Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:22][C:19]([F:20])([F:21])[CH2:18][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCC(F)(F)F)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-(2,2,2-trifluoro-ethoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 218.4 ([M+H]+, 100%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.[C:24](=O)([O:35]C1C=CC([N+]([O-])=O)=CC=1)[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33]>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:5][C:4]([CH3:7])([O:3][C:1](=[O:2])[NH:8][CH:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][C:24](=[O:35])[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=C(OCCOCCO[N+](=O)[O-])Oc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(COC(=O)OCCOCCO[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a solution or N-Boc-L-Serine (1.66 g, 8.12 mmol), diisopropylethyl amine (DIPEA) (1.41 ml, 8.12 mmol), N,N-dimethylaminopyridine (DMAP) (1.19 g, 9.74 mmol) and scandium triflate (1.20 g, 2.43 mmol) in CH2Cl2 (40 ml), cooled to −10° C., a solution of 2-[2-(nitrooxy)ethoxy]ethyl 4-nitrophenyl carbonate in CH2Cl2 (40 ml) was added drop-wise. The reaction was slowly warmed to room temperature and stirred for 24 h. Then the organic phase was washed with pH 3 aqueous buffer and concentrated under reduced pressure. The crude was partitioned between aqueous 5% aqueous Na2HPO4 and diethyl ether and extracted twice with diethyl ether. The aqueous phase was acidified to pH 3 and extracted with CH2Cl2. The organic phase was finally dried over sodium sulphate and concentrated under reduced pressure to give the title compound as an oil. (2.4 g, 80%)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.O.C([BH3-])#N.[Na+]>ClCCl>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8]2
Reactant: O=Cc1ccccc1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(Cc1ccccc1)CC2
Reaction time: 6 h
Yield: 62.2 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and benzaldehyde (0.71 mL, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for six hours. The reaction mixture was then added to dichloromethane (150 mL) and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and activated charcoal, filtered through a plug of silica gel and concentrated under vacuum to dryness. The solids were triturated in hexane, filtered, and oven dried to give the title compound (0.73 g, 62% yield) as an orange solid, mp=150-152° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](O)=[O:40].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:33])[CH:7]([NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccco1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (350 mg, 0.77 mmol) and 2-Furoic acid (87 mg, 0.77 mmol, 1 equiv.) in DMF (6 mL) was added BOP reagent (409 mg, 0.92 mmol, 1.2 equiv.) and Hunig base (0.16 mL, 0.92 mmol, 1.2 equiv.) under N2. The mixture was stirred at room temperature overnight. Reaction was complete was determined by LC-MS. The reaction mixture was then poured onto cold water. Solid precipitated from the mixture was collected by filtration. The solid was then dissolved in EtOAc, washed with 1N HCl, saturated NaHCO3, and brine, and then dried over MgSO4. After removing the solvent, the solid was dried under vacuum overnight to provide 2-({4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester in 87% yield (369 mg). MS (ESI) m/z 549.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[NH:13][C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[NH:13][C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(OCc3ccccc3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Yield: 92.2 %

Procedure:
The product of Example 352B (277 mg, 0.7398 mmol) in ethanol (20 mL) was hydrogenated at 1 atmosphere hydrogen pressure (balloon) with 10% palladium on carbon (28 mg, 10 weight %) for 1.25 hour. The reaction was filtered through a PTFE membrane filter (0.45 μm) and the catalyst thoroughly washed with ethanol (50 mL). The filtrate was concentrated under reduced pressure and the resulting oil triturated with dichloromethane/hexanes (1:1 v/v) to give the title compound as a crystalline white solid (194 mg, 92%). MS (ESI−) m/z 283 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.17 Hz, 3 H) 3.64 (s, 2 H) 4.15 (q, J=7.23 Hz, 2 H) 7.06 (d, J=2.57 Hz, 1 H) 7.11 (dd, J=8.83, 2.57 Hz, 1 H) 7.20 (d, J=8.83 Hz, 1 H) 10.21 (s, 1 H) 12.11 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.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>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([OH:10])=[C:6]([CH2:7][NH:8][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:15]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: CC(C)(C)NCc1cc(-c2cc3ccccc3o2)cc(-c2ccccc2)c1O
Temperature: 56.5 °C
Yield: 53 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (from Example 42, Step 2) (0.552 g, 1.6 mmol), benzofuran-2-ylboronic acid (0.387 g, 1.5 equiv), and potassium carbonate (0.885 g, 4 equiv) in 2-methoxyethyl ether (10 mL) and water (2 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (82 mg, 0.073 mmol, 4.5 mol %) was added and the resulting mixture was heated at 51-62° C. for 1.5 hours. To the reaction mixture, additional benzofuran-2-ylboronic acid (0.173 g, 1.07 mmol) was added. The resulting mixture was allowed to heat at 60-62° C. overnight. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatography to give 5-(benzofuran-2-yl)-3-((tert-butylamino)methyl)-[1,1′-biphenyl]-2-ol (0.315 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:3])[CH3:2].C(C1C=CC(C(C)C(C)C(O)(C(F)(F)F)CO)=C(OC)C=1)(C)C.CS(C)=O.[NH4+].[Cl-]>ClCCl.C(N(CC)CC)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:17])([F:16])[F:18])[CH:13]=[O:14])=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCC(CC(O)(CO)C(F)(F)F)c1ccc(C(C)C)cc1OC
Agent: COc1cc(C(C)C)ccc1C(C)C(C)C(O)(CO)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(C(C)C)cc1OC
Temperature: 25 °C

