Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(CC)C.[Na+].Cl[C:9]1[N:14]=[C:13]2[O:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:17]([C:18](=[O:21])[NH:19][CH3:20])[C:12]2=[CH:11][C:10]=1[C:29]1[CH:30]=[N:31][C:32]([O:39][CH3:40])=[C:33]([CH:38]=1)[C:34]([O:36]C)=[O:35].[F:41][C:42]([F:46])([F:45])[CH2:43][NH2:44]>O1CCOCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[O:15][C:13]3=[N:14][C:9]([NH:44][CH2:43][C:42]([F:46])([F:45])[F:41])=[C:10]([C:29]4[CH:30]=[N:31][C:32]([O:39][CH3:40])=[C:33]([CH:38]=4)[C:34]([OH:36])=[O:35])[CH:11]=[C:12]3[C:17]=2[C:18](=[O:21])[NH:19][CH3:20])=[CH:23][CH:24]=1
Reactant: NCC(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3cnc(OC)c(C(=O)OC)c3)cc12
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cnc(OC)c(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
Sodium 2-methylbutan-2-olate (0.281 g, 2.55 mmol) was added to a stirring solution of methyl 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinate (0.120 g, 0.255 mmol), 2,2,2-trifluoroethanamine (0.253 g, 2.55 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (0.020 g, 0.026 mmol), in dioxane (2.55 ml) at 100° C. Immediately, the reaction mixture turned to a dark amber color. LCMS after 1 h shows complete conversion to the desired coupled product with simultaneous deprotection of the tButyl ester. The reaction mixture was cooled to rt and concentrated to a dry solid. The resultant solid was then taken up in EtOAc and diluted with 1 M HCl. The layers were separated and the aq layer was extracted with EtOAc (2×15 mL). The layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to give a yellow solid. This solid was then triturated with DCM (25 mL) for 3 h. The solids were filtered to give the desired 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinic acid (110 mg, 0.21 mmol, 83% yield) as a yellow solid. LC-MS retention time: 1.68 min; m/z (observed boronic acid M+H): 519. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, METHANOL-d4) δ 8.38 (d, J=2.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.91 (dd, J=8.2, 6.1 Hz, 3H), 7.69 (s, 1H), 7.23-7.19 (m, 3H), 4.18 (d, J=9.3 Hz, 2H), 4.07 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>CCCCCC>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Fc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 24 h
Yield: 91 %

Procedure:
Using a THF solution of p-methoxyphenylmagnesium bromide (1.88 mL, 0.64 M, 1.2 mmol) and 1-chloro-4-fluorobenzene (130.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound (0.184 g, yield=91%, purity=>99% (GC analysis)) was obtained as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][O:8][C:9]([CH:11](P(OCC)(OCC)=O)[F:12])=[O:10].[CH2:21]([C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:33](=O)[CH3:34])[CH:31]=2)[O:26][C:25]([CH3:39])([CH3:38])[CH:24]=1)[CH3:22]>C1COCC1>[CH2:21]([C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30](/[C:33](/[CH3:34])=[C:11](/[F:12])\[C:9]([O:8][CH2:7][CH3:6])=[O:10])[CH:31]=2)[O:26][C:25]([CH3:39])([CH3:38])[CH:24]=1)[CH3:22]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCC1=CC(C)(C)Oc2cc(OC)c(C(C)=O)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2CC
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5 M in hexanes, 1.3 mL, 3.28 mmol) in THF (5 mL) at 0° C. was slowly added triethyl-2-fluoro-2-phosphonoacetate (700 mg, 2.89 mmol). The solution was stirred for 10 min at −40° C. The mixture was cooled to −78° C., and a solution of 1-(4-ethyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 53, 222 mg, 0.97 mmol) in THF (5 mL) was added by cannula. After stirring at 0° C. for 4 h, the reaction mixture was quenched with water. The product was extracted with ethyl acetate and the combined extracts were washed with water and brine, and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 10% ethyl acetate in hexane) to produce the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:7]1[C:8]2[N:9]([CH:12]=[CH:13][N:14]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2n2ccnc12
Product: Clc1ccc2nc(Cl)c3nccn3c2c1

