Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=2)[N:15]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:14]=1[CH3:37])=[N:11][OH:12].CC([O-])=O.[Na+].CC(OC(C)=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C:10]([C:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:19][CH:20]=4)[N:15]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:14]=3[CH3:37])=[N:11][O:12][C:2]=2[CH:7]=1
Reactant: COc1ccc(C(=NO)c2c(C)n(S(=O)(=O)c3ccc(C)cc3)c3cc(OC(F)(F)F)ccc23)c(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(-c3c(C)n(S(=O)(=O)c4ccc(C)cc4)c4cc(OC(F)(F)F)ccc34)noc2c1
Temperature: 110 °C

Procedure:
To a solution of 9 (3.8 g, 7.1 mmol) and NaOAc (3 eq, 1.8 g) in DMF (120 mL) was added Ac2O (3 eq, 2 mL). The reaction was heated to 110° C. for 4 hours at which time no starting material was detected by LC analysis. The reaction was cooled and diluted with DCM. The solution was washed with NH4Cl, brine and NaHCO3, then dried over Na2SO4 and concentrated. The residue was purified via flash chromatography eluding with 20% EtOAc/hexanes. Product was isolated as white foam.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[NH2:31][NH2:32].O>CN(C=O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:31][N:32]=[C:19]([CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCCc1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(CCCc3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a suspension of 4-hydroxy-3-(1-oxo-4-phenylbutyl)-1-phenyl-1,8-naphthyridin-2 (1H)-one (384 mg, 11.0 mmol, prepared in Synthetic Example 30) in DMF (4 ml) was added hydrazine monohydrate (80%, 160 μl, 4.0 mmol, 4.0 eq.), and the mixture was stirred at 100 to 110° C. for 2 hours. The reaction mixture was admixed with water, and filtered to give precipitates which were washed with water and dried to afford 5-phenyl-3-(3-phenylpropyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (354 mg, 93%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C>[ClH:26].[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=2[O:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCCNCC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCCNCC(F)(F)F

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-[2-(2,2,2-trifluoroethylamino)-ethoxy]-1H-pyrazole-3-carboxylic acid ethyl ester I-1g (48 mg, 0.1 mmol) and 6 N aqueous KOH (0.1 ml) in ethanol (1 ml) was heated at 50° C. for 2 hours. The reaction solution was cooled, acidified with concentrated aqueous hydrochloric acid, and concentrated in vacuo to a solid. These solids were slurried with ethanol, filtered and the remaining mass was washed with additional portions (2×) of ethanol. The combined filtrates were concentrated in vacuo to afford the title compound (I-1h), which was taken on the next step without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=2)[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:10](=[O:11])[C:9]2[CH:13]=[C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2)cc(OC2CCCC2)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(OC3CCCC3)c2)s1

Procedure:
The title compound was prepared from 3-cyclopentyloxy-5-(4-fluoro-phenoxy)benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]([CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:11][C:12]=1[CH3:13])(=O)=O.[CH3:25][N:26](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:7]1[CH:8]=[CH:9][C:10]([CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:11][C:12]=1[CH3:13])#[N:26]
Reactant: CN(C)C=O
Reactant: Cc1nc(CCC(=O)OC(C)(C)C)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(CCC(=O)OC(C)(C)C)ccc1C#N
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 729 mg (1.97 mmol) of tert-butyl 3-(5-trifluoromethylsulfonyloxy-6-methylpyridin-2-yl)propanoate (from Step E) and 464 mg (3.95 mmol) of zinc cyanide in 10 mL of DMF was added 137 mg (0.12 mmol) of tetrakis(triphenylphosphine)palladium(0). After stirring at 85° C. for 4 h, the reaction mixture was diluted with 10 mL of EtOAc and filtered through a cake of Celite. Solid was washed with EtOAc (3×10 mL) and the filtrate was concentrated. Chromatography on a Biotage 40M cartridge using 3:17 v/v EtOAc/hexanes as the eluant afforded 487 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 2.71 (d, J=7.4, 2H), 2.73 (s, 3H), 3.09 (d, J=7.3, 2H), 7.12 (d, J=8.0, 1H), 7.77 (d, J=8.0, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N:12]=[C:13]=[O:14].[CH2:15]([NH2:17])[CH3:16].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:10])([CH3:11])[CH3:9])[C:3]=1[NH:12][C:13]([NH:17][CH2:15][CH3:16])=[O:14]
Reactant: CCN
Reactant: C[Si](C)(C)c1cccc(Cl)c1N=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1c(Cl)cccc1[Si](C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of the compound of Example h (4 mmol) in 50 mL toluene was added 70% ethyl amine (4 mL). The solution was stirred for 0.5 h and then stood overnight. Ethyl acetate was added and the mixture was washed with water. The organic layer was concentrated to a semisolid, which was triturated with hexane. The title compound was collected by filtration as 0.9 g of crystals, an 83% yield. m.p. 161-163° C.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:2].O.O.P([O-])(O)(O)=O.[Na+].[Br-:18].[Na+].BrBr.[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.O1CCCC1>[Br:18][C:7]1[S:6][C:5]([CH2:4][NH:3][CH:1]=[O:2])=[N:9][CH:8]=1
Reactant: [Br-]
Reactant: O=CNCc1nccs1
Agent: BrBr
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=CNCc1ncc(Br)s1
Temperature: 30 °C
Yield: 33.6 %

