Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:6]1[CH:5]=[C:4]([F:3])[C:13]([O:14][CH3:15])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: COc1c(F)ccc2cccnc12
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1c(F)cc(Br)c2cccnc12
Temperature: 40 °C

Procedure:
Bromine (0.48 ml) was added dropwise to a solution of 7-fluoro-8-methoxyquinoline (1.6 g) in glacial acetic acid (24 ml). The mixture was heated to 40° C. for 4 h and the reaction quenched with 5% aqueous sodium metabisulphite (100 ml). The solution was basified with 25% aqueous sodium hydroxide to pH13 and the product extracted with ethyl acetate (3×150 ml). The extracts were combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in hexane to yield the desired product as a white solid (0.50 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[C:12]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Na]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[C:12]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc([N+](=O)[O-])cc2)cc(-c2ccccc2)n1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Temperature: 70 °C

Procedure:
The yellow suspension obtained by mixing ethyl 6-{[4-(4-nitrophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (5.3 g), stannous chloride (11.6 g) in ethanol (100 cc) is heated at 70° C. for 2 hours and 30 minutes under inert atmosphere. The clear brown solution thus obtained is concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water (100 cc). The pH of this aqueous phase is brought to 6 by addition of sodium hydrogenocarbonate. The solution is then extracted with ethyl acetate (3×200 cc). The organic phases are combined, washed with distilled water (3×50 cc), dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The residue obtained is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 7-3). (yellowish oil).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].CI.Cl[CH2:27]Cl>CN(C)C=O>[CH3:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)[C:5]([N:7]([CH3:27])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: ClCCl
Reactant: CN(C(=O)Nc1cccnc1)c1ccc2c(ccn2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)N(C)c1ccc2c(ccn2C)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of 80% sodium hydride (0.06 g; 2 mM) in dimethylformamide (5 ml), was added the monomethyl urea (E9) (0.5 g; 1.79 mM). After stirring at room temperature for 0.5 h, methyl iodide (0.12 ml; 1.93 mM) was added dropwise. Stirring was continued at room temperature for 1 h, then heated at 50° C. for 1 h. The reaction mixture was cooled in ice, then quenched with water. The mixture was then extracted with dichloromethane, washed with water, dried over sodium sulphate and evaporated to give the crude product (0.59 g). Chromatography on silica using dichloromethane as eluant afforded the title compound (0.31 g; 60%) which was recrystallised from cyclohexane to give a white solid (160 mg) m.p. 91°-92.5° C.
Reaction SMILES: [N:1]1([C:13](=[O:14])[C:12]2[N:10](C)[CH:9]=[N:8][C:7]=2[N:5](C)[C:3]1=[O:4])C.N1C(=O)C2N(C)C=NC=2N(C)C1=O.N1(C(=O)C2NC=NC=2N(C)C1=O)C>>[NH:1]1[C:13](=[O:14])[C:12]2[NH:10][CH:9]=[N:8][C:7]=2[NH:5][C:3]1=[O:4]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1

Procedure:
