Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2>[Pd].CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2cc(O)ccc2cn1
Temperature: 25 °C

Procedure:
To a solution of methyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (0.72 g, 3.5 mmol) in xylenes (70 mL) was added 10% palladium on carbon (0.58 g). The mixture was heated at reflux for 18 h, and then cooled to rt. MeOH (5 mL) was added and the mixture was filtered through Celite. The solvents were evaporated and the residue was purified by column chromatography give methyl 6-hydroxyisoquinoline-3-carboxylate as yellow solid. (0.26 g, 36%). LCMS: (FA) ES+ 204.0, ES− 202.0.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](C3C(O)=CC=CN=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]3=[O:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Oc1cccnc1C1=CCC2(CC1)OCCO2
Reactant: O=c1cccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1ccccn1C1CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
A solution of 4-dioxaspiro[4.5]decan-8-yl methanesulfonate (497 mg, 2 mmol) from example 1, step A and pyridin-2(1H)-one (200 mg, 2 mmol) in DMF was treated with Cs2CO3 (1 g, 3 mmol) and heated at 80° C. for 18 h. DMF was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]2[CH2:14][CH2:15][NH:16][CH2:17][C:12]2=[CH:11][N:10]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([N:16]1[CH2:15][CH2:14][N:13]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:10][CH:11]=[C:12]2[CH2:17]1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Fc1ccc(-c2ncc3n2CCNC3)c(F)c1
Product: O=C(c1ccc(F)cc1F)N1CCn2c(cnc2-c2ccc(F)cc2F)C1

Procedure:
This compound 2 was prepared as described for Example 1 (Step H) starting from 50 mg of 3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Step D) and 2,4-difluorobenzoyl chloride. Yield: 14 mgs, [M+H]+ 376.18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9]CC)=[O:8])=[N:3][C:2]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[N:3][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1ccnc(C(=O)OCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Next, to a stirred solution of diethyl pyrimidine-2,4-dicarboxylate (130 mg, 0.58 mmol) in MeOH (3 mL) is added 1N NaOH (2 mL) and the mixture is stirred at room temperature for 3 hours. The solution is carefully acidified with 1N HCl and the solvent is removed under reduced pressure to give pyrimidine-2,4-dicarboxylic acid. This is used as is in subsequent reactions.
Reaction SMILES: [CH3:1][Li].[C:3]12([C:13](=[O:22])[CH:14]=[CH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>C1COCC1.CCOCC>[C:3]12([C:13](=[O:22])[CH2:14][CH:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH3:1])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: [Li]C
Reactant: O=C(C=Cc1cccnc1)C12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CC(=O)C12CC3CC(CC(C3)C1)C2)c1cccnc1
Temperature: -18 °C
Yield: 81.9 %

Procedure:
To a suspension of cuprous bromide-dimethylsulfide (1.28 g, 6.25 mmol) in THF (20 ml) cooled to -18° C., was added dropwise methyllithium (1.4 M; 8.93 ml, 12.5 mmol) in ether. The resulting clear solution was left to stir for a further 45 minutes before a solution of 1-(1-adamantyl)-3-(3-pyridyl)-2-propen-1-one (1.34 g, 5.0 mmol) in THF (8 ml) was added at -18° C. After 4 hours at 0° C. the reaction mixture was quenched with aqueous ammonium hydroxide solution and extracted with ether. The ether extracts were combined, dried (Na2CO3) and concentrated. Chromatography, on elution with petrol-ether-triethylamine 125:50:1, provided the title compound (1.16 g, 82%) as an oil. Analytical data were the same as given in Example 10.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].CC(C)([O-])C.[K+].[CH3:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[S:22])[CH2:20]Br)=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[S:22])[CH2:20][CH:3]([C:1]#[N:2])[C:4]([O:6][CH3:7])=[O:5])=[CH:17][CH:16]=1
Reactant: COC(=O)CC#N
Reactant: Cc1ccc(C(=S)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=S)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
5.70 g (57.6 mmol) of methyl cyanoacetate were dissolved in 150 ml of anhydrous tetrahydrofuran, and 7.10 g (63.3 mmol) of potassium t-butoxide were added to the resulting solution, whilst ice-cooling, and the mixture was then stirred for 30 minutes. At the end of this time, a solution of 14.11 g (57.6 mmol) of 4-methylthiophenacyl bromide in 50 ml of tetrahydrofuran was slowly added dropwise to the mixture, whilst ice-cooling. The mixture was stirred, whilst ice-cooling for 2 hours, and then a saturated aqueous solution of ammonium chloride and ethyl acetate were added. The insolubles were then filtered off. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and the solvent was then removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 1:2 by volume mixture of ethyl acetate and hexane, to give 3.11 g (yield 21%) of the title compound as a slightly yellow powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]=2[CH:10]=1
Reactant: Ic1ccccc1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c3ccccc3n(-c3ccccc3)c2c1
Reaction time: 12 h
Yield: 37.3 %

