Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[CH3:12][C:13]1[C:18]([CH3:19])=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N+:14]=1[O-:23]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:16]=[CH:15][N+:14]([O-:23])=[C:13]([CH3:12])[C:18]=2[CH3:19])=[CH:4][C:3]=1[F:9]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: Oc1ccc(Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(Br)c(F)c2)cc[n+]([O-])c1C
Temperature: 180 °C
Yield: 175.5 %

Procedure:
To a room temperature solution of 4-bromo-3-fluorophenol (15 g, 78.53 mmol) in DMF (50 ml) was added sodium hydride (3.32 g, 85.67 mmol, 60% in mineral oil) portionwise. After stirring for 10 minutes 2,3-dimethyl-4-nitro-pyridine 1-oxide (1.05 g, 6.28 mmol) was added The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was filtered through a diatomaceous earth pad and the filtrate was then diluted with EtOAc and washed with water. The solution was then extracted with additional EtOAc (2×150 ml). The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH up to 5% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 21 (3.44 g, 19%).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[OH-].[Na+].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:22]=1)[CH:20]=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C.C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:20]([OH:21])[CH2:4][N+:1]([O-:3])=[O:2])[CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=[N+]([O-])CC(O)c1cc(OCc2ccccc2)ccc1Br
Reaction time: 18 h

Procedure:
A solution of nitromethane (2.02 mL, 37.3 mmol) in ethanol (10 mL) was treated with 10N NaOH (3.0 mL) at ambient temperature. A white solid precipitated immediately, and a solution of 5-benzyloxy-2-bromo-benzaldehyde (8.67 g, 29.8 mmol) in CH2Cl2 (50 mL) was added. The reaction mixture was stirred for 18 h and quenched with water (100 mL). The mixture was extracted with CH2Cl2 (2×50 mL), dried (Na2SO4), and concentrated to a residue, which was then purified by silica gel chromatography (hexanes/EtOAc 8/2) to afford 1-(5-benzyloxy-2-bromo-phenyl)-2-nitro-ethanol as yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([I:14])[CH:4]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([I:14])[CH:4]=1
Reactant: CCOC(=O)c1cc(I)cc(CO)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)cc(COC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2 (2.89 g, 9.4 mmol), 3,4-dihydro-2H-pyran (1.19 g, 14.1 mmol), pyridine p-toluenesulfonate (0.236 g, 0.94 mmol) and CH2Cl2 (50 ml) was stirred overnight at r.t. The solvent was evaporated and the product purified on silica gel (petroleum ether, by 40-60° C./ethyl acetate 2:5), yielding 3.18 g (86%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:15].[CH3:16][NH:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C.O.C(O)(=O)C>[ClH:15].[ClH:15].[CH3:16][N:17]([CH3:18])[CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: CN(C)C1CCN(Cc2ccccc2)CC1

Procedure:
After adding 1-benzyl-4-piperidone (20 ml) and acetic acid (6.15 ml) to a suspension of dimethylamine hydrochloride (11.0 g) in dichloroethane (300 ml), the mixture was stirred in an ice bath. Sodium triacetoxyborohydride (34.3 g) was added thereto, and after stirring in an ice bath for 20 minutes, the mixture was further stirred for 5.5 hours at room temperature. Water (200 ml) was then added to the reaction mixture. Sodium carbonate was further added thereto until the aqueous layer became weakly alkaline, and the mixture was stirred for 10 minutes at room temperature. It was then partitioned and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure. Diethyl ether (100 ml) and a 4N hydrochloric acid-ethyl acetate solution (59.5 ml) were added to the residue. This was diluted with diethyl ether (50 ml) and hexane (50 ml), and then the solid was filtered. The filtered solid was washed with diethyl ether. It was then subjected to aeration drying to provide a crude product of the title compound (30.0 g) as a pale brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Yield: 73 %