As is commonly known in the art, bracers can be obtained by extraction from a natural source or can be synthetically produced. Non-limiting examples of bracers include methylxanthines, e.g., caffeine, theobromine, and theophylline. Additionally, numerous other xanthine derivatives have been isolated or synthesized, which may be utilized as a bracer in the compositions herein. See e.g., Bruns, Biochemical Pharmacology, Vol. 30, pp. 325-333 (1981) which describes, inter alia, xanthine, 9-methyl xanthine, 7-methyl xanthine, 3-methyl xanthine, 3,7-dimethyl xanthine, 8-chloromethyl-3,7-dimethyl xanthine, 8-hydroxymethyl-3,7-dimethyl xanthine, 3,7-diethyl xanthine, 3,7-bis-(2-hydroxyethyl) xanthine, 3-propyl-7-(dimethylaminoethyl) xanthine, 1-methyl xanthine, 1,9-dimethyl xanthine, 1-methyl-8-methylthio xanthine, 8-phenyl-1-methyl xanthine, 1,7-dimethyl xanthine, 1,7-dimethyl-8-oxo xanthine, 1,3-dimethyl xanthine, 1,3,9-trimethyl xanthine, 8-fluoro theophylline, 8-chloro theophylline, 8-bromo theophylline, 8-thio theophylline, 8-methylthio theophylline, 8-ethylthio theophylline, 8-nitro theophylline, 8-methylamino theophylline, 8-dimethylamino theophylline, 8-methyl theophylline, 8-ethyl theophylline, 8-propyl theophylline, 8-cyclopropyl theophylline, theophylline-8-propionate(ethyl ester), 8-benzyl theophylline, 8-cyclopentyl theophylline, 8-cyclohexyl theophylline, 8-(3-indolyl) theophylline, 8-phenyl theophylline, 9-methyl-8-phenyl theophylline, 8-(p-chlorophenyl) theophylline, 8-(p-bromophenyl)theophylline, 8-(p-methoxyphenyl) theophylline, 8-(p-nitrophenyl) theophylline, 8-(p-dimethylaminophenyl) theophylline, 8-(p-methylphenyl)theophylline, 8-(3,4-dichlorophenyl) theophylline, 8-(m-nitrophenyl)theophylline, 8-(o-nitrophenyl)theophylline, 8-(o-carboxyphenyl)theophylline, 8-(1-naphthyl) theophylline, 8-(2,6-dimethyl-4-hydroxyphenyl) theophylline, 7-methoxy-8-phenyl theophylline, 1,3,7-trimethyl xanthine, S-chloro caffeine, S-oxo caffeine, S-methoxy caffeine, S-methylamino caffeine, 8-diethylamino caffeine, 8-ethyl caffeine, 7-ethyl theophylline, 7-(2-chloroethyl) theophylline, 7-(2-hydroxyethyl) theophylline, 7-(carboxymethyl) theophylline, 7-(carboxymethyl) theophylline (ethyl ester), 7-(2-hydroxypropyl) theophylline, 7-(2,3-dihydroxypropyl) theophylline, 7-b-D-ribofuranosyl theophylline, 7-(glycero-pent-2-enopyranosyl) theophylline, 7-phenyl theophylline, 7,8-diphenyl theophylline, 1-methyl-3,7-diethyl xanthine, 1-methyl-3-isobutyl xanthine, 1-ethyl-3,7-dimethyl xanthine, 1,3-diethyl xanthine, 1,3,7-triethyl xanthine, 1-ethyl-3-propyl-7-butyl-8-methyl xanthine, 1,3-dipropyl xanthine, 1,3-diallyl xanthine, 1-butyl-3,7-dimethyl xanthine, 1-hexyl-3,7-dimethyl xanthine, and 1-(5-oxohexyl)-3,7-dimethyl xanthine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[C@H:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]4[O:34][CH2:35][O:36][C:29]=34)=[O:24])[CH2:19][CH2:18]2)[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:44]([O:63][NH2:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(OCC)(=O)C>[C:44]([O:63][NH:64][C:14](=[O:16])[C@H:13]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:37][C:38]1[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]3[O:34][CH2:35][O:36][C:29]=23)=[O:24])[CH2:19][CH2:18]1)([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)O)C2CCN(C(=O)OCCc3cccc4c3OCO4)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C2CCN(C(=O)OCCc3cccc4c3OCO4)CC2)cc1
Reaction time: 18 h

Procedure:
To a solution of the crude 2-(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxyphenyl)-ethoxycarbonyl))-4-piperidinyl]acetic acid (0.66 mmol) in methylene chloride (35 ml) is added O-tritylhydroxylamine (547 mg, 1.98 mmol), N-methylmorpholine (0.44 ml, 3.97 mmol), 1-hydroxy-7-azabenzotriazole (90 mg, 0.66 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (165 mg, 0.86 mmol). The reaction mixture is stired at room temperature for 18 hours, diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product is purified by silica gel chromatography (2% to 4% methanol in methylene chloride) to provide N-(trityl-oxy)-2-(R)-[(4-methoxybenzenesulfonyl) (4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxy-phenyl)-ethoxycarbonyl))-4-piperidinyl]acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.O>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([C:16]([F:19])([F:17])[F:18])[CH:4]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(c1ccccc1)c1ccc(Br)c(C(F)(F)F)c1