Procedure:
30.51 g (149.56 mmol) of iodobenzene, 18.32 g (74.78 mmol) of 2-bromo-9H-carbazole, 14.37 g (149.56 mmol) of sodium t-butoxide, and 1.81 ml (7.48 mmol) of tritertbutylphosphine were dissolved in 300 ml of toluene, and 0.68 g (0.75 mmol) of Pd2(dba)3 was added thereto, and refluxed and agitated for 12 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=9:1 (v/v) to obtain 8.99 g of 2-bromo-9-phenylcarbazole (yield 37%).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].[C:29]([OH:32])(=[O:31])[CH3:30]>C1COCC1.[Zn]>[C:29]([OH:32])(=[O:31])[CH3:30].[NH2:1][C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-azido-1-methyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in the previous step, 13.6 mg, 0.0362 mmol) and zinc (9.5 mg, 0.15 mmol) in 1 mL of THF was added acetic acid (0.20 mL). The resulting mixture was stirred at RT for 3 h under Ar. The solid was removed by filtration on Celite and the filtrate was concentrated in vacuo to give a light brown oil. The mixture was triturated with DCM (2×4 mL). The solvent was removed by filtration and the solid was dried in vacuo to give 13.5 mg (91%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.27 (s, 1H), 7.70 (s, 1H), 7.43 (d, 1H, J=7.3 Hz), 7.29 (s, 1H), 5.81 (m, 1H), 2.11-2.37 (m, 4H), 1.91 (s, 3H), 1.59-1.84 (m, 4H), 1.71 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:30](=[O:31])[CH2:29][C:24]2[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)CC(=O)OC)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-butyric acid methyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: Mixture of Diastereomers, MS m/z 437.2 (M+1). The diastereomers were separated using ChiralOD column, elute 85:15 heptane:ethanol; Flow Rate 85 mL/min. Diastereomer #1 (RT=9.39 min.) C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 19.2, 21.5, 21.6, 28.3, 30.5, 35.9, 41.9, 42.2, 43.0, 50.6, 50.7, 52.1, 53.1, 102.7, 104.9, 112.3, 112.5, 132.2, 138.0, 169.2, 169.6, 170.7; MS m/z 437.2 (M+1) Diastereomer #2 (RT=13.6 min.) C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 21.6, 35.8, 42.0, 43.1, 50.8, 52.1, 53.1, 102.9, 104.8, 112.3, 112.6, 132.4, 137.9, 169.3, 170.6; MS m/z 437.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(N(CC)CC)C>[CH2:20]([N:19]([CH2:17][CH3:18])[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CCNCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: CCN(Cc1ccccc1)C(=O)c1cnoc1-c1ccc(OC)cc1

