc(CCl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
80 g (250 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) was added in portions over 20 minutes to a mixture of NaH (19.98 g, 500 mmol) in anhydrous DMF (400 mL) at 0° C. under nitrogen. After the addition was complete the ice bath was removed and the mixture was stirred at rt for 1 hour before cooling the solution to 0° C. To the cooled solution was added a solution of 1-(chloromethyl)-2,4-dimethoxybenzene (107 g, 575 mmol) in benzene and the reaction mixture was allowed to warm to rt. After 16 hours the reaction mixture was poured into ice water (2 L) and extracted with EtOAc (3×1 L). The organics were pooled, washed with water (3×1 L), sat. aq. NaCl solution (1 L), dried (MgSO4), filtered and concentrated in vacuo to provide a thick yellow oil. Purification on the Combiflash XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) using four stacked 330 g columns and one 1.5 kg column and eluting with 35-40-45-50-55% EtOAc/hexanes provided a very pale yellow oil. This was dissolved in benzene and the solvent removed in vacuo and dried under vacuum for 2 days to provide the title compound as a white foam (105.8 g, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1)(=O)=O.C(N(CC)CC)C>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Yield: 20.8 %

Procedure:
A solution of 1-(4-pyridinyl)piperazine (1.63 g), N-[4-(2-methylsulphonyloxyethyl)phenyl]methanesulphonamide (2.93 g) and triethylamine (1.01 g) in ethanol (25 ml) was heated under reflux for 18 hours and then evaporated. The resulting oil was partitioned between dichloromethane and water (some insoluble material remained in the aqueous layer). The aqueous layer was washed with dichloromethane and the organic layers were combined, washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed in silica gel. Elution with dichloromethane/methanol (19:1) first gave some impurity followed by a solid which was crystallised from methanol/ethyl acetate to give the title compound (0.75 g), m.p. 208°-210° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[C:12]([C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][CH:18]=2)=[CH:15][N:16]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:26][CH2:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[N:16][C:11]([NH2:10])=[C:12]([C:27](=[O:28])[NH:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[N:13]=2)=[CH:18][CH:19]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(-c2ccc(CCCO)cc2)nc1C(=O)Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Dichloromethane (200 mL) and diisopropylethylamine (2 g, 17.16 mmol) were added to the product of step (vii) (4 g, 11.46 mmol). The resulting solution was cooled to 0° C. and MsCl (2 g, 17.16 mmol) added dropwise. When the addition was completed, the resulting solution was stirred at 0° C. for 10 minutes and at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane and washed with water (×3). The combined organic extract was dried over MgSO4, filtered and concentrated in vacuo, which afforded the subtitle compound (viii) as a yellow brown solid (4.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2cc(Cl)cc(Cl)c2)CCCCC1
Reaction time: 0.02 h
Yield: 79.1 %

Procedure:
To a solution of 2-(3,5-dichlorophenyl)acetonitrile (2 g, 10.75 mmol) in N,N-dimethylformamide (40 mL) at 0° C. was added 60% sodium hydride (0.946 g, 23.65 mmol) and the mixture was stirred for 1 min. Then 1,5-dibromopentane (1.464 mL, 10.75 mmol) was added, and the mixture was stirred at 0° C. for 1 hr and at room temperature for 14 hrs. About 100 mL of water was added, and the product was extracted with ethyl acetate. The extract was washed with water and brine. The combined aqueous layers were extracted with ethyl acetate once and washed with brine. The extracts were dried over sodium sulfate and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) by eluting with 5:95 EtOAc-hexane to give the desired 1-(3,5-dichlorophenyl)cyclohexanecarbonitrile (2.16 g, 79% yield) as a crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.38 (2H, d, J=1.76 Hz), 7.32 (1H, t, J=1.76 Hz), 2.14 (2H, d, J=11.86 Hz), 1.67-1.94 (8H, m).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:46])([CH2:43][CH2:44][CH3:45])[C:40](Cl)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:46])([CH3:38])[CH2:43][CH2:44][CH3:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCC(C)(C)C(=O)Cl
