Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:10])C=C[C:4]1[CH:9]=CC=CC=1.[N:11]([CH2:14][C:15](OC)=O)=[N+]=[N-].[N-]=[N+]=[N-].C1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)C2C=CC=CC=2)C=CC=CC=1>>[PH3:28]=[N:11][CH:14]=[CH:15][CH:9]=[CH2:4].[CH:1](=[O:10])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=CC=Cc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [N-]=[N+]=[N-]
Product: C=CC=CN=[PH3]
Product: O=Cc1ccccc1

Procedure:
Scheme 5 illustrates a method for the synthesis of title compounds of general formula I wherein the R1 substituent is an carboxylic ester or similar functional group that can in turn be prepared from an ester. In this synthetic method, a cinnamaldehyde of general formula 22 is used as the starting material. If the cinnamaldehyde derivative of general formula 22 with the desired substitution pattern is not readily available, it may be prepared in two step from the cinnamic acid of general formula 20 as shown. In this case the cinnamic acid of general formula 20 is converted to a mixed anhydride with a reagent such as ethyl chloroformate in a solvent like THF. The intermediate mixed anhydride is then reduced with sodium borohydride which affords a cinnamyl alcohol of general formula 21. The cinnamyl alcohol of general formula 21 is then oxidized to the cinnamaldehyde of general formula 22 using one of the methods for the oxidation of alcohols known in organic synthesis. For example reaction of the cinnamyl alcohol of general formula 21 with DMSO and oxalyl chloride using the Swern modification of the Moffatt reaction affords the cinnamaldehyde 22. The aldehyde 22 is condensed with methyl azidoacetate under basic conditions to afford the azidodiene 23. Reaction of the azide 23 with triphenylphosphine affords the intermediate 2-aza-1λ5-phosphahexa-1,3,5-triene 24 which condenses with an benzaldehyde of general formula 25 to yield the methyl 5,6-diarylpyridine-2-carboxylate 26 after endocyclic ring closure and air oxidation of an intermediate dihydropyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=CC=C[C:5]=1[NH2:6])([O-:3])=[O:2].C([C:15]1[CH:20]=[C:19](C)[CH:18]=[C:17](C(C)(C)C)[C:16]=1O)(C)(C)C.C(N(CC)CC)C.C(Cl)(=[O:37])C=C>CN(C1C=CN=CC=1)C.ClCCl>[N+:1]([C:4](=[CH2:10])[C:5]([NH:6][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:37])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)Nc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 239 %

Procedure:
To a mixture of 2-nitroaniline (1.73 g, 12.5 mmol), DMAP (321 mg, 2.6 mmol) and 2,6-di-tert-butyl-4-methylphenol (308 mg) in dry dichloromethane (50 mL) at 0° C. was added triethylamine (10.6 mL, 76 mmol) followed by acryloylchloride (3.2 mL, 38 mmol, 3.0 equiv.), and the mixture was stirred at room temperature for 16 h. The solution was diluted with dichloromethane (250 mL), cooled to 0° C. and the excess of reagent quenched with saturated NaHCO3 (stirring for 1 h). The organic layer was then washed (5% KHSO4, then brine), dried (MgSO4), filtered and concentrated under reduced pressure. After purification through chromatographic column on silica gel (elution 50% ether in hexanes), 642 mg (3.34 mmol, 27% yield) of the amide was obtained. 13C NMR (300 MHz, CDCl3) δ (ppm): 163.6, 136.0, 135.6, 134.5, 131.3, 128.6, 125.4, 123.1, 121.8. LRMS=193.2 (M+1).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:2].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.C(N(CC)CC)C>C(Cl)Cl.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][B:19](/[CH:2]=[CH:1]/[CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[O:18]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A solution of tert-butyl 4-ethynylpiperidine-1-carboxylate (0.414 g, 1.98 mmol) in methylene chloride (1 mL) was added with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.380 g, 2.97 mmol) and triethylamine (0.0201 g, 0.198 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with bis(cyclopentadienyl)zirconium(IV) chloride hydride (0.0766 g, 0.297 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]piperidine-1-carboxylate (0.600 g, 89%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[N:14]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])[CH:15]=[CH:16][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCOCC1.Cl>O.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([C:13]1[N:14]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
1N-Sodium hydroxide solution (1.5 ml) was added to a mixture of methyl 3-(2-benzyloxycarbonylpyrrol-1-yl)benzoate (0.5 g) and dioxane (20 ml), and the mixture was stirred for 3 days at ambient temperature. The reaction mixture was poured into the mixture of ethyl acetate and water and the separated aqueous layer was adjusted to pH 1 with 6N-hydrochloric acid. The mixture was extracted with ethyl acetate and extract was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with n-hexane to give 3-(2-benzyloxycarbonylpyrrol-1-yl)benzoic acid (0.24 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(c2ccc(F)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Methyl 2-(2,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (2.34 g, 8.02 mmol) was dissolved in DCM (50 mL), then DIPEA (3.50 mL, 20.05 mmol) was added. Methyl carbonochloridate (0.884 mL, 11.23 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h, washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(2,4-difluorophenyl)piperidine-1,4-dicarboxylate (2.38 g, 95%) as an orange oil.
Reaction SMILES: [CH2:1]([N:3]([S:30]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)(=[O:32])=[O:31])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][C:15]([CH2:18][O:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[CH:16][N:17]=1)=[CH:9]2)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.CO>[CH2:1]([N:3]([S:30]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:32])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][C:15]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=3)=[CH:16][N:17]=1)=[CH:9]2)[CH3:2]
Reactant: CCN(c1cccc2cc(-c3ncc(COc4ccc(C(=O)OC)cc4)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(c1cccc2cc(-c3ncc(COc4ccc(C(=O)O)cc4)s3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 53.4 %