Procedure:
2-Formylaminomethylthiazole (200 g) was added to a solution of 4.5 kg of sodium dihydrogenphosphate dihydrate in 6 L of water, and the mixture was stirred at 30° C. Sodium bromide (4.0 kg) and 2 L of tetrahydrofuran were added thereto in that order. Bromine (1.49 kg) was added while adjusting the solution to pH 3 by the addition of a 6 N aqueous sodium hydroxide solution, and the mixture was stirred for 2 hr. The reaction mixture was added to a solution of 500 g of sodium sulfite in 4 L of water to stop the reaction and was then adjusted to pH 4.9 by the addition of a 6 N aqueous sodium hydroxide solution while maintaining the temperature of the mixture at 30° C. The reaction mixture was extracted with 10 L of ethyl acetate and then with 5 L of ethyl acetate. The organic layers were combined and were dried over anhydrous magnesium sulfate. The solvent was removed to bring the volume to 1 L, and the concentrate was stirred at 6° C. for 12 hr for crystallization to give 104.4 g of 5-bromo-2-formylaminomethylthiazole. The results of NMR analysis were in agreement with the results of analysis in Example 3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)(=[O:22])[C:19]([CH3:21])=[CH2:20]>>[CH3:21][C:19]([C:18]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:18]([C:19]([CH3:21])=[CH2:20])=[O:22])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)=[O:22])=[CH2:20]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: C=C(C)C(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C(=C)C)cc2)cc1

Procedure:
adduct of 1 mole of bisphenol A with 2 moles of glycidyl methacrylate
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:4]=2[N:3]=1.[Cl:21]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([Cl:21])=[N:3][C:4]=3[C:14]=2[CH:15]=1
Reactant: COc1ccc2oc3c4ccccc4c(O)nc3c2c1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: COc1ccc2oc3c4ccccc4c(Cl)nc3c2c1

Procedure:
The procedure was similar to step S19C, while the starting material was 21B in stead of 19B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:22][C:23]1([CH3:26])[CH2:25][O:24]1.[I-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][C:23]3([CH3:26])[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(CCl)CO1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Agent: [I-]
Agent: [K+]
Product: CC1(CN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CO1

Procedure:
In analogy to the procedure described for example 166, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 2-chloromethyl-2-methyloxirane with 0.3 equivalent of potassium iodide gave the intermediate 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-methyl-oxiranylmethyl)-[1,4]diazepan-5-one which was reacted with no work up with piperidine in ethanol to give the title compound as light yellow waxy solid. MS: 468.2 (MH+, 2Cl).
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][C:10](O)=[O:11].[C:16](O)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.C([O-])(=O)CC([O-])=O.C[Mg+2]>O1CCOCC1>[O:11]=[C:10]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:9][C:8]([O:14][CH3:15])=[O:13]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: COC(=O)CC(=O)O
Agent: CC[O-]
Agent: C[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCC(=O)CC(=O)OC
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a suspension of magnesium ethoxide (10.82 g, 94.61 mmol) in 1,4-dioxane (100 mL) was added methyl hydrogen malonate (25.0 g, 189 mmol) in 1,4-dioxane (100 mL). The resulting slurry was stirred overnight. The mixture was concentrated in vacuo. In a separate flask, lauric acid (28, 20.85 g, 104.1 mmol) was dissolved in 1,4-dioxane (50 mL) and a solution of CU (16.88 g, 104.1 mmol) in 1,4-dioxane (150 mL) was added at room temperature. The resulting solution was stirred overnight. The mixture was then transferred to the methyl magnesium malonate flask. The resulting suspension was refluxed overnight. The mixture was concentrated in vacuo. The residue was redissolved in DCM (300 mL) and filtered through a silica plug (10 g). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (360 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 80 min, 100 mL/min) to afford product 29 (17 g, 61%) as a pale yellow syrup.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl indole-4-carboxylate (402 mg, 2.30 mmol) in DMF (5 mL) was cooled with an ice/water bath and treated with NaH (100 mg, 2.5 mmol, 60% in mineral oil). The resulting yellow solution was allowed to stir at 0° C. for 30 min., then a solution of MeI (482 mg, 212 μL, 3.4 mmol) in DMF (3.5 mL) was added dropwise. The solution was allowed to warm to ambient temperature. The reaction was quenched at 0° C. with saturated aqueous NH4Cl and extracted with EtOAc (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl (N-methyl)-indole-4-carboxylate as a yellow oil, 430 mg (99%). The N-methyl carboxy indole was converted into the N-methyl-[5,6,7]-tricyclic indole in a manner similar to that described for Compound (10) to give 1-N-methyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one as a shiny white solid, 256 mg mg (54%, after recrystallization (CH2Cl2/MeOH/hexanes)). mp 194-195° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.96 (m, 2H), 3.43 (m, 2H), 3.82 (s, 3H), 7.29 (m, 2H), 7.64 (d, 1H, J=7.7 Hz), 7.72 (d, 1H, J=7.7 Hz), 8.09 (br t, 1H); HRMS (FAB, MH+) Calcd for C12H13N2O: 201.1028, Found: 201.1020; Anal. (C12H12N2O.0.2 H2O) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][C@@H:9]1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Product: COC(=O)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Yield: 97.6 %

