Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].[CH3:8][O:9][C:10]1[CH:20]=[CH:19][C:13]([CH2:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>CO>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:16]2[S:17][C:3]([C:4](=[O:6])[CH3:5])=[C:2]([CH3:1])[N:18]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(CNC(N)=S)cc1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(CNc2nc(C)c(C(C)=O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 3-chloro, 2,4-pentanedione (1.0 g, 7.43 mmol) and 1-(4-methoxy benzyl)-2-thiourea (1.46 g, 7.43 mmol) in methanol (10 ml) is treated with pyridine (0.6 ml). The reaction mixture is stirred at room temperature for 2 hours and then the solvent is removed in vacuo. The crude residue is triturated with ether to yield the titled compound as a white solid.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1([CH3:22])[C@@H:9](/[CH:10]=[CH:11]\[C:12](O)=[O:13])[C@H:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:6][C:7]1([CH3:22])[C@@H:9](/[CH:10]=[CH:11]\[C:12]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:13])[C@H:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reactant: OC1CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC2CCC2)C1(C)C

Procedure:
1.7 ml of cyclobutanol were added to a solution of 4 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxyethenyl]-cyclopropane-carboxylate in 20 ml of methylene chloride and 3.45 g of dicyclohexylcarbodiimide and a solution of 28 mg of 4-dimethylamino-pyridine in 20 ml of methylene chloride were added thereto at 0° to 5° C. with stirring. The mixture was stirred for 2 hours at 5° C. and 2 hours at room temperature and was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 n-hexane-isopropyl ether mixture yielded 2.3 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-(cyclobutoxycarbonyl)-ethenyl]cyclopropane-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[Cl:33])(C)(C)C.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+].N1CCCC(=O)C2C=CC=CC1=2.Cl.O1CCOCC1>>[ClH:32].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[Cl:33]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1)C2
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Agent: O=C1CCCNc2ccccc21
Solvent: C1COCCO1
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(Cl)c1)C2
Yield: 100 %

Procedure:
[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-carbamic acid tert-butyl ester from Example E106.1 (570 mg, 1.13 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (490 mg, 100%).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH3:24][O:25][C:26]([C:28]1[CH2:29][S:30][CH2:31][CH2:32][C:33]=1[OH:34])=[O:27]>O>[CH3:24][O:25][C:26]([C@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][S:30][CH2:29]1)=[O:27]
Reactant: COC(=O)C1=C(O)CCSC1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: COC(=O)[C@@H]1CSCC[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
A suspension of baker's yeast (Saf-Instant yeast, 30 g) in water (700 mL) was treated with sucrose (142 g). The mixture was stirred at 25° C. for 6 h. At this time, 4-hydroxy-5,6-dihydro-2H-thiopyran-3-carboxylic acid methyl ester (4.06 g, 23.31 mmol) was added. The resulting slurry was stirred at 25° C. for 22 h and then was filtered through a pad of celite. The filtrate was extracted with ethyl acetate (5×300 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 hexanes/ethyl acetate) afforded 4(S)-hydroxy-tetrahydro-thiopyran-3(R)-carboxylic acid methyl ester (4.08 g, 99.3%) as a colorless oil: [α]23589=+37.76° (c=2.9, methanol)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4](I)[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[CH3:37])[CH:3]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a solution of N-(6-chloro-4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (200 mg, 393 μmol) in DME (4 mL) under argon atmosphere was added 4-fluoro-2-methylphenylboronic acid (66.6 mg, 433 μmol, CAS RN 39911-29-8) and 2M aqueous Na2CO3 solution (1 mL). The reaction mixture was stirred for 15 minutes. Pd(II)acetate (4.41 mg, 19.7 μmol) and triphenylphosphine (10.3 mg, 39.3 μmol) were added and the reaction was stirred at 90° C. for 18 hours. The reaction mixture was poured on 10% aqueous NaHCO3 solution (30 mL) and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless solid (157 mg, 81.3%). MS (TurboSpray): m/z=491.075 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C@@H:16]([CH:22]([CH3:24])[CH3:23])[CH2:15]1.O1CCOCC1.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:23][CH:22]([C@H:16]1[CH2:15][C@@H:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:33]4[CH:34]=[CH:35][S:31][CH:32]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][S:17]1(=[O:21])=[O:20])[CH3:24]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)[C@H]1C[C@@H](c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@H]1C[C@@H](c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CCS1(=O)=O
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
5-Bromo-3-[cis-2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-7-carboxamide (37 mg, 0.090 mmol) was placed in a microwave vial and dissolved with 1,4-Dioxane (1 mL) and Water (0.500 mL). Thiophene 3-boronic acid (22.91 mg, 0.179 mmol) and K2CO3 (37.1 mg, 0.269 mmol) were added. Argon was bubbled in the mixture for 10 mins, stirring. PdCl2(dppf) (3.45 mg, 7.16 μmol) was added, and argon was bubbled another 10 mins. The vial was sealed and put under microwave 5 mins at 100° C. with high absorption parameter. The mixture was run through a thiol-SPE column, eluting with methanol. The collected solution was concentrated in vacuo. The brown solid was dissolved in 2-3 mL of DMSO, and run through the ammonium Gilson, in 3 injections to afford 10 mg of the title compound. The cis stereochemistry of the product was confirmed by a 1H NMR NOE study.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:20]([Mg]Br)[CH3:21].C(OCC)C>C1COCC1>[OH:2][CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:20][CH3:21]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(C(O)CC)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Ethyl 4-(6-formylpyridin-3-yl)benzoate (500 mg, 1.9 mmol) in THF (15 mL) was cooled to 0° C., 3M Ethyl magnesium bromide in diethyl ether (1.3 mL, 3.9 mmol) was slowly added at 0° C., and the reaction mixture was stirred for 2 h at 0° C., while monitoring reaction progress by TLC. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120 microns) using 15% ethyl acetate in hexane eluent to afford ethyl 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzoate as a brown liquid (250 mg, 44.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 8.13-8.11 (d, 1H), 8.04 (d, 2H), 7.87 (d, 2H), 7.57 (d, 1H), 5.33 (d, 1H), 4.57-4.53 (m, 1H), 4.35-4.30 (m, 2H), 1.89-1.76 (m, 1H), 1.68-1.34 (m, 1H), 1.24 (t, 3H), 0.86 (t, 3H), LC-MS m/z calcd for [M+H]+ 286.14. found 286.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16](=[O:17])[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[BH4-].[Na+]>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([OH:17])[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2O
Temperature: 50 °C