Procedure:
Methyl 4-[(2-{7-[ethyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methoxy]benzoate (98 mg), tetrahydrofuran (2 mL), methanol (2 mL) and 1N aqueous sodium hydroxide solution (2 mL) was stirred at 50° C. for 16 hr. The reaction mixture was acidified with 1N hydrochloride, diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtrated. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography and recrystallized from an ethyl acetate-hexane (4:1) mixture to give the title compound (51 mg, yield 54%) as crystals. melting point 188° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][C:26](O)=[O:27])=[CH:19][CH:18]=1.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:26](=[O:27])[CH2:25][C@H:24]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:23][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=2)[CH2:2]1
Reactant: c1ccc2[nH]c([C@@H]3CCCNC3)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3[nH]2)C1)Cc1ccc(Br)cc1
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
(R)-2-(Piperidin-3-yl)-1H-benzo[d]imidazole (5A) (0.29 mmol, 58 mg) in DMF (15 mL) was added (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.32 mmol, 115 mg) and N-methylmorphine (1.16 mmol, 0.13 mL). The reaction mixture was stirred at rtfor 5 min and then added HATU (0.32 mmol, 122 mg) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by preparative LC/MS (35-60% CH3CN in H2O) to afford tert-butyl (R)-4-((R)-3-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(4-bromophenyl)-4-oxobutan-2-ylcarbamate (5B) (0.22 mmol, 120 mg, two-step yield: 75.9%). ESI-MS: m/z 542.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O.[NH2:10][NH2:11]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:10][NH2:11])[CH2:4][CH2:3]1
Reactant: NN
Reactant: CN1CCC(=O)CC1
Solvent: CO
Solvent: O
Product: CN1CCC(=NN)CC1