Procedure:
The above-described mixture of 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexan-1-ol and 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pentan-1-ol (5.35 g, 16 mmol) is dissolved in dichloromethane (164 ml). Following addition of dimethyl sulphoxide (54.8 ml) and triethylamine (11.1 ml) the SO3/pyridine complex (6.37 g, 40 mmol) is added in portions over the course of 40 minutes. After four-hour stirring at room temperature, the batch is poured onto a mixture of saturated NH4Cl solution and ice. The mixture is extracted twice with diethyl ether (250 ml each time) and the combined extracts are washed twice with brine (50 ml each time). Following removal of the solvent by evaporation, the residue is chromatographed on silica gel (eluent: hexane/diethyl ether). This isolates 3.05 g (57%) of a mixture of the two aldehydes, 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-hexanal and 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pentanal.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:25]1([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]4[CH:24]=[CH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]=4)[CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: C1CNCCN1
Reactant: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: c1ccc2nc(N3CCC(Oc4nccnc4N4CCNCC4)CC3)ccc2c1
Temperature: 160 °C
Yield: 30 %

Procedure:
To a mixture of 2-(4-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (see PREPARATION P2.1; 0.34 g, 1.0 mmol) and piperazine (0.83 g, 1.0 mmol) and K2CO3 (0.27 g, 2.0 mmol) was added i-PrOH (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.11 g, 0.30 mmol, 30% yield) as white solid. ESI-MS (M+1): 391 calc. for C22H26N6O 390.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:15]1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[Cl:2]
Reactant: CC(C)(C)N=C=O
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Yield: 44 %

Procedure:
A solution of 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) (0.29 mmol), tert-butyl isocyanate (0.29 mmol) and triethylamine (0.58 mmol) in dichloromethane (3 mL) was shaken at room temperature overnight, quenched with water, filtered through a PTFE phase separator cartridge and reduced in vacuo to yield a colourless gum (52 mg, 44%).
Reaction SMILES: CC(C)([S@@]([NH:6][C@H:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:8])=O)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[NH2:6][CH:7]([CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]1)[CH3:8]
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 110.5 %

Procedure:
To a 1 L round bottomed flask charged with a magnetic stir bar was added crude tert-butyl 4-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)piperidine-1-carboxylate (29 g) was taken up in MeOH (200 mL) before addition of a 4 N solution of HCl in 1,4-dioxane (24.06 ml, 96 mmol). The resulting solution was then stirred at room temperature for 1H at rt. The methanol was then removed in vacuo to afford viscous oil which was treated with sat'd aqueous NaHCO3 (˜500 mL) and extracted with ethyl acetate (2×500 mL). This organic phase was combined, dried with MgSO4, filtered, and solvent was then removed in vacuo affording the title compound (22 g) which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:8]([N:13]=1)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3]C.NC1C=NC=CC=1N>>[CH2:1]([C:5]1[NH:6][C:7]2[C:8]([N:13]=1)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3]
Reactant: CCCCc1nc2ncccc2[nH]1
Agent: Nc1ccncc1N
Product: CCCc1nc2ncccc2[nH]1

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-butylimidazo[4,5-b]pyridine starting with 3,4-diaminopyridine and burytic acid. Yield: 6.60 g (89%) amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCCc1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCc2c[nH]cn2)cc1

Procedure:
2.09 mg (1.5 mmol) of 4-nitrophenol, 251 mg (1.4 mmol) of 4-[2-chloroethyl]-1H-imidazole hydrochloride, 475 mg (3 mmol) of potassium carbonate and sodium iodide (catalyst) are stirred at 80° C. for 5 days in 5 ml of dimethylformamide. The reaction mixture is cooled and 100 ml of diethyl ether are added. The precipitate is separated by filtration. The filtrate is evaporated under reduced pressure to give a residue which is subjected to column chromatography (using, as first eluent, chloroform and, as second eluent, a 9/10 chloroform/methanol mixture) to give the title compound which, after crystallization from methanol, melts at: 197°-200° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1.C1(C=O)CC1>CN(C=O)C.O>[CH:17]1([CH:21]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:19][CH2:18]1
Reactant: C1CCOC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 13.0 ml (64.85 mmol) of ethyl diethylphosphonoacetate were added dropwise to a suspension of 2.59 g (64.85 mmol) of sodium hydride (60% in mineral oil) in 110 ml of abs. THF. After 30 min, the mixture was warmed to RT and, after cooling again to 0° C., 5.3 ml (71.34 mmol) of cyclopropanecarboxaldehyde were added dropwise. After the end of the addition, the reaction mixture was warmed to RT and diluted with 35 ml of DMF. The mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the crude product was purified by filtration through silica gel (mobile phase cyclohexane/ethyl acetate 10:1→6:1). This gave 8.53 g of the target product (93.8% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(Cl)nc1
Yield: 51.1 %