Procedure:
A mixture of the product from step (ii) (1.43 g), and sodium borohydride (0.42 g) in ethanol (100 ml) and dichloromethane (20 ml) were heated at 50° C. for 4 h. The solvents were evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with dilute aqueous sodium hydroxide solution, dried (CaCl2), and evaporated to give the subtitled product as a brown solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[CH:3]=[C:4]([C:9]([O:11]C)=[O:10])[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+]>CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:8][O:7][C:5]([CH:4](/[CH:3]=[C:2](\[CH3:1])/[CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[C:9]([OH:11])=[O:10])=[O:6]
Reactant: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(/C=C(\C)CCC1=C(C)CCCC1(C)C)C(=O)O
Reaction time: 0.5 h

Procedure:
Conjugated malonate 3a (0.5 g, 1.5 mmol, from a 5% stock solution in methanol) was incubated with 375 Units Pig Liver Esterase (Sigma-Aldrich) in 100 mM potassium phosphate buffer pH 7.5, at 25 and with constant stirring. After 20 h of incubation the pH of the reaction mixture was set to 9 with 30% NaOH followed by incubation at room temperature for 30 min with constant stirring. The reaction mixture was then extracted 3 times with 250 ml tert-butyl methyl ether. The organic phase was washed twice with 125 ml deionized water and once with saturated NaCl solution, dried over Na2SO4 and finally evaporated under reduced pressure at 45° C. 0.4 g of conjugated malonate 3a were recovered. The pH of the aqueous phase left from the basic (pH 9) extraction was set to 3 with conc. HCl, Extraction with tert-butyl methyl ether, washing with water and saturated NaCl, drying over Na2SO4, filtration and evaporation under reduced pressure at 45° C. gave 62 mg (13%) of deconjugated half malonate 1a as colorless oil and E/Z 72:28 according to NMR. The suppression of byproduct 1b depends on the quality of the PLE employed, with aged PLE (>1 year) giving exclusively isomer 1a. Analytical data of the E-isomer: 1H-NMR (400 MHz, CDCl3): δ0.96 (s, 6 H), 1.56 (3 H), 1.67 (s, 3 H), 1.4 (2 H), 1.5 (2 H), 1.9 (2 H), 2.0 (4 H), 3.6 (s, 3 H, OMe), 4.2 (d, 1 H), 5.4 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): 16.4 (q), 19.1 (t), 19.6 (q), 27.2 (t), 28.4 (2 q), 32.3 (t), 34.6 (s), 39.3 (t), 39.7 (t), 50.9 (d), 52.2 (q), 116.3 (d), 126.8 (s), 136.3 (s), 141.0 (s), 169.1 (s), 169.6 (s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13](O)[CH3:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:13]=[CH2:14])([O-:3])=[O:2]
Reactant: CC(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
3,5-Dinitrophenylethanol (1.0 g, 4.7 mmol) was mixed with P2O5 (1.0 g, 0.71 mmol) and the stirred mixture was heated to 100° C. After 3 h, the mixture was allowed to cool to room temperature and water (0.4 ml) was added. The pH was adjusted to 9 using 1 M aqueous NaOH and extracted with diethyl ether (2×25 ml). The combined organic phases were dried (Na2SO4) and evaporated. The crude product was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH2:20][CH2:19]3)[C:12]3[CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)=[C:4]([F:32])[CH:3]=1.[OH-].[Na+].Cl.Cl.CCOC(C)=O>C1COCC1.O.C1COCC1.CCO>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:22][CH2:23]3)[C:12]3[CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)=[C:4]([F:32])[CH:3]=1
Reactant: CCOC(=O)CCCC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CCC3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCCC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CCC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 134.4 %

Procedure:
A mixture of 37.04 g ethyl 4-{1-[2-(4-chloro-2,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperidin-4-yl}butanoate, 160 ml of 1M aqueous sodium hydroxide, and 400 ml of THF-EtOH (1:1) was stirred at ambient temperature for 4 hours. To the reaction mixture, 160 ml of 1M hydrochloric acid aqueous solution and 700 ml of water were added, and the mixture was extracted twice with chloroform. The organic phase obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The solid obtained was dissolved in 300 ml of THF, 50 ml of 4M HCl-EtOAc solution was added, the solution was concentrated under reduced pressure, and the resultant solid was recrystallized from water-acetonitrile to yield 25.35 g of 4-{1-[2-(4-chloro-2,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperidin-4-yl}butanoic acid hydrochloride.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[C:15]([C:26]([O:28]C)=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:24][CH3:25])=[CH:19][CH:18]=2)C.C(O)(=O)C>O1CCCC1>[CH3:25][O:24][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]=[C:15]3[C:14](=[CH:23][C:22]=2[CH:21]=1)[NH:13][CH:12]=[C:7]([C:6]#[N:8])[C:26]3=[O:28]
Reactant: COC(=O)c1cc2ccc(OC)cc2cc1/N=C/N(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2cc3c(=O)c(C#N)c[nH]c3cc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.81 mL (7.03 mmol) of n-butyllithium (2.5M in hexane) in 2.0 mL of tetrahydrofuran at −78° C. is added dropwise a solution of 0.448 mL (8.44 mmol) of acetonitrile in 4.4 mL of tetrahydrofuran. After completion of addition, the suspension is stirred for 10 minutes. To this is added 804.5 mg (2.81 mmol) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate in 18 mL of tetrahydrofuran dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour and at −5° C. for 1 hour. The reaction mixture is again cooled to −78° C. and 4.0 mL (69.9 mmol) of acetic acid is added dropwise. The reaction mixture is warmed up to room temperature and stirred overnight. The precipitate is collected by filtration and washed sequentially with water, acetonitrile and methanol. After drying in vacuo, this yields 468.6 mg (67%) of 8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>265° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]([F:26])([F:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:11]2=[O:27])=[CH:6][CH:5]=1.[Br:29]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]([F:25])([F:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:12]([Br:29])[C:11]2=[O:27])=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-n2c(C)cc(OC(F)(F)c3ccccc3)cc2=O)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(-n2c(C)cc(OC(F)(F)c3ccccc3)c(Br)c2=O)cc1
Yield: 85.5 %