Procedure:
A solution of 3-iodo-nitrobenzene (3.0 g, 12.0 mmol), piperazine (1.6 g, 18.1 mmol), copper (I) iodide (0.23 ml, 1.2 mmol) and potassium carbonate (3.3 g, 24.1 mmol) in 40 ml DMSO was stirred at 45° C. for 16 hours. The run was quenched with 10 ml water and extracted with ethyl acetate (3×30 ml). The extraction was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. 1-(3-Nitrophenyl)piperazine hydrochloride (2.0 g, 80%) was obtained when bubbling the HCl gas in ether solution. A solution of 1-(3-nitrophenyl)piperazine (1.50 g, 7.2 mmol), benzoyl chloride, and triethylamine (5.0 ml, 36.1 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. (4-(3-Nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 73%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). The obtained (4-(3-nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 3.8 mmol) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (0.12 mg, 10%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. (4-(3-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.81 g, 80%) was obtained by flash column chromatograph (90% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCl gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.25 (s, br, 4H), 3.53 (d, br, 4H), 6.83 (dd, J=1.2, 7.7 Hz, 1H), 6.99 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 7.44-7.48 (m, 5H), 10.35 (s, br, 2H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 42.4, 48.1, 110.0, 112.8, 115.1, 120.2, 127.1, 127.2, 128.4, 129.6, 129.9, 130.2, 135.7, 151.0, 169.1.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[N:32]=1>CN(C=O)C.C(Cl)Cl.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:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:3]=2)[N:32]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (1.00 g, 1.914 mmol) and 4-chloro-2-(tributylstannyl)pyrimidine (0.966 g, 2.393 mmol) in DMF (5 mL) followed by Pd(PPh3)4 (0.111 g, 0.096 mmol, Strem) and Cut (0.072 g, 0.383 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 1 h. The mixture was then diluted with DCM and washed with H2O, brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified with flash chromatography (eluent: 25%-60% EtOAc in Hexanes) to give 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (550 mg, 1.081 mmol, 56.4%) as a green solid. MS (ESI, pos. ion) m/z: 508.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12](I)=[CH:11][N:10]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1CCCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:11][N:10]=1
Reactant: Clc1ccc(-c2cnc(I)cn2)c(Cl)c1
Reactant: C#C[Si](C)(C)C
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cnc(-c2ccc(Cl)cc2Cl)cn1

Procedure:
The product was prepared analogously to Example 48.1c from 450 mg (1.28 mmol) of 2-(2,4-dichlorophenyl)-5-iodopyrazine and 0.20 mL (1.41 mmol) of trimethylsilylacetylene (using triethylamine as base). Yield: 300 mg (73% of theoretical); C15H14Cl2N2Si (M=321.276); calc.: molpeak (M+H)+:321/323/325 (2 Cl); found: molpeak (M+H)+:321/323/325 (2 Cl); Rf value: 0.6 (silica gel, cyclohexane/EtOAc 9:1).
Reaction SMILES: CO[CH:3]=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[NH2:14][C:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[CH2:18][C:17](=[O:28])[CH:16]=1>C(#N)C>[CH3:12][C:7]1([CH3:11])[O:6][C:5](=[O:13])[C:4](=[CH:3][NH:14][C:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH2:18][C:17](=[O:28])[CH:16]=2)[C:9](=[O:10])[O:8]1
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC#N
Product: CC1(C)OC(=O)C(=CNC2=CC(=O)CC(c3ccccc3Cl)C2)C(=O)O1
Temperature: 25 °C
Reaction time: 13 h
Yield: 49.5 %