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(Cc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of (4-bromo-3-(trifluoromethyl)phenyl)(phenyl)methanol (168 mg, 0.507 mmol) in 0.34 mL of anhydrous DCM (C=1.5M), were successively added dropwise trifluoroacetic acid (195 μL, 5 eq) and triethylsilane (243 μL, 3 eq). After 1 h45 of stirring at r.t., the reaction mixture was hydrolyzed with a saturated NH4Cl solution (5 mL). The layers were diluted with 20 mL of DCM and 20 mL of water and then separated. The aqueous layer was extracted with DCM (3×10 mL) The combined organic phase was washed with a saturated NaHCO3 solution (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane) to afford the desired product in 84% yield (135 mg) as uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.34 (tt, J=7.9, 1.8 Hz, 2H), 7.26 (t, J=7.3 Hz, 1H), 7.22-7.15 (m, 3H), 4.00 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 141.0 (C), 139.5 (C), 135.1 (CH), 133.6 (CH), 130.2 (q, J=31.3 Hz, C), 129.0 (CH), 128.9 (CH), 128.4 (q, J=5.4 Hz, CH), 126.8 (CH), 123.1 (q, J=273.4 Hz, C), 117.5 (q, J=1.9 Hz, C), 41.3 (CH2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]3)[S:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]O)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C:12]3[N:13]=[C:14]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]4)[S:15][CH:16]=3)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)[CH:29]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(O)cc(C(F)(F)F)c3)cs2)c1
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(OCc4cccnc4)cc(C(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (7 mL) of the compound (300 mg, 0.75 mmol) obtained in Example 86a, 3-pyridinemethanol (0.088 mL, 0.91 mmol) and triphenylphosphine (260 mg, 0.98 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (1.9M toluene solution, 0.51 mL, 0.98 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (370 mg, 100%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11](/[N:13]=[CH:14]/[N:15](C)C)=O)=[N:8][C:4]=2[CH:3]=1.[NH2:28]N>C(O)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:7]([C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11]3[N:13]=[CH:14][NH:15][N:28]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)n1c(-c2ccccc2-c2nc[nH]n2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-[1-dimethylamino-meth-(E)-ylidene]-benzamide (230 mg, 0.538 mmol) in glacial acetic acid (3 mL), followed by the addition of hydrazine (35% wt solution in water) (2 mL). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, washed with sat. NaHCO3 and brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-4% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (180 mg, 84%) as an off-white solid. LCMS (ESMS): m/z 396.68, 398.64 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15]([O:24][CH2:25][C:26]([O:28]C)=[O:27])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1.O.[OH-].[Li+].O.