Procedure:
Step AJ (1): 2-(6-Chloropyridin-3-yl)acetic acid (2.5 g, 14.57 mmol) was deprotonated with NaHMDS (1.0 M in THF, 29.1 mL, 29.1 mmol) and reacted with 1-chloro-4-iodobutane (1.78 mL, 14.6 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(6-chloropyridine-3-yl)hexanoic acid (1.95 g, 51% yield). LC-MS (M−H)− 262.04.
Reaction SMILES: O1C2C=CC(CO[C:13](=O)[NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=5)[CH:26]=[CH:25][C:24]4=[O:35])[CH2:17][CH2:16]3)=CC=2OCC1.[ClH:37].[C:38]([O:41][CH2:42][CH3:43])(=O)[CH3:39]>>[ClH:37].[O:41]1[C:38]2[CH:39]=[CH:27][C:28]([CH2:13][NH:14][CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=5)[CH:26]=[CH:25][C:24]4=[O:35])[CH2:19][CH2:20]3)=[CH:29][C:30]=2[O:33][CH2:43][CH2:42]1
Reactant: CCOC(C)=O
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OCc4ccc5c(c4)OCCO5)CC3)c2n1
Agent: Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2n1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
To 0.50 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl(1-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 15 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 43 hours. The solvent was distilled off under reduced pressure, methanol was added to the resultant residue, and the solvent was distilled off under reduced pressure. Then, ethyl acetate was added to the resultant residue, and the solid was filtered off to obtain 0.41 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[N:14]=[C:15]([NH2:18])[O:16][CH:17]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[N:14]=[C:15]([NH:18][C:26](=[O:28])[CH3:27])[O:16][CH:17]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1-c1coc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1-c1coc(NC(C)=O)n1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 4-(2-methoxy-naphthalen-1-yl)-oxazol-2-ylamine (17, 450 mg), triethylamine (0.78 mL) and dichloromethane (5 mL) at 0° C. was added acetyl chloride (0.2 mL). The solution was allowed to warm to room temperature overnight and the reaction was quenched by the addition of a mixture of dichloromethane and methanol. The solution was washed with brine (×2), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography, eluting with 2% methanol in dichloromethane, to afford N-[4-(2-methoxy-naphthalen-1-yl)-oxazol-2-yl]-acetamide (25) (190 mg, 36%) as an off-white solid. 1H NMR (DMSO-D6): 2.1 (3H, br s), 3.9 (3H, s), 7.2 (1H, s), 7.35-7.40 (1H, m), 7.45-7.50 (1H, m), 7.55 (1H, d, J=9.2 Hz), 7.90-7.95 (2H, m), 8.05 (1H, d, J=9.2 Hz), 11.2 (1H, br s). Mass Spectrum (m/z): 283 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:2]3[N:18]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1
Reactant: Clc1nc2c(NCc3cccnc3)cccn2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5cccnc5)cccn4n3)cc2)CC1

Procedure:
N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(8)-pyridin-3-ylmethyl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-pyridin-3-ylmethyl-amine (75.0 mg, 0.289 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (61.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.075 g, 63%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.66 (s, 1H), 8.55 (d, J=4.1 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.31-7.25 (m, 1H), 6.95 (d, J=8.9 Hz, 2H), 6.66 (t, J=7.3 Hz, 1H), 6.57 (s, 1H), 6.30 (d, J=7.7 Hz, 1H), 5.08 (t, J=5.6 Hz, 1H), 4.50 (d, J=5.8 Hz, 2H), 3.17-3.13 (m, 4H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17](=[O:20])[NH:18][CH:19]=3)[S:13][C:6]=12.Cl[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.ClCCl.C(O)(=O)C.CO>[CH3:32][N:31]([CH3:33])[CH2:30][CH2:29][N:18]1[CH:19]=[C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:2]=3[F:1])[CH:11]=2)[CH:15]=[CH:16][C:17]1=[O:20]
Reactant: CN(C)CCCl
Reactant: O=c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)ccc1=O
Temperature: 25 °C

Procedure:
The pyridinone 420 (0.283 g, 0.739 mmol), 2-chloro-N,N-dimethylethanamine (0.128 g, 0.887 mmol), cesium carbonate (0.547 g, 1.68 mmol) and sodium iodide (0.132 g, 0.88 mmol) were heated in DMF (10 mL) at 70° C. for 3 days. An additional portion of 2-chloro-N,N-dimethylethanamine (64 mg, 0.44 mmol) and cesium carbonate (0.289 g, 0.887 mmol) were added. The reaction mixture was heated for additional 8 hours, cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between water (50 mL) and 5% ethanol/dichloromethane. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by silica gel chromatography using a 25M Biotage column and a gradient of 3 to 20% methanol in dichloromethane with 1% acetic acid, to provide title compound 421 as a solid material (0.108 g, 32% yield). MS (m/z): 228.0 ([M+2H]/2), 455.0 (M+H), 477.0 (M+Na).