Procedure:
To a solution of 5-methoxymethylene-2,2-dimethyl-[1,3]dioxane-4,6-dione (1.7 g) in acetonitrile (15 ml) was added 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.2 g), and the mixture was stirred at room temperature for 13 hours. Precipitated crystals were filtered and washed with acetonitrile to give colorless crystals of 2,2-dimethyl-5-[(3-oxo-5-(2-chlorophenyl)-1-cyclohexenylamino)methylene]-[1,3]dioxane-4,6-dione (1.7 g).
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:3].S(=O)(=O)(O)O>C(OCC)C>[CH3:1][C:2]1([CH3:3])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(CCCC(C)(C)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(C)(C)CCC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
A solution of 2-methyl-5-(p-tolyl)-pentan-2-ol (10.4 g, 54.1 mmol) in ethyl ether (100 mL) at 0° C. was treated with concentrated sulfuric acid (64 mL). The mixture was stirred at 0° C. for 1.5 hours, and then poured into a mixture of ice/water. The mixture was diluted with ethyl ether, the organic phase was separated, washed with water (2×), saturated sodium bicarbonate and brine. The aqueous phase was extracted with ethyl ether and combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (9.6 g, 100% crude) as a yellowish oil which was used for the next reaction.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH3:6])=[O:4])=[O:2].[O:8]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:8]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][C:17]=1[C:1](=[O:2])[C:3]([O:5][CH3:6])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1=C(COc2ccccc2)OCCC1
Reactant: COC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)C1=C(COc2ccccc2)OCCC1
Reaction time: 8 h
Yield: 36.2 %

Procedure:
35 g (0.29 mol) of methoxalyl chloride are added dropwise to 31 g (0.16 mol) of 6-phenoxymethyl-2,3dihydropyran (Example 7c), 39.5 g (0.5 mol) of pyridine and 2.5 g (0.02 mol) of p-dimethylaminopyridine in 200 ml of methylene chloride. During this procedure, the reaction mixture warms up to 30°-35 ° C. Stirring is carried out overnight and the reaction mixture is then poured onto water. The aqueous phase is separated off and the organic phase is extracted once again with water. The organic phase is then dried over MgSO4 and evaporated down. The residue is purified by column chromatography using hexane/ethyl acetate mixtures. 16 g of starting material and 8.5 g (0.031 mol=19%, pale yellow oil) of the title compound are obtained.
Reaction SMILES: [PH2:1](=[O:3])[O-:2].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[CH2:14]=[C:15]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>ClCCl>[C:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][PH:1]([OH:2])=[O:3])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH3:22])([CH3:21])[CH3:20]
Reactant: C=C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[PH2][O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Temperature: 105 °C
Yield: 99.8 %

Procedure:
A mixture of ammonium phosphinate (162.6 g, 1.96 mol) and 1,1,1,3,3,3-hexamethyldisilazane (316 g, 1.96 mol) was heated to 105° C. for 2 hours. The reaction mixture was cooled in an ice bath and di-tert-butyl 2-methylenepentane-1,5-dioate (251 g, 0.979 mol) dissolved in dichloromethane (1000 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then quenched with distilled water (500 ml) and the organic layer was retained. The aqueous layer was washed a second time with dichloromethane and the combined organic layers were dried over magnesium sulfate. Then the solvent was removed under reduced pressure leaving a slightly yellow oil (315 g, 100%). This product was found to be of sufficient purity for use in the next reaction. 1H NMR (CDCl3): δ 1.4 (m, 18H), 1.9 (m, 3H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7 (m, 1H), 6.5 & 7.9 (d, 1H, the P-H), 11.0 (s, 1H)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:30])=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>>[F:30][C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:31]=[N+:32]=[N-:33])[O:14][C:15]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:20][C:19]=1[F:29]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4C)c3O2)cc1
Agent: [Na+]
Product: Cc1ccccc1-c1cc(F)c(F)c2c1OC(CN=[N+]=[N-])C2
Yield: 90.1 %