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15]([O:24][CH2:25][C:26]([OH:28])=[O:27])([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)COC1(c2ccccc2)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COC1(c2ccccc2)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl [(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-yl)oxy]acetate (40.0 mg, 0.0000966 mol, example 387) in tetrahydrofuran (1 mL, 0.01 mol) was added lithium hydroxide hydrate (4.87 mg, 0.000116 mol) in water (0.5 mL, 0.03 mol). The solution was stirred at rt for 2 hours and then acidified with 1N HCl (aq.). The product was purified by prep-HPLC. LCMS: m/z 400.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=O.Cl.C[O:16][NH2:17]>N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[N:17][OH:16])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Trifluoromethylacetophenone (13.6 g, 72.3 mmol) and O-methylhydroxylamine hydrochloride were combined in pyridine (100 mL) and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was suspended in diethyl ether. The suspension was filtered and the filter cake was washed with diethyl ether. The filtrate was washed with water, 1N HCl, and water. The organic phase was concentrated to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 7.90-7.68 (m, 4H), 3.97 and 3.78 (2s, 1H), 2.20 and 2.17 (2s, 3H); MS (DCI/NH3) m/e 218 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[N:6][C:7]=1[C:8]#[N:9].C(Cl)Cl.[C:31](O)([C:33](F)(F)F)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[N:6][C:7]=1[C:8]1[NH:3][C:2]([C@H:31]2[CH2:33][CH2:4][CH2:5][NH:6][CH2:7]2)=[N:1][N:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1nc(-c2cccc(C(=O)N[C@H]3CCc4ccccc43)c2)cnc1N
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Nc1ncc(-c2cccc(C(=O)N[C@H]3CCc4ccccc43)c2)nc1-c1nnc([C@H]2CCCNC2)[nH]1

Procedure:
A solution of 3-(5-amino-6-cyanopyrazine-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzamide (2.4 g, 6.6 mmol) and 1,1-dimethyl (3S)-3-(hydrazinocarbonyl)piperidine-1-carboxylate (2.4 g, 10.1 mmol) in NMP (3 mL) was heated to 180-200° C. for 1 h. The solvent was removed under reduced pressure. The residue obtained was stirred with CH2Cl2/TFA (20% v/v)) for 30 min., concentrated and purified by hplc. The compound was converted to the hydrochloride salt using a 4 M solution of HCl in dioxane to afford 3-(5-amino-6-{5-[(3S)-piperidin-3-yl]-4H-1,2,4-triazol-3-yl}pyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzamide: 1H NMR (400 MHz; CD3OD): 8.65 (s, 1H); 8.6 (d, 1H); 7.6 (t, 1H); 7.7-7.8 (m, 4H); 5.7 (t, 1H); 3.75-3.4 (m, 4H); 3.8-3.36 (m, 3H); 3.35-2.8 (m, 3H); 2.6 (m, 1H); 2.4 (m, 2H); 2.1-2.0(m, 4H); 1.3 (t, 3H); MS (EI) for C27H28N8O: 481 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][Sn:8](Cl)(Cl)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2].[S-2:18].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][Sn:8](=[S:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2]
Reactant: [S-2]
Reactant: CCOC(=O)CC[Sn](Cl)(Cl)CCC(=O)OCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC[Sn](=S)CCC(=O)OCC

Procedure:
To a solution of 78.4 L g (0.2 mole) bis(ethoxycarbonylethylene)tin dichloride in 160 ml toluene was added 15.6 g (0.2 mole) sodium sulfide as a 40% aqueous solution, while warming the mixture to maintain 85°-90° C. After the completion of the reaction, the layers were separated and the toluene solution of the product vacuum stripped to give the product as a viscous liquid, with refractive index 1.573 at 25° C. and infra-red absorption peaks at 1700, 1660, and 1190. The product analyzed 33.9% tin, (C2H5OCOCH2CH2)2SnS requires 33.7% Sn.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][S-:14].[Na+]>C(#N)C.CN(C=O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([S:14][CH3:13])[N:7]=1
Reactant: C[S-]