Procedure:
1-Methyl-piperidin-4-one (22.6 g, 0.2 mol) and methanol (200 mL) were charged to a 500 mL three-necked flask fitted with an addition funnel. The vessel was cooled in an ice bath and kept under a nitrogen atmosphere while a solution of hydrazine monohydrate (5 g, 0.1 mol) in 50 mL of methanol was added drop-wise over a period of one hour. A white precipitate formed after about half of the hydrazine was added. Stirring was continued overnight, and subsequent TLC indicated one product. The methanol was removed in vacuo, and the residue was slurried in hexane and filtered to provide N,N′-bis-(1-methyl-piperidin-4-ylidene)-hydrazine. 1H NMR (300 MHz, CDCl3) δ (ppm): 2.6 (m, 8H), 2.5 (m, 8H), 2.33 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH2:24][C:25]([CH3:39])=[CH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=[O:28].C(O)(=O)C>CC(O)C>[CH3:23][C:16]1[NH:24][C:25]([CH3:39])=[C:26]([C:27](=[O:28])[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:31][CH:30]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(N)=CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(C(C)(C)C)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 69 mg (0.53 mmol) of ethyl 3-oxobutanoate, 115 mg (0.53 mmol) of 3-amino-1-[4-(tert-butyl)phenyl]but-2-en-1-one and 5 μl (0.053 mmol) of acetic acid in 8 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 169 mg (64% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])C.FC(F)(F)C(O)=O.CCOC(C)=O.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[O:13]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][N:7]1[CH2:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(CCN1CCCCC1=O)OCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCCN1CCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[3,3-bis(ethyloxy)propyl]-2-piperidinone (1.52 g, 6.61 mmol) in CH2Cl2 (100 mL) under nitrogen was treated with trifluoroacetic acid (TFA) (1.5 mL, 19.5 mmol) and stirred at ambient temperature for 1 h. After adding an additional 1.5 mL of TFA and monitoring by TLC (EtOAc, KMnO4 stain) for complete consumption of starting materials the reaction mixture was partitioned between CH2Cl2 and 1:1 Sat. NaHCO3:water (150 mL) solution. Extracted the aqueous with CH2Cl2 two additional times before combining the organics, washing them with brine, drying over MgSO4, filtering, and concentrating in vacuo to provide the desired product as a clear oil: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78-1.91 (m, 4 H), 2.67 (t, J=6.11 Hz, 2 H), 2.85 (td, J=6.42, 0.91 Hz, 2 H), 3.50 (t, J=5.48 Hz, 2 H), 3.71 (t, J=6.32 Hz, 2 H), 9.53-9.58 (m, 1 H); ES+ MS: 156 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14]([C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:15][C:10]2=[N:9][N:8]=1.C(Cl)(Cl)Cl.CC#N.I([O-])(=O)(=O)=[O:33].[Na+]>O.O.[Ru](=O)=O>[O:33]=[C:15]1[N:14]([C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]12
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1=O
Reaction time: 4 h
Yield: 367.9 %

Procedure:
To a vigorously stirred solution of 2-(trimethylsilyl)ethyl 3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (172 mg, 0.5 mmol) in 1:1 CHCl3:MeCN (3.8 mL) was added a solution of ruthenium (IV) oxide hydrate (9.8 mg, 0.07 mmol) and sodium metaperiodate (504 mg, 2.3 mmol) in water (4.7 mL). After 4 h, the reaction mixture was diluted with water and extracted with CHCl3 (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a green oil. Purification by chromatography (SiO2; EtOAc—10% IPA/EtOAc) provided the desired product as a white solid (663 mg, 63%). MS (ESI): mass calcd. for C15H20H6O3Si, 360.1; m/z found, 361.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.59 (d, J=1.5 Hz, 1H), 8.63 (d, J=2.5 Hz, 1H), 8.55 (dd, J=2.5, 1.6 Hz, 1H), 4.88-4.75 (m, 2H), 4.47-4.33 (m, 2H), 4.33-4.24 (m, 2H), 1.18-1.04 (m, 2H), 0.04-(−0.02) (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:25](=[O:26])[CH2:24][C:17]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Product: COc1ccc(OC)c(CC(=O)NCCc2ccc(OC)c(OC)c2)c1

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 2,5-dimethoxyphenyl acetyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.BrC1C=CC(C(C)C)=C(F)C=1.[CH:21]1([C:26]([OH:39])([C:37]#[CH:38])[CH2:27][C:28]2[O:33]C(C)(C)O[C:30](=[O:36])[CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:26]2([CH2:37][CH2:38][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=3)[O:39][C:30](=[O:36])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: CCc1cccc(Br)c1
Agent: CC(C)c1ccc(Br)cc1F
Product: CCc1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1

Procedure:
The title compound was prepared analogously to Example A(64), where 1-Bromo-3-ethyl-benzene was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzene of that example and Enantiomer B of 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one was used in place of the racemic alkyne.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=2)=[CH:4][N:3]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:4][N:3]=1
Reactant: COc1cccc(-c2cnc(N)cn2)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1cnc(-c2cccc(O)c2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 17.9 %