Procedure:
To the compound of step 2 (2.317 g, 5.90 mmol) in 40 ml of MOH was added 0.063 g of 10% palladium on charcoal and the mixture was hydrogenated under a hydrogen pressure of 4 bar for 45 min at room temperature. The catalyst was filtered off and the filtrate evaporated to dryness under reduced pressure. 1.488 g of the title compound were obtained as a pale grey oil.
Reaction SMILES: [CH2:1]([C:15]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[C:43]([CH3:48])([CH3:47])[C:44](Br)=[O:45].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[CH3:47][CH:43]1[C:44](=[O:45])[C:25]2=[CH:26][C:27]3[C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:16]4[C:21]([C:22]=3[CH:23]=[C:24]2[CH2:48]1)=[CH:20][CH:19]=[CH:18][CH:17]=4
Reactant: CC(C)(Br)C(=O)Br
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A 5000 mL round flask was charged with 9,9-ditetradecyl-9H-fluorene (30 g, 53.7 mmol) and 2-bromo-2-methylpropanoyl bromide (12.7 g, 55.3 mmol), and then dissolved with 300 mL of carbon disulfide inputted thereto. Then, the reactor was cooled with ice water. Under nitrogen atmosphere, aluminum trichloride (15.7 g, 118.1 mmol) was slowly added thereto in ten lots over 2 hours. The mixture was stirred at room temperature for 8 hours, and then the reaction was terminated by addition of 100 mL of distilled water, followed by washing with 500 mL of distilled water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, to thereby obtain 30.0 g of 2-methyl-9,9-ditetradecyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (yield: 89.1%) as highly viscous oil.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7](=[O:13])[NH:8]2)[NH2:2].[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26](O)=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.CC(O)=O>[C:14]1([C:6]2[C:7](=[O:13])[NH:8][C:9]3[CH:10]=[CH:11][N:12]4[C:26]([C:21]5[N:22]=[CH:23][CH:24]=[CH:25][N:20]=5)=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ncccn1
Reactant: NNc1nccc2[nH]c(=O)c(-c3ccccc3)cc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=c1[nH]c2ccn3c(-c4ncccn4)nnc3c2cc1-c1ccccc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-hydrazino-3-phenyl-1,6-naphthyridine-2(1H)-one (2-3) (1.4 g, 5.55 mmol), 2-pyrimidinecarboxylic acid (0.69 g, 5.55 mmol), HOBt (0.85 g, 5.55 mmol), and DIPEA (0.97 mL, 5.55 mmol) in DMF (50 mL) was added EDC (1.23 g, 6.66 mmol). After stirring for overnight, AcOH (5 mL) was added, and the mixture was heated under microwave irradiation at 150° C. for 15 minutes. The solvent was removed under reduced pressure, and the residue was diluted with MeOH, and added water. The resulting solid was collected by filtration to give 9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8(7H)-one (2-4) as a colorless solid.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH:10]1[CH:11]=[CH:12][C:13]2[C:26](=[O:27])[C:25]3[C:17]4[C:18]([CH:22]=[CH:23][N:24]=3)=[CH:19][CH:20]=[N:21][C:16]=4[C:14]=2[CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:10]1[CH:15]=[C:14]2[C:16]3[C:17]4[C:25]([C:26](=[O:27])[C:13]2=[CH:12][CH:11]=1)=[N:24][CH:23]=[C:22]([Br:7])[C:18]=4[CH:19]=[CH:20][N:21]=3
Reactant: O=C1c2ccccc2-c2nccc3ccnc1c23
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2-c2nccc3c(Br)cnc1c23
Reaction time: 0.5 h

