Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:30]=1[NH2:31])(=[O:28])=[O:27].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CCOC(C)=O>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:31][C:30]1[CH:32]=[C:33]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH:34]=[CH:35][C:29]=1[S:26]([CH3:25])(=[O:28])=[O:27])=[C:3]([CH3:24])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:23])(=[O:22])=[O:21])=[N:5]2
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)cc1N
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1S(C)(=O)=O
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A screw-cap vial was charged with 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (50 mg, 0.136 mmol), 2-(methylsulfonyl)-5-morpholinoaniline (Matrix Scientific; 34.8 mg, 0.14 mmol), XPhos precatalyst (CAS 1028206-56-5; 10.0 mg, 0.014 mmol), sodium tert-butoxide (32.7 mg, 0.34 mmol), and toluene (1.5 mL). The mixture was stirred at 95° C. under nitrogen gas for 18 h. The reaction was then cond, and the resulting residue was dissolved in EtOAc. This solution was washed with water, and the product extracted twice with EtOAc and once with DCM. The combined organic layer was then dried over magnesium sulfate and cond, affording a crude residue that was purified by flash-chromatography (silica gel, 0-50% EtOAc in hexanes). This afforded 5,7-difluoro-3-methyl-N-(2-(methylsulfonyl)-5-morpholinophenyl)-2-(2-(methylsulfonyl)phenyl)quinolin-4-amine. Mass Spectrum (ESI) m/e=588.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (1H, br. s.), 8.20 (1H, d, J=8.0 Hz), 7.66-7.86 (3H, m), 7.50 (1H, br. s.), 7.45 (1H, d, J=7.4 Hz), 7.08 (1H, br. s.), 6.43 (1H, d, J=8.8 Hz), 6.04 (1H, br. s.), 3.72 (4H, t, J=4.6 Hz), 3.17-3.23 (4H, m), 3.16 (3H, s), 3.13 (3H, s), 1.94 (3H, s).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][C:12]1=[O:25])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>ClCCl>[C:1]([O:5][CH2:6][CH:7]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][C:12]1=[O:25])[C:8]([NH:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=1)=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1ccccc1OC1=CC(=O)N(C(COC(C)(C)C)C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N(C(COC(C)(C)C)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
A solution of 3-t-butoxy-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (100 mg, 0.29 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (45 mg, 0.29 mmol) and 1-hydroxybenzotriazole (40 mg, 0.30 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 50 mg, 0.32 mmol). The reaction mixture was then stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 3-t-butoxy-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (45 mg, 32%) as an off-white solid: LR-ES-MS m/z calculated for C25H34N4O6 [M]+ 486, observed [M+H]+ 487; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 6H) 1.12 (s, 9H) 3.64-3.78 (m, 2H) 3.81 (s, 3H) 3.89 (s, 2H) 4.15 (d, J=18.4 Hz, 1H) 4.45 (d, J=18.4 Hz, 1H) 4.67 (s, 1H) 4.73 (s, 1H) 4.80 (dd, J=7.1, 4.7 Hz, 1H) 6.43 (d, J=2.2 Hz, 1H) 6.94-7.09 (m, 1H) 7.13-7.39 (m, 3H) 7.53 (d, J=2.2 Hz, 1H) 10.64 (s, 1H).
Reaction SMILES: [NH2:1]N.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O.NN>C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:11]1[C:12](=[O:15])[NH:13][N:14]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[CH:10]=1
Reactant: O=c1ccc(-c2ccncc2)n[nH]1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: Oc1ccc(-c2ccncc2)nn1
Agent: [K+]
Solvent: O
Product: Nc1cc(-c2ccncc2)n[nH]c1=O
Yield: 69 %