Procedure:
By reaction of 8-chloroimidazo[1,2-a]quinoxaline-4(5H)-one (example 17) with POCl3, following a procedure that is similar to that described in example 1, there is obtained 4,8-dichloroimidazo[1,2-a]quinoxaline that is subsequently reacted with cyclopentylamine according to the method described in example 3, thereby obtaining 4-cyclopentylamino-8-chloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=140.1° C.(onset); IR (KBr): 3401, 2955, 1554 cm-1 ; 1H-NMR (CDCl3): δ7.8 (1H,d, J=2 Hz), 7.7÷7.2 (4H,m), 6.15 (1H,d), 4.6 (1H,m), 2.3÷2.05 (4H,m), 2.05÷1.3 (4H,m); UV (EtOH): λmax =229, 245, 289, 301, 326, 340 nm. Elementary analysis for C15H15ClN4 (m.w. 286.76): calcd. C 62.83, H 5.27, N 19.54%; found C 63.04, H 5.36, N 19.64%.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>C1COCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(Cl)nc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of cyanuric chloride (1.5 g, 8.13 mmol) in THF (50 mL) Diisopropyethylamine (1.56 mL, 8.94 mmol) was added. The solution was placed in an ice-water bath (0° C.). Using a syringe, 4-methoxy-benzyl amine (1.16 mL, 8.94 mmol) dissolved in THF (150 mL) was slowly dripped into the reaction mixture. The reaction stirred at 0° C. for 3 hours. The crude compound was purified by column chromatography initially eluting with EA:Hexane (1:6). Compound was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21](F)[CH:20]=3)[N:16]=[C:15]([NH2:28])[N:14]=2)[CH2:8]1)[CH3:3].[NH2:30][NH2:31]>C(O)C>[CH3:3][CH:2]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]4[C:22]([C:25]([NH2:26])=[N:30][NH:31]4)=[CH:21][CH:20]=3)[N:16]=[C:15]([NH2:28])[N:14]=2)[CH2:8]1)[CH3:1]
Reactant: NN
Reactant: CC(C)OC(=O)N[C@@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: CCO
Product: CC(C)OC(=O)N[C@@H]1CCCN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 100 °C

Procedure:
Into a 5 mL sealable vial was added 1-methylethyl{(3R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinyl}carbamate (116 mg, 0.291 mmol) followed by ethanol (3 mL) and hydrazine (0.428 mL, 8.73 mmol). The mixture was then capped and heated at 100° C. overnight. The reaction was concentrated, then dissolved in 2 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 mL/min, 10% CH3CN/H2O, 0.1% TFA to 35% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the water left behind was added saturated NaHCO3. It was then extracted with EtOAc (3×15 mL) and the organic fractions were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was then transferred to a haystack vial and 1 mL of water was added and freeze dried. LC-MS (ES) m/z=411 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (d, 3H), 1.16 (d, J=6.3 Hz, 3H), 1.39-1.49 (m, 2H), 1.70-1.77 (m, 1H), 1.85-1.93 (m, 1H), 2.87 (bs, 1H), 3.03 (bs, 1H), 4.06-4.16 (m, 1H), 4.28 (bs, 1H), 4.77 (ddd, J=12.51, 6.19, 6.06 Hz, 1H), 5.38 (s, 2H), 6.09 (bs, 2H), 6.56 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.92 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:30]2[NH:29][C:28]3[CH:27]=[C:26](C(O)=O)[C:25]4[C:36](=[O:40])[NH:37][C:38](=[O:39])[C:24]=4[C:23]=3[C:22]=2[CH:21]=1.CCN(CC)CC>C(O)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:15][C:26]1[C:25]2[C:36](=[O:40])[NH:37][C:38](=[O:39])[C:24]=2[C:23]2[C:22]3[CH:21]=[C:20]([O:19][CH3:18])[CH:32]=[CH:31][C:30]=3[NH:29][C:28]=2[CH:27]=1
Reactant: COc1ccc2[nH]c3cc(C(=O)O)c4c(c3c2c1)C(=O)NC4=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c3cc(N)c4c(c3c2c1)C(=O)NC4=O
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Diphenylphosphoryl azide (1.81 mL, 8.38 mmol) was added to a mixture of the 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid (2.55 g, 8.22 mmol), prepared as in example 4, and Et3N (1.17 mL, 8.38 mmol) in anhydrous t-butanol (300 mL) and the mixture was refluxed under an atmosphere of nitrogen for 16 h. The solution was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3. Insoluble material was removed by filtration of the two layers through Celite, washing through with more EtOAc. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness and gave a yellow solid. This material was dissolved in CH2Cl2/trifluoroacetic acid (1:1) (200 mL) and the solution was held at room temperature for 1 h. After concentration in vacuo the residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc solution was dried, the drying agent was removed and the solution was concentrated to dryness to give an orange solid which was adsorbed onto silica and chromatographed. Elution with ethyl acetate/petroleum ether (1:1) followed by ethyl acetate and then methanol/ethyl acetate (1:9) gave 4-amino-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (6) as an orange powder (2.16 g, 93%), mp 342–345° C. 1H NMR δ [(CD3)2SO] 11.18 (s, 1H), 10.78 (br s, 1H), 8.18 (d, J=2.5 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.01 (dd, J=8.7, 2.5 Hz, 1H), 6.83 (s, 1H), 6.28 (br s, 2H), 3.82 (s, 3H). Found: C, 63.05; H, 3.99; N, 14.05. C15H11N3O3, 1/2H2O requires C, 63.04; H, 4.06; N, 14.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([NH2:29])=[O:31])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3Cl)cc1CCO2
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: NC(=O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3Cl)cc1CCO2
Yield: 88.6 %