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1nc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 6-chloro-2-methoxy-3-nitropyridine (300 mg, 1.591 mmol) in acetonitrile/DMF (2:1, 3 mL) was added sodium thiomethoxide (133 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound (290 mg, 91%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:18]=[CH:19][C:20]([CH2:23][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:16]=[CH:15][C:10]4[NH:11][C:12](=[O:14])[NH:13][C:9]=4[CH:8]=3)[CH2:5][CH2:6]2)=[CH:21][CH:22]=1
Reactant: O=c1[nH]c2ccc(C3CCNCC3)cc2[nH]1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c2ccc(C3CCN(Cc4ccc(-c5ccccc5)cc4)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A representative procedure for the synthesis of the piperidinyl aldehydes is the following. To a solution of compound 5 (0.15 g, 0.45 mmol) and biphenyl-4-carbaldehyde a (0.1 g, 0.55 mmol) in DMSO (2 mL) at 0° C. was added Et3N (0.13 mL, 0.97 mmol). After being stirred for 0.5 h at room temperature, NaBH(OAc)3 (0.11 g, 0.53 mmol) was added, and the mixture was stirred for 6 h. To the reaction mixture was added sat. NaHCO3 solution (10 mL), and the mixture was stirred for 15 min, followed by the addition of ethyl acetate (30 mL). The organic layer was separated and washed with sat. NaHCO3 and brine, and dried over Na2SO4 and evaporated. The light yellow solid was crystallized from diethyl ether to obtain the title compound 5a. Yield: 51%, off-white solid, mp>260° C. IR (KBr, cm−1) 3429 (CONH), 3055 (Ar—H), 2966 (Alph-H), 1703 (CO), 1620, 1518, 1422 (C—C), 1226 (C—N), 1145 (C-0); 1H NMR (500 MHz, DMSO d6) δ 1.62-1.71 (m, 4H, 2CH2), 2.04 (m, 2H, CH2), 2.48 (m, 1H, CH), 2.92 (m, 2H, CH2), 3.51 (s, 2H, NCH2), 6.77-6.81 (m, 3H, 3Ar—H), 7.32 (m, 1H, Ar—H), 7.40-7.45 (m, 4H, 4Ar—H), 7.59-7.64 (m, 4H, 4Ar—H), 10.43 (br. s, 1H, NH), 10.48 (br. s, 1H, NH), 13C NMR (125.7 MHz, DMSO d6) δ 33.64 (CH2), 41.86 (CH), 53.66 (CH2), 59.45 (NCH2), 106.91 (Ar—C), 108.42 (Ar—C), 118.99 (Ar—C), 126.56 (Ar—C), 126.66 (Ar—C), 127.42 (Ar—C), 127.98 (Ar—C), 129.03 (Ar—C), 129.06 (Ar—C), 129.63 (Ar—C), 138.92 (Ar—C), 140.11 (Ar—C), 155.59 (C═O). Anal. Calcd for C25H25N3O: C, 78.30; H, 6.57; N, 10.96%. Found: C, 78.22; H, 6.63; N, 10.86%.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].CI.[C:17](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:17])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1ccc2c(c1)N(C)C(=O)CO2
Yield: 83.9 %

Procedure:
6-Acetyl-2H-benzo[b][1,4]oxazin-3(4H)-one (1 g, 5.23 mmol), methyl iodide (1.13 g, 7.84 mmol) and cesium carbonate (2.55 g, 7.84 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 6-acetyl-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.9 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.60 (d, 1H), 7.01 (d, 1H), 4.70 (s, 2H), 3.42 (s, 3H), 2.60 (s, 3H); MS (ESI) m/z: Calculated for C11H11NO3: 205.1. found: 206.1 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1S(C1C=CC(C)=CC=1)(=O)=O.[Mg]>CO>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2C)cc1
Agent: [Mg]
Solvent: CO
Product: C[C@@H]1Cc2ccccc2CN1
Reaction time: 96 h

Procedure:
To a solution of 31.15 g (103.15 mmol) of the monotosyl compound obtained in Step B in 500 mL of anhydrous methanol there are added, in portions, 3.92 g (161 mmol) of magnesium turnings. The batch is stirred in the presence of ultrasound for 96 hours. The reaction mixture is then filtered and the solid is washed several times with methanol. The filtrate is then concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and ammonia-in-ethanol as eluants, the title product is obtained in the form of an oil.