Procedure:
The title compound was prepared from 5-(4-methoxyphenyl)isoxazole-4-carboxylic acid (11.0 mg, 0.050 mmol) and N-ethylbenzylamine (8.1 mg, 0.060 mmol) as described in synthetic method A (using 21 μL of triethylamine and 45 μL of 1-propanephosphonic acid cyclic anhydride) and thereafter purified by preparative HPLC method B (without the extraction step) to give a solid (10.5 mg). MS (pos) m/z 337.2 (M+H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl-].[In+3].[Cl-].[Cl-].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:27]2[CH2:29][C:28]2([F:31])[F:30])(O)[CH3:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH2:10]2)([CH:27]2[CH2:29][C:28]2([F:30])[F:31])[CH3:25])=[CH:22][CH:23]=1
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1(F)F
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Product: CSCc1cccc2c1NCC2C(C)(c1ccc(Cl)cc1)C1CC1(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
76.2 mg (0.43 mmol) of the compound from Example 8A, dissolved in 1 ml of toluene, were added to 190 mg (0.86 mmol) of indium(III) chloride and 100 mg (0.43 mmol) of the compound from Example 134A in 1 ml of toluene at RT, and the mixture was stirred at 80° C. for 2 h. Then a further 1.90 g (8.60 mmol) of indium(III) chloride were added, and the mixture was stirred at 80° C. for 1 h. It was diluted with toluene and washed with water, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 16.0 mg (10% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]([NH:20][C@H:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH3:22])=[O:19])[CH:11]=[CH:10]2)=[CH:4][CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Pd](Cl)Cl.O.O1CCOCC1>[C:32]1([C:2]2[N:7]=[CH:6][C:5]([CH2:8][N:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[C:18]([NH:20][C@H:21]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=4)[CH3:22])=[O:19])[CH:11]=[CH:10]3)=[CH:4][CH:3]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)nc3)c12)c1ccc(C(=O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(-c4ccccc4)nc3)c12)c1ccc(C(=O)O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a mixture of 4-{(1S)-1-[({1-[(6-chloropyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (0.15 g), phenylboronic acid (84 mg), tripotassium phosphate (0.22 g), palladium (II) chloride (9.2 mg), and biphenyl-2-yl(dicyclohexyl) phosphine (36 mg) were added dioxane (6.0 mL), water (1.5 mL), followed by stirring at 100° C. for 1 hour. The reaction mixture was adjusted to pH 3 by adding a 10% aqueous citric acid solution. The mixed liquid was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF=2/1-1/1) to obtain 4-{(1S)-1-[({1-[(6-phenylpyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (66 mg).
Reaction SMILES: [OH:1][C:2]1([C:15]#[C:16][CH2:17][OH:18])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C.O>[Pd].C(O)C>[OH:1][C:2]1([CH2:15][CH2:16][CH2:17][OH:18])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CCO)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCCO)CC1
Yield: 57 %

Procedure:
Palladium on carbon (5%, 800 mg) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (from step (ii) above; 8.37 g, 32.8 mmol) in ethanol (400 ml), acetic acid (40 ml) and water (5 ml) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 20 hours. The mixture was filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (4.84 g, 57%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=O)[CH2:5]1)(=[O:3])[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[NH:22][N:23]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)N1CCC(=O)C(C(=O)c2cccc(C#N)c2)C1
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCc2[nH]nc(-c3cccc(C#N)c3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-(1-Acetyl-4-oxo-piperidine-3-carbonyl)-benzonitrile (2a) (8 g, 29.6 mmol) in ethanol (26 ml) at 10° C. hydrazine hydrate (4.44 g, 88.8 mmol) was added slowly within 5 min. The mixture was stirred 3 h and allowed to warm to room temperature overnight. The mixture was concentrated to ¼ of its volume until a precipitate formed. The suspension was stirred for 2 h, cooled down and filtrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: COc1cccc(CCl)c1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(OC)c5)o4)cc23)cc1
Yield: 87 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1
Reactant: CCOC(=O)C=Cc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCCO)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Synthesized from 3-(3,5-dimethoxyphenyl)acrylic acid ethyl ester according to an analogous synthetic method to Example 22,ethyl 3-(3,5-dimethoxyphenyl)propionate (38.4 g) was added dropwise to a solution of lithium aluminum hydride (12.3 g) in tetrahydrofuran (200 ml) on an ice bath, and the solution was stirred for 15 minutes at room temperature. To the reaction solution were sequentially added water (12 ml), an aqueous solution of 5N sodium hydroxide (12 ml) and water (28 ml), the suspension was filtered, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (24.3 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=3)[O:10][C:3]=12.[CH3:20][C:21]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:30][C:29]3[C:21]([CH3:20])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)[CH:8]=2)=[CH:12][C:13]=1[CH3:19]
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1C
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1C