Product: CCCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 54.9 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 2.16 g (14.5 mmol) of 2,2-dimethylpentanoyl chloride, to provide 1.31 g of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=[O:23])C1C=CC=CC=1>CN(C)C=O.CCOCC.[Pd]>[OH:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=[O:23]
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1O
Yield: 154.3 %

Procedure:
A solution of 3.6 g (7.3 mmol) of 8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 0.7 g of 10% Pd/C in 240 mL of dimethyl formamide is hydrogenated in a Parr shaker at 40 psi for 24 hours. The catalyst is filtered through a pad of Celite, washed with dimethyl formamide and the solvent is reduced in vacuo to yield a solid. The crude product is suspended in ether, collected by filtration, further washed with ether and dried to yield 3.0 g of 8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH2:10][CH3:11].O>C1COCC1>[CH2:10]([N:3]1[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[N:5]=[CH:4]1)[CH3:11]
Reactant: Cc1nc[nH]c1C=O
Reactant: CCI
Solvent: O
Solvent: C1CCOC1
Product: CCn1cnc(C=O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol) and iodoethane (3.4 mL, 45.4 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added before THF was evaporated. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-1% MeOH/DCM), affording 1-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (730 mg, 12% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][OH:11].N1C=CC=CC=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:18][C:19]([C:29]([F:30])([F:31])[F:32])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:11][CH2:10][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])=[O:25])[C:22]1([CH3:28])[CH3:27]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OCc1c(F)cc(F)cc1F
Agent: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
A stirred solution of 1.5 grams (0.009 mole) of 2,4,6-trifluorophenylmethyl alcohol and 0.8 gram (0.01 mole) of pyridine in 30 ml of toluene was warmed to 50° and 2.4 grams (0.009 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride was added. The addition caused a solid precipitate to form in the reaction mixture. Upon completion of the addition of the carbonyl chloride, the reaction mixture was heated under reflux for two hours, then allowed to cool to ambient temperature as it was stirred for 16 hours. The reaction mixture was placed on a column of 100 grams of silica gel and eluted with toluene. The appropriate fractions were combined and concentrated under reduced pressure to a clear residual oil. The residual oil was distilled under reduced pressure using a Kugelrohr distilling system. The appropriate fractions were combined to give 0.4 gram of 2,4,6-trifluorophenylmethyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate as an oil; nD25 1.4681.
Reaction SMILES: CS(C)=O.[N+]([C:8]1[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=1)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of 5-nitro-2-thiophene carbonitrile (5.00 g, 32.4 mmol) were added 4-fluorophenol (5.45 g, 48.6 mmol) and potassium carbonate (11.2 g, 81.0 mmol) under nitrogen atmosphere, which was stirred for 16 hours at 60° C. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:10→1:5) to obtain the title compound (6.10 g, 85.9%).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:9][N:10]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:5]2[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:9][N:10]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(S(C)(=O)=O)nn1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2ncc(C(C)NC(=O)OC(C)(C)C)nn2)cc(OC)c1OC
Reaction time: 24 h
Yield: 49.3 %

Procedure:
To a stirred solution of tert-butyl 1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethylcarbamate (Intermediate 7) (2.0 g, 6.5 mmol) in tetrahydrofuran (50 mL) was added 3,4,5-trimethoxyaniline (1.8 g, 9.7 mmol) and 4-toluenesulfonic acid monohydrate (60 mg). After stirring for 24 hours, silica gel (10 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (50:50) using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give tert-butyl 1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethylcarbamate (1.3 g) as a white solid. 1H NMR (CDCl3): δ8.30 (s, 1H), 7.49 (br, 1H), 6.95 (s, 2H), 5.40-5.30 (m, 1H), 5.00-4.83 (m, 1H), 3.89 (s, 6H), 3.84 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.43 (s, 9H). MS m/z 406 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1>O1CCCC1.C(N(C(C)C)CC)(C)C>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=4)=[O:42])=[CH:3][C:4]=3[F:29])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (84.3 mg) in tetrahydrofuran (2.5 ml) were added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 5.02 ml) and diisopropylethylamine (0.218 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (34.0 mg, 28%) as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]=[CH:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].[CH3:24][N+:25]([O-:27])=[O:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH2:21][CH:20]([CH2:24][N+:25]([O-:27])=[O:26])[CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Reactant: C[N+](=O)[O-]
Product: CCOC(=O)c1c[nH]c2c1C(=O)CC(C[N+](=O)[O-])CC2
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (6.81 g, 21.3 mmol) is dissolved in CH3NO2 (50 ml), Triton B (40% aqueous, 2.5 mL) is added quickly. The reaction mixture was kept at 80° C. for 8 h. The mixture is cooled and the solvent removed under reduced pressure. The residue is taken into 50 ml CH2Cl2 and 25 ml H2O. The aqueous phase is adjusted to slightly basic with 1N HCl and sat. NaHCO3, and extracted with CH2Cl2 (30 mL×4). Organic phases are combined, dried (Na2SO4), and evaporated. Flash chromatography (1:1 hexanes/EtOAc) provides the title compound (5.6 g, 93%) as white solid. 1H NMR (400 MHz, CD3OD) δ 7.21 (1H, s), 4.45 (2H, d), 4.20 (2H, q), 2.97-2.62 (5H, m), 2.04 (1H, m), 1.65 (1H, m), 1.27 (3H, t). MS (ES+) 281 (M+1) Step 2: Dimethylaminomethyl4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][OH:21])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][O:21][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(O)cc1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(CO)c(F)cc12
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(OCc2nc3c(cc2F)c(=O)cc(Nc2ccccc2)n3-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (62 mg, 0.175 mmol) was dissolved in CH2Cl2 (1.2 mL). 4-methoxyphenol (22 mg, 0.175 mmol) was added followed by Ph3P (91.8 mg, 0.35 mmol), and ADDP (88.31 mg, 0.35 mmol). The reaction was left to stir overnight at room temperature under argon. Hexanes (5 mL) were added and the reaction was filtered. The filtrate was concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 7:3 to 9:1 EtOAc:Hex provided 2-anilino-6-fluoro-7-[(4-methoxyphenoxy)methyl]-1-phenyl-1,8-naphthyridin-4(1H)-one (30.0 mg, 37%) as a white solid: LCMS RT 2.87 min, MH+: 464.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20]([O:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26](F)[C:25]=1[N+:33]([O-:35])=[O:34])[CH:21]=[CH2:22]>C1COCC1.C(OCC)(=O)C>[CH2:20]([O:23][C:24]1[C:25]([N+:33]([O-:35])=[O:34])=[C:26]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:27]([F:31])=[C:28]([F:30])[CH:29]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 2-fluoro-4-iodo-phenylamine (1.1 g, 4.6 mmol) in THF (50 mL) was dropwise added LHMDS solution (6.0 mL, 6.0 mmol, 1 M in THF) at −78° C. After stirring for 1 h at −78° C., a solution of 1-allyloxy-3,4,5-trifluoro-2-nitrobenzene (1.2 g, 5.1 mmol) in THF (10 mL) was dropwise added into the reaction mixture. The reaction mixture was stirred at −78° C. for additional 1 h and brought to room temperature and stirred for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the solvent was removed under reduced pressure. The residue obtained was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was triturated with hexane to yield (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine as a yellow solid (900 mg). 1H-NMR (400 MHz, CDCl3): δ 4.62 (2H, d, J=4.8), 5.33-5.36 (1H, d, J=10), 5.48 (1H, d, J=17.2), 5.98-6.02 (1H, m), 6.22 (1H, dd, J=2.4, 9.6), 6.36 (1H, dd, J=2, 10.4), 7.04-7.08 (1H, m), 7.45-7.52 (2H, m), 7.79 (1H, s).