Procedure:
To a stirred solution of 2-[4-(2-chloro-4-fluoro-phenyl)-4H-[1,2,4]-triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carbonitrile (90 mg; 0.21 mmol) in DMSO (3 ml) and MeOH (5 ml) was added K2CO3 (36 mg; 0.26 mmol) then H2O2 (30 μl of a 30% aqueous soln.). The reaction mixture was stirred at room temperature overnight (16 h) upon which time the methanol was removed on a rotary evaporator and the residue was diluted with water (40 ml). The resulting solid was collected by filtration, washed with water and dried to give 281 as a white solid (82 mg; 89%). δH (400 MHz, CDCl3) 3.15 (t, J=5.2, 2H), 4.34 (t, J=5.2, 2H), 5.50-6.30 (br s, 2H), 6.88 (s, 1H), 7.07 (d, J=8.4, 1H), 7.22-7.27 (m, 1H), 7.42-7.63 (m, 3H), 8.06 (d, J=2.0, 1H), 8.22 (s, 1H). [M+H]+: 441
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]([NH:23][C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:31])=[N:14][CH2:15][CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:32][CH3:33].[CH3:34][Si](C=[N+]=[N-])(C)C>>[CH3:33][O:32][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH3:34])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]([NH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:31])=[N:14][CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22]
Reactant: COc1cc2c(NC(=NCCC3CCCN3C)Nc3c(C)cccc3C)ncnc2cc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COc1cc2ncnc(NC(=NCCC3CCCN3C)Nc3c(C)cccc3C)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 11. N-(7-hydroxy-6-methoxyquinazolin-4-yl)-N′-(2,6-dimethylphenyl)-N″-[2-(N-methylpyrrolidin-2-yl)ethyl]guanidine was reacted with trimethylsilyldiazomethane to give the title compound; NMR Spectrum: (DMSOd6, 100° C.) 1.65 (m, 3H), 1.68 (m, 1H), 1.8–1.96 (m, 2H), 2.07 (q, 1H), 2.15 (s, 3H), 2.32 (s, 6H), 2.32 (s, 6H), 2.79 (br t, 1H), 2.59 (m, 1H), 2.69 (m, 1H), 3.84 (s, 3H), 3.95 (s, 3H), 7.08 (s, 1H), 7.20 (m, 4H), 7.74 (s, 1H), 8.47 (s, 1H), 10.9–11.3 (br s, 1H); Mass Spectrum: M+H+ 463.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].CO.O.O[Li].O>C1COCC1>[C:10]1([C:8]2[O:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(-c2ccccc2)on1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (3.86 g, 0.01754 mole) in methanol (78 mL) was added hydroxylamine hydrochloride (3.657 g, 0.0526 mole) at ambient temperature. The resulting mixture was then heated to reflux overnight. Volatiles were then removed by evaporation and the resulting residue was diluted with water and the product extracted with chloroform. The chloroform layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 2.8 g (79%) of 5-phenyl-isoxazole-3-carboxylic acid methyl ester. LCMS: 204.06 (M+1)+, 97.58%. To a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid methyl ester (2.8 g, 0.01379 mol) in a mixture of THF (10 mL), methanol (10 mL) and H2O (10 mL) was added LiOH.H2O (0.87 g, 0.02073 mol) and the resulting mixture was stirred at ambient temperature for 2.5 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 2.2 g (85%) of 5-phenyl-isoxazole-3-carboxylic acid. LCMS: 190.04 (M+1)+, 96.4%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:2]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([C:12]([Cl:18])=[O:14])[CH:8]=2)[CH:2]=1
Reactant: O=C(O)c1cc(-c2cccnc2)on1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2cccnc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g (2.63 mmol) of 5-(pyridin-3-yl)-1,2-oxazole-3-carboxylic acid (known from the literature, no reference) in 25 ml of dichloromethane was admixed with 2 drops of N,N-dimethylformamide. Subsequently, 0.97 g (7.63 mmol) of oxalyl chloride was added dropwise under argon and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was converted farther immediately.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[CH2:24]([O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH2:8])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Lastly, (3-benzyloxybenzyl)iminodicarboxylic acid di-tert-butyl ester (691 mg, 1.67 mmol) was cooled on an ice bath, trifluoroacetic acid (3 mL) was added, and the solution was stirred for 30 minutes. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution, which was then extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (292 mg, 82%) was obtained as a white waxy solid. This was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:6]2[N:7]([CH3:16])[C:8](=[O:15])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][CH:10]=3)#[N:2].Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:18]1[C:3]([C:1]#[N:2])=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1C#N)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C[C@H](N)COc1cc2c(cc1C#N)c1ccncc1c(=O)n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
In a 25 mL round-bottomed flask, (S)-tert-butyl (1-((9-cyano-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (75 mg, 0.167 mmol) was taken up in MeOH (4 mL) and cooled to 0° C. The mixture was treated with 4M solution of HCl in 1,4-dioxane (2 mL, 8 mmol) and stirred for 2 h at RT. The MeOH was removed and the crude product was dissolved in EtOAc (20 mL). The ethyl acetate layer was washed with water (2×10 mL) and dried over sodium sulfate. Removal of the solvent gave crude product which was purified by silica-gel column (MeOH—CHCl3 mixture) to obtain (S)-8-((2-amino-4-methylpentyl)oxy)-6-methyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridine-9-carbonitrile (4 mg, 0.01 mmol, 7% yield over 2 steps) as a yellow solid. LC/MS (ESI) m/e 351.2. [(M+H)+, calcd for C20H23N4O2, 351.4]; LC/MS retention time (method B): tR=1.43 min. HPLC retention time (method A): tR=9.69 min; HPLC retention time (method B): tR=9.31 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.56 (bs, 1H), 8.93 (s, 2H), 8.37 (d, J=4.77 Hz, 1H), 7.25 (s, 1H), 4.63 (dd, J=10.67, 3.14 Hz, 1H), 4.47 (dd, J=10.79, 6.02 Hz, 1H), 3.81-3.89 (m, 4H), 1.83-1.91 (m, 2H), 1.72 (t, J=6.53 Hz, 1H), 1.08 (d, J=5.02 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C3C=NC=C(C(F)(F)F)C=3)[CH2:13][CH2:12]2)[N:3]=1.Cl[C:28]1[N:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][C:29]=1[C:30]#[N:31]>>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:28]3[N:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][C:29]=3[C:30]#[N:31])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C#CC=C2CCN(c3cncc(C(F)(F)F)c3)CC2)n1
Reactant: N#Cc1cc(-c2ccccc2)cnc1Cl
Product: Cc1cccc(C#CC=C2CCN(c3ncc(-c4ccccc4)cc3C#N)CC2)n1