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(4-methoxy-3-methylphenyl)furo[3,2-b]pyridine (29.40 mg; 0.11 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (16.49 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (30 mg, 73%). (HPLC (method F): 97%, RT: 4.34 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.14 (s, 1H), 8.49 (s, 1H), 7.92 (d, J=5.5, 1H), 7.77 (d, J=8.6, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 7.30 (d, J=8.4, 1H), 7.22 (s, 1H), 7.02 (dd, J=17.9, 8.5, 2H), 6.52 (s, 1H), 6.09 (d, J=5.5, 1H), 3.85 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H); MS (m/z) 384 [M+H]+, RT: 4.2 min.
Reaction SMILES: [C:1](/[C:3](/[CH:6](OC)OC)=[CH:4]\[O-])#[N:2].[Na+].Cl.[S:13]1[CH:17]=[C:16]([NH2:18])[C:15]([NH2:19])=[CH:14]1>CO>[NH2:19][C:15]1[C:16]2=[N:18][CH:4]=[C:3]([C:1]#[N:2])[CH:6]=[C:17]2[S:13][CH:14]=1
Reactant: Nc1cscc1N
Reactant: COC(OC)/C(C#N)=C/[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnc2c(N)csc2c1
Reaction time: 0.08 h
Yield: 23.3 %

Procedure:
To a solution of sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (1012 mg, 6.13 mmol) in methanol (12 mL) was added concentrated hydrochloric acid (503 μL 6.13 mmol). The solution was stirred for 5 minutes, and then a solution of thiophene-3,4-diamine (700 mg, 6.13 mmol) in methanol (12 mL) was added. The solution was stirred at reflux for 3 hours, and then a solution of concentrated HCl (1.0 mL) in methanol (2 mL) was added. The reaction was stirred at reflux for an additional two hours, quenched with TEA (3 mL), and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-100% ethyl acetate in heptanes, to provide the title compound (250 mg, 1.427 mmol). MS m/z=176 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([NH:17][C:18](=[O:24])[C:19]([O:21]CC)=O)[CH:15]=[CH:16][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:27])[CH3:26]>C1COCC1>[CH2:25]([NH:27][C:19](=[O:21])[C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:10]2[C:11]([N:13]=1)=[N:12][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:8][N:9]=2)=[O:24])[CH3:26]
Reactant: CCN
Reactant: CCOC(=O)C(=O)Nc1ccc2ncc(-c3ccccc3)nc2n1
Solvent: C1CCOC1
Product: CCNC(=O)C(=O)Nc1ccc2ncc(-c3ccccc3)nc2n1

Procedure:
23 mg (0.07 mmol) of ethyl N-(3-phenylpyrido[2,3-b]pyrazin-6-yl)oxalamidate were dissolved in 5ml of dry THF and admixed with 0-15 ml (0.38 mmol) of a 2.0 M ethylamine solution in THF.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([O-:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30]([CH3:41])=[CH:29][CH:28]=1)([OH:21])=[O:20].[CH3:42][N+:43]([CH2:46][C:47]([OH:49])=[O:48])([CH3:45])[CH3:44]>CO.O>[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30](/[CH:41]=[CH:15]/[C:9]2[C:10](=[O:14])[O:11][C:12]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=3)=[CH:29][CH:28]=1)([OH:21])=[O:20].[CH3:42][N+:43]([CH2:46][C:47]([OH:49])=[O:48])([CH3:45])[CH3:44]
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Reactant: Cc1cc[n+](CCCCCC(=O)O)c2ccc(S(=O)(=O)[O-])cc12
Agent: C[N+](C)(C)CC(=O)O
Solvent: O
Solvent: CO
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)c4ccc(S(=O)(=O)O)cc34)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-4-methyl-6-sulfonato-chinolinium betaine are converted according to the general directions given above. Column chromatography: SiO2 (RP 18), eluent: methanol/water.