Procedure:
The following procedure describes the preparation of the entitled compound by reacting hydrazine with 6-(4-pyridinyl)-3(2H)-pyridazinone, the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol. A mixture containing 10 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 70 ml. of hydrazine hydrate was heated on a steam bath for 3 days and the excess hydrazine distilled off in vacuo. The remaining residue was heated with about 300 ml. of methanol and the solid was collected by filtration. The solid was combined with the corresponding solid obtained from another run starting with 15.7 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 21 ml. of hydrazine hydrate and the combined solids were dissolved in aqueous potassium carbonate solution and reprecipitated by addition of acetic acid. The precipitate was dried for 9 hours at 40° C. over P2O5 and then overnight at 80° C. After its NMR spectrum had shown the solid still to contain acetic acid, it was next dried in a vacuum oven at 80° C. for 2 days to yield 18.2 g. (69% yield) of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. >300° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[OH:27]>O>[Br:1][CH2:2][CH2:3][CH2:4][O:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(OCCCBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-dibromo propane (1.3 mL, 12.65 mmol) and cesium carbonate (4.1 g, 12.65 mmol) was added to the DMF (18 mL) solution of 2-chloro-5-nitro phenol (2.0 g, 11.5 mmol) and the reaction mixture stirred overnight at room temperature. Water (20 mL) was added to the mixture, extracted with DCM (3×25 mL) and combined extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography to get the title compound 26a in 64% (2.176 g) yield as colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][O:10][CH2:11][O:12][CH3:13])=[C:4]([Cl:14])[N:3]=1.O.C(OCC)(=O)C>CN(C)C=O.C(N(CC)CC)C.C(O)=O.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>[Cl:14][C:4]1[C:5]([CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:6][C:7]([F:8])=[CH:2][N:3]=1
Reactant: COCOCc1cc(F)c(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOCc1cc(F)cnc1Cl
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of 0.62 g of 2,6-dichloro-3-fluoro-5-((methoxymethoxy)methyl)pyridine in 18 mL of N,N-dimethylformamide, 0.54 mL of triethylamine, 0.15 mL of formic acid and 0.15 g of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was stirred at 90 to 100° C. for 4 hours 30 minutes under a nitrogen atmosphere. Thereto were added water and ethyl acetate, the insoluble substance was filtered off, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=8:1 to obtain 0.39 g of 2-chloro-5-fluoro-3-((methoxymethoxy)methyl)pyridine as a colorless oily substance.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20]1([CH:26]=[CH:27][CH2:28]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]1([CH:26]=[CH:27][CH2:28][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCC=Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCC=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.200 g (1.5 mmol) of (3-phenyl)-allyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.21 g).
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([O:39]C)=[O:38])=[CH:34][CH:35]=4)[N:30]([CH3:41])[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1.Cl>CO.O.ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH:35]=4)[N:30]([CH3:41])[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:17])=[O:18])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Temperature: 45 °C
Yield: 92.4 %

Procedure:
Aqueous sodium hydroxide (9.0 liters of a 20% aqueous solution) was added to a stirred suspension of methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy4-methylphenyl)-sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate (from step (b), 5.0 kg) in methanol (25 liters) and demineralised water (20 liters). The suspension was warmed to 45° C. for 1.5 h, cooled to room temperature and diluted with dichloromethane (25 liters). The pH of the aqueous phase was adjusted to 3 with the addition of concentrated hydrochloric acid (7.0 liters) and the phases separated. The organic phase was concentrated to low volume and filtration of the precipitated product gave the subtitle compound as a white crystalline solid (4.5 kg, 92%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:25][C:24]1[C:19]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[N:20][CH:21]=[N:22][CH:23]=1
Reactant: Cc1cnc(Cl)nc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cncnc1NCC1CCNCC1

Procedure:
A mixture of 4-[(2-chloro-5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 59, 2.00 g, 5.34 mmol), Pd/C (10%, 0.20 g) in absolute ethanol (15 mL) was vigorously stirred under 1 atm H2. Filtered and concentrated, the reaction gave 4-[(5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine. M.S.(M+1):207.29
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH3:16][N:17]([CH3:22])[CH2:18][C:19](O)=[O:20].Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:16][N:17]([CH3:22])[CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottom flask with stirbar was charged with tert-butyl 4-aminophenylcarbamate (2.38 g, 11.43 mmol), 2-(dimethylamino)acetic acid (1.25 g, 12.12 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.59 g, 13.51 mmol) and 4-dimethylaminopyridine (0.05 g, 0.409 mmol) in dichloromethane (50 ml). The solution was stirred at ambient temperature for 2 hours. The mixture was shaken in a separatory funnel with 50 mL aqueous sodium bicarbonate, and the organics were separated and dried over magnesium sulfate and filtered. Solvent removal gave the title compound. MS (ESI(+)) m/e 294.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9](C)(C)C)=[O:7])#[CH:2].C(O)(C(F)(F)F)=O.OS(O)(=O)=O>C(Cl)Cl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)OC(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
tert-Butyl 3-ethynylbenzoate (I17) (1.50 g, 9.37 mmol) was dissolved in dry DCM (70 mL) and TFA (35.9 mL, 468 mmol) was added carefully. The reaction was stirred at room temperature for 3 hours, concentrated in vacuo and toluene was added and then removed in vacuo to give a pale yellow solid. This material was dissolved in methanol (50 mL) and conc. H2SO4 (˜1 mL) was added and the resulting solution was stirred at 65° C. for 20 hours. Upon cooling to room temperature, the volatiles were removed in vacuo and the residue was diluted with EtOAc (200 mL) and sat. aq. NaHCO3 (100 mL) was added slowly. The layers were separated and the aqueous layer was extracted with EtOAc (200 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I31) (1.136 g, 96% yield over 2 steps) as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.17 (t, J=1.5 Hz, 1H), 8.03-8.00 (m, 1H), 7.66 (dt, J=7.7, 1.4 Hz, 1H), 7.41 (td, J=7.8, 0.4 Hz, 1H), 3.93 (s, 3H), 3.12 (s, 1H). LCMS Method C: rt 5.84 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([F:17])[F:16])[CH3:12]>[Cu].CS(C)=O>[CH2:11]([O:13][C:14](=[O:19])[C:15]([F:17])([F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccccc1I
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 15 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 2-iodonitrobenzene (Compound 1c; 250.0 mg, 1.0 mmol), bromodifluoroacetic acid ethyl ester (203 mg, 1.0 mmol), copper powder (128 mg, 2.0 mmol) and DMSO (2.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 15 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2,2-difluoro-2-(2-nitrophenyl)acetic acid ethyl ester (Compound 2c) was obtained with a yield of 13%.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[NH:14][CH2:13][CH:12]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]([C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH:12]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)NC2CCCCC2)c2ccccc2NC1=O
Yield: 68 %