Procedure:
A mixture of pyridinium bromide perbromide (390 mg, 1.2 mmol) and sampangine, (232 mg, 1.0 mmol) in chloroform (12 mL) was heated at reflux for 15 h. Saturated sodium bicarbonate solution (100 mL) was added to the cooled reaction and the mixture stirred vigorously for 30 min. The two layers were separated and the aqueous phase extracted with chloroform (2×30 mL). The combined organic layers were dried over potassium carbonate and concentrated to dryness. The residual solid was applied to a 2×40 cm column of silica gel (Merck 230-400 mesh) and the pure product (200 mg, 64%) eluted with chloroform, mp 180° C. dec. IR (KBr) 1670, 1590, 1400, 1320, 1310, 1275, 1230, 980, 790, 755, 720 cm-1 ; 1H NMR (CDCl3) δ9.28 (s, 1 H), 8.99 (d, J=5.9 Hz, 1 H), 8.85 (dd, J=7.9, 1.4 Hz, 1 H), 8.46 (dd, J=7.9, 1.4 Hz, 1 H), 7.96 (d, J=5.9 Hz, 1 H), 7.86 (ddd, J=7.7, 7.9, 1.4 Hz, 1 H), 7.72 (ddd, J=7.9, 7.9, 1.4 Hz, 1 H); 13C NMR (CDCl3) 181.6 (0), 151.7 (0), 150.2 (1), 148.6 (1), 146.7 (0), 138.6 (0), 135.1 (0), 135.0 (1), 132.3 (0)), 131.8 (1), 128.7 (1), 125.8 (1), 123.7 (0), 120.5 (0), 118.3 (1) ppm; HR MS calc. for C15H7BrN2O 309.9741, found 309.9747.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:11][OH:12].[CH:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:14]([CH:13]1[O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:11][O:12]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccc(O)c(CO)c1
Reactant: CCCCCC=O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCCCCC1OCc2cc(C(=O)O)ccc2O1
Reaction time: 5 h
Yield: 46.8 %

Procedure:
A mixture of 16.8 g of 4-hydroxy-3-(hydroxymethyl)-benzoic acid, 1000 ml of benzene, 15.0 g of caproaldehyde and 0.36 ml of concentrated sulphuric acid is boiled for 5 hours while stirring under a water separator. After cooling, the mixture is filtered. The filtrate is concentrated and the residue is boiled up with hexane. The insoluble material is dissolved in ether/hexane and stirred up in the cold with active carbon. The mixture is filtered, the filtrate is evaporated and the residue is boiled with isopropyl ether. There are obtained 11.7 g of beige colored 2-pentyl-1,3-benzodioxan-6-carboxylic acid; m.p. 148° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH3:25])([CH:23]=[CH2:24])[C:7]=2[N:6]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH2:23][CH3:24])([CH3:25])[C:7]=2[N:6]=1)=[O:4]
Reactant: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)OC)nc21
Agent: [Pd]
Solvent: CO
Product: CCC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)OC)nc21
Yield: 99.2 %

Procedure:
The mixture solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (360 mg, 1 mmol) and 10% palladium on active carbon (120 mg) in methanol (50 mL) was stirred at room temperature under hydrogen (14 psi) for 8 hours. The catalyst was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (360 mg, quant.) as a yellow oil. MS (ESI+) [(M+H)+] 363.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[CH:14]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:29](=[O:37])[C:28]([C:38](O)=[O:39])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:28]5[C:29](=[O:37])[N:30]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[C:25]([CH3:24])=[CH:26][CH:27]=5)=[O:39])=[N:7][CH:6]=4)=[CH:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cn2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
To a solution of N-{6-[(6-aminopyridin-3-yl)oxy]imidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (200 mg, 0.647 mmol) and 6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (178 mg, 0.776 mmol) in N,N-dimethylformamide (3 mL) were added N,N-diisopropylethylamine (233 μL, 1.29 mmol) and HATU (320 mg, 0.841 mmol), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration. The obtained white solid was suspended in methyl ethyl ketone (2 mL), and the mixture was stirred at 80° C. for 17 hr. The suspension was collected by filtration to give the title compound (175 mg, 52%) as a white solid.