Procedure:
Treatment of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.3 g, 3.02 mmol) with sodium azide (0.983 g, 15.11 mmol) generally according to the procedure described for intermediate 98 gave 0.82 g (90%) of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide as a colorless oil. Rf=0.69 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 7.25 (d, 2H); 7.14 (m, 3H); 5.06 (m, 1H); 3.67 (dd, 1H); 3.55 (dd, 1H); 3.46 (dd, 1H); 3.11 (dd, 1H); 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1.[OH2:20]>CCOC(C)=O.[Cl-].[Na+].O.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:20])[N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O
Reactant: Cc1cc(Cl)nc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl[Ru](Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2c1C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of ruthenium trichloride (0.141 g, 0.681 mmol) and NaI04 (8.32 g, 38.9 mmol) in H2O (30 mL) at 0° C., a solution of tert-butyl 2-chloro-4-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.75 g, 9.73 mmol) in EtOAc (30 mL) was added. After stirring for 5 min., the reaction mixture was warmed up to rt and stirred. After stirring for 21.5 h, the mixture was diluted with EtOAc and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography on 80 g of silica gel (with 25 g pre-column of silica gel; eluent: heptane/EtOAc=100:0 to 70:30) to give tert-butyl 2-chloro-4-methyl-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.10 g) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (s, 1H), 3.98 (t, J=6.32 Hz, 2 H), 3.13 (t, J=6.32 Hz, 2 H), 2.70 (s, 3 H), 1.58 (s, 9 H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:36]([C:37]#[N:38])=[C:35]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:34]=[C:33]([S:44][CH2:45][C:46]3[N:47]=[C:48]([C:51]4[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=4)[S:49][CH:50]=3)[C:32]=2[C:58]#[N:59])=[CH:27][CH:26]=1)=[O:20])[CH3:18])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:57].[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:36]([C:37]#[N:38])=[C:35]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43]3)[N:34]=[C:33]([S:44][CH2:45][C:46]3[N:47]=[C:48]([C:51]4[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=4)[S:49][CH:50]=3)[C:32]=2[C:58]#[N:59])=[CH:29][CH:30]=1)=[O:20])[CH3:18])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
414 mg (0.482 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-isoleucyl-L-alaninate were dissolved in 3 ml dichloromethane, and 4.822 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, 2 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and the mixture was stirred at room temperature for a further 24 hours. The precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. Since the reaction was still incomplete, the solid was stirred in 5 ml of a 1N solution of hydrogen chloride in diethyl ether for a further 24 h. The precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 312 mg (81% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)NC(=O)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-2-ylmethyl-ethylamine (780 mg.; 2.4 mmol, from Example 13) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.67 mL; 4.8 mmol) and a solution of cyclohexanecarbonyl chloride (0.33 mL; 2.45 mmol) in dichloromethane (5 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour. The mixture was washed with saturated NaHCO3 (15 mL), dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to afford the free base of the title compound as a white gummy foam (750 mg; 72%). Treatment with an equimolar amount of fumaric acid in ethanol yielded the fumarate salt as a white amorphous solid, m.p. 136–141° C.; MS (+) FAB [M+H]+ @ m/z 437, [M+Na]+ @ m/z 459; 1H NMR, 400 MHz, DMSO-d6. Analysis for C26H36N4O2. C4H4O4.2H2O Calculated: C, 61.21; H, 7.53; N, 9.52 Found: C, 61.79; H, 7.27; N, 9.31
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][N:18]=4)=[CH:29][N:28]=3)=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)nc1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnc(F)c2)nc1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetic acid 208-3 (42 mg, 0.18 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (31 mg, 0.18 mmol), 1,3-dicyclohexylcarbodiimide (45 mg, 0.22 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.036 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered and the filtrate was purified by reverse phase HPLC to give 2-(2′-fluoro-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 208 as white solid. MS m/z 387.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.31 (d, 1H), 9.11 (d, 1H), 8.73-8.71 (m, 2H), 8.62 (d, 1H), 8.52 (dd, 1H), 8.36 (d, 1H), 8.23-8.17 (m, 2H), 8.06-8.02 (m, 1H), 7.95 (dd, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 3.94 (s, 2H).
Reaction SMILES: [N+](C1C=C([O:10][C:11](=O)[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)C=CC=1)([O-])=O.[N+](C1C=C(C=CC=1)C=CC(O)=O)([O-])=O.S(Cl)([Cl:40])=O.Cl>CN(C=O)C.C(OCC)(=O)C>[N+:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH:13]=[CH:12][C:11]([Cl:40])=[O:10])([O-:22])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 96.9 %

Procedure:
Synthesis of (3′-nitrophenyl)-3-nitrocinnamate 193.2 g (1 mole) of 3-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and poured into hexane. The precipitate was separated by filtration and dried. 205 g of 3-nitrocinnamoyl chloride was yielded.