Procedure:
Cyclohexyl isocyanate (363 mg) was added to a solution of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (800 mg) in tetrahydrofuran (50 ml), the mixture was refluxed for 2 days. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 790 mg of the title compound (Yield: 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][O:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:23][C:22]1[NH:21][CH:20]=[C:19]2[C:14](=[O:13])[O:15][CH2:16][CH2:17][C:18]=12
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
5-Methoxy-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:18]([O:17][C:15]([C:12]1([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 118.6 %

Procedure:
To a solution of 7.84 g (30.0 mmoles) ethyl 1-benzoyl-4-piperidinecarboxylate (G. R. Clemo and E. Hoggarth, J. Chem. Soc., 41, (1941) in 60 ml dry tetrahydrofuran at -78° C. under argon was added dropwise over 10 minutes 33.0 ml (33.0 mmoles) lithium bis(trimethylsilyl)amide in tetrahydrofuran and the resulting solution was stirred 30 minutes. To this solution was added dropwise over 2 minutes 5.64 g (33.0 mmoles) benzyl bromide in 10 ml dry tetrahydrofuran and the resulting solution was stirred overnight while warming from -78° C. to room temperature. The reaction was quenched with 20 ml saturated ammonium chloride solution and extracted with 2×100 ml ethyl acetate. The combined extracts were washed with 20 ml water and brine, dried, and the solvent removed in vacuo to give an oil. The oil was stirred under 25 ml hexane at -15° C., the hexane was decanted and the oil was dried in vacuo to give 12.5 g crude product as a viscous oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:47][O:48][CH:49]1[CH2:53][CH2:52][N:51]([CH2:54][C:55]2[CH:63]=[CH:62][C:58]([CH2:59][NH:60][CH3:61])=[CH:57][CH:56]=2)[CH2:50]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:60]([CH2:59][C:58]3[CH:57]=[CH:56][C:55]([CH2:54][N:51]4[CH2:52][CH2:53][CH:49]([O:48][CH3:47])[CH2:50]4)=[CH:63][CH:62]=3)[CH3:61])=[O:23])[N:20]=2)[CH3:14])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), [4-(3-methoxy-pyrrolidin-1-ylmethyl)-benzyl]-methyl-amine hydrochloride (37 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:28][N:29]1[C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=[CH:30]1.[Cl-].[Li+]>O1CCOCC1.C(Cl)Cl.CO.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>[CH3:28][N:29]1[C:33]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]6)=[CH:19][CH:20]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:32][N:31]=[CH:30]1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cn1cncc1-c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 100 °C
Yield: 19.2 %

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (100 mg, 0.16 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (120 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) and lithium chloride (68 mg, 1.6 mmol) in 1,4-dioxane (3 mL) was degassed and flushed with nitrogen and the reaction heated at 100° C. for 16 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in (DCM containing 1% 7M ammonia in methanol)) to afford a residue that was purified by preparative HPLC [20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a pale orange solid (13 mg, 20%). 1H NMR (DMSO-D6, 400 MHz): 12.26 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.95 (d, J=0.9 Hz, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.58 (d, J=0.9 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.72 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.39 (d, J=1.0 Hz, 1H), 3.96 (s, 3H), 3.49 (s, 2H), 2.36 (s, 4H), 1.57-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method D): KT=6.54 min, M+H+=423.