Procedure:
Following the procedure reported above for the compound of Example 262 but replacing 5-(trifluoromethyl)pyridine with 2-chloro-5-phenylnicotinonitrile the title product was synthesized. After the reaction work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from 9:1 to 4:6, affording the title product (10%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:22])=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:5].[C:23]([C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH:27]=[C:28]([C:33]([CH3:35])=O)[C:29]([O:31][CH3:32])=[O:30])#[N:24]>C1(C)C=CC=CC=1>[CH3:22][C:2]1[NH:1][C:33]([CH3:35])=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:27]([C:26]2[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=2[C:23]#[N:24])[C:3]=1[C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:5]
Reactant: C/C(N)=C/C(=O)OCC=Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C(=Cc1ccccc1C#N)C(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1ccccc1C#N

Procedure:
297 mg (1 mM) of 3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-yl 3-aminocrotonate and 229 mg (1 mM) of methyl 2-(2-cyanobenzylidene)acetoacetate were dissolved in 5 ml of toluene and refluxed for six hours. After cooling, the crystals produced were filtered off and recrystallized from methanol whereby the captioned compound was obtained. The yield was 402 mg (79.1%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5][CH:4]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc(N)nc1
Yield: 93.9 %

Procedure:
A solution of dimethyl-(6-nitro-pyridin-3-yl)-amine (0.64 g, 3.83 mmol) in ethanol (45 mL) was treated with 10% palladium on activated carbon (203 mg). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure overnight. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethanol. The filtrate was concentrated in vacuo to afford N5,N5-dimethyl-pyridine-2,5-diamine (493.6 mg, 94%) as a dark red-purple oil: EI-HRMS m/e calcd for C7H11N3 (M+) 137.0953, found 137.0957.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 22 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst (no substance acting as auxiliary catalyst). 624 mg Styrene and 732 mg methyldichlorosilane were introduced into a glass tube, and 0.9 mg of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The tube was sealed with Teflon tape and a rubber septum and placed in a 50° C. oil bath where it was heated for 30 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 75% and a phenethylmethyldichlorosilane yield of 22%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 1.2:1.