Procedure:
2-amino-5-(3-methoxyphenyl)pyrazine (566 mg) was dissolved in methylene chloride (10 mL). To this mixture was added under ice-cooling boron tribromide (530 μL) and the whole was stirred at room temperature for 14 hours. To the reaction mixture was added 1N aqueous sodium hydroxide. The whole was extracted with ethylacetate (30 mL×2). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent provides the subject compound (94 mg) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Na+].C(O)(=O)C>CO.O>[F:20][CH:18]([F:19])[O:17][C:10]1[C:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)=[C:8]([CH3:33])[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:11]=1
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.1 %

Procedure:
A solution of [2-difluoromethoxy-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.43 g) in methanol (7.0 mL) and water (0.7 mL) was treated with 5.0 M aqueous sodium hydroxide solution (0.36 mL), and the resulting mixture was stirred at room temperature for 1.5 hours. The mixture was acidified by the addition of glacial acetic acid, diluted with water and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel gave title compound as a white solid (0.034 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6]1.[C:29](=[O:32])([O-])[O-].[K+].[K+].[I-].[Na+].O.[C:38]([O:41][CH2:42]C)(=O)[CH3:39]>C(O)C>[NH3:7].[CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:6][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:23])([F:24])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:8][CH2:9][N:10]1[CH2:39][CH2:38][O:41][CH2:42][CH2:29][OH:32]
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCCC1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCOCCO
Product: N
Reaction time: 22 h
Yield: 23 %

Procedure:
Add (S)2-(2-chloro-ethoxy)-ethanol (0.267 mL, 2.53 mmol) to a slurry of (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.52 g, 1.26 mmol), powdered potassium carbonate (0.87 g, 6.32 mmol), and sodium iodide (0.95 g, 6.32 mmol) in absolute ethanol (5.2 mL), and heat to reflux. After 22 hours, cool and add powdered potassium carbonate (0.09 g, 0.65 mmol), sodium iodide (0.09 g, 0.60 mmol), and (S)-(2-2-chloro-ethoxy)-ethanol (0.100 mL, 0.938 mmol); rinse in solids with absolute ethanol, and reflux. After 4 hours, add (S)-2-(2-chloro-ethoxy)-ethanol (0.307 mL, 2.88 mmol) and reflux. After 17.5 hours, cool and add deionized water and ethyl acetate. After separation of layers, extract aqueous layer with ethyl acetate (2×), and combine, dry (sodium sulfate), filter, and concentrate organics under reduced pressure to a solid (1.54 g). Purify the solid by flash chromatography, eluting with a gradient of solutions of 2M ammonia in methanol: ethyl acetate (1%-5% 2M ammonia in methanol in ethyl acetate over 61 minutes), and then with a 5% solution of 2M ammonia in methanol, in ethyl acetate for 30 minutes to give the title compound (0.146 g, 23%): mass spectrum (APCI, m/e): 500 (M+1); NMR (1H, 300 MHz, DMSO-d6) δ 8.47 (s, 1H), 6.96-6.81 (m, 3H), 6.71 (m, 1H), 4.60 (t, 1H, J=5.1 Hz), 3.56-3.10 (m, 15H), 2.76 (m, 2H), 2.61-2.41 (m, 3H), 1.68 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:34][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC1CCCCC1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC3CCCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 8.73 g (0.088 mol) of cyclohexylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.7 g (73.2%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 174°-176° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[Se](=O)=[O:10]>O1CCOCC1>[CH3:7][C:3]1[C:2]([CH:8]=[O:10])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccnc1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: Cc1cccnc1C=O
Yield: 37.3 %

Procedure:
2,3-Lutidine (1.0 g, 9.33 mmol) was refluxed in a 1,4-dioxane (20 ml) solution in the presence of selenium dioxide (1.24 g, 11.2 mmol) in an argon atmosphere for one hr. The temperature of the reaction solution was then returned to room temperature, and the reaction solution was filtered. The solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:2) to give 422 mg (37.3%) of 3-methylpyridine-2-carbaldehyde as a colorless liquid.