Procedure:
Methyl-4-[4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (Step 2) (6.74 g, 17.49 mmol) suspended in acetonitrile (100 mL) was cooled in an ice-bath. N-bromosuccinimide (3.27 g, 18.36 mmol) was added. After 1 hour the ice-bath was removed and after an additional 30 minutes the reaction was diluted with acetonitrile (20 mL). The precipitate was collected by filtration to provide the title compound as an off-white solid (6.94 g, 85%). 1H NMR (300 MHz, CDCl3) δ8.20 (d, J=8.7 Hz, 2H), 7.61 (q, J=7.9 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H), 7.02-6.96 (m, 1H), 6.90 (app dt, J=2.4, 9.5 Hz, 1H), 6.14 (s, 1H), 5.28 (s, 2H), 3.98 (s, 3H), 2.00 (s, 3H). ES-HRMS m/z 464.0304 (M+H calcd for C21H16BrF2NO4 requires 464.0301).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:26])=[CH:23][CH:22]=1)[CH3:20])=[O:17]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44, 250 mg, 0.60 mmol), methanesulfonamide (60 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (139 mg, 0.73 mmol) and dimethylaminopyridiene (78 mg, 0.63 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The solution was washed with 1M hydrochloric acid, water, and brine, dried over sodium sulfate, and evaporated. The residue was purified by flush column chromatography on silica gel eluting with dichloromethane/methanol (40/1) to afford 292 mg (98%) of the title compound: 1H-NMR (CDCl3) δ 8.52 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz), 8.16–8.02 (1H, m), 7.81 (2H, d, J=8.3 Hz), 7.46 (2H, d, J=8.3 Hz), 7.23–7.10 (4H, m), 5.44–5.28 (1H, m), 3.41 (3H, s), 1.59 (3H, d, J=7.0 Hz); MS (ESI) m/z 492 (M+H)+, 490 (M−H)−.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([NH2:15])=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=O)[CH3:2]>C(O)(=O)C>[CH3:2][C:1]1[NH:15][C:14]2=[N:13][C:12]3[C:7]([N:6]=[C:5]2[N:4]=1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: CC(=O)Nc1nc2ccccc2nc1N
Solvent: CC(=O)O
Product: Cc1nc2nc3ccccc3nc2[nH]1

Procedure:
A solution of 19 parts of 2-acetamido-3-aminoquinoxaline in 200 parts of glacial acetic acid was heated at reflux for 30 minutes. Concentration in vacuo left a pale yellow solid. Recrystallization from ethyl acetate-methanol (2:1) gave 16.8 parts of pale yellow 2-methyl-1H-imidazo[4,5-b]quinoxaline, mp 360° (dec.).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][CH:16]=[N:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][CH:16]=[N:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2ncnc2c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2ncnc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-pentyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (20 mg, 0.081 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.11 mol). The reaction mixture was stirred at room temperature for 1 hour and then quenched by phenol. After removing solvent, the residue was purified by preparative LCMS (method B) to yield the desired product. 1HNMR (400 MHz, CD3OD): δ 8.30 (s, 1H), 4.30 (t, J=7.4 Hz, 2H), 1.86 (m, 2H), 1.41 (m, 4H), 0.93 (t, J=7.0 Hz, 3H). LCMS calculated for C11H14BrN6O (M+H): 325.0. found: 325.0, 327.0.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.O>CN(C)C=O.CS(C)=O.CN(C)C=O>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:11]2=[N:10][CH:9]=[CH:8][CH:7]=[C:6]2[CH:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
A solution of sodium hydride (1.44 g, 60 mmol) in dimethyl formamide/dimethyl sulfoxide (5:1, 120 mL) cooled to 0° C. was treated with a solution of 7-azaindole (4.72 g, 40 mmol) in dimethyl formamide dropwise. The mixture was then stirred at 0° C. for 15 min, then room temperature for 30 min and then recooled to 0° C. After this time, 2-(trimethylsilyl)ethoxymethyl chloride (10.62 mL, 60 mmol) was added dropwise. The mixture was then stirred for 30 min at 0° C. and then warmed to room temperature and stirred for 2 h. The mixture was then poured into water (200 mL) slowly. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. The orange oil was then purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 33% ethyl acetate/hexanes) to afford 1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (10.02 g, 99%) as a pale yellow liquid.