Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:14])(=[O:13])[CH2:9][C:10]([CH3:12])=O.[CH2:15]([CH2:22][C:23](=O)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>>[CH3:12][C:10]1[C:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:23]([CH3:24])[NH:14][C:8](=[O:13])[CH:9]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: CC(=O)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1cc(=O)[nH]c(C)c1Cc1ccccc1
Temperature: 125 °C
Yield: 53.7 %

Procedure:
To a mixture of PPA (10 g) and acetoacetamide triethylamine (2.02 g, 20 mmol) was added benzylacetone (5.92 g, 5.98 mL, 40 mmol). The resulting mixture was heated at 125° C. for 3 hours. The brown mixture was poured onto crushed ice and neutralized with solid NaHCO3. The mixture was filtered to give a yellow solid, which was purified by flash column (silica, 10% MeOH/DCM) to give the pyridinone (2.29 g, 53.8%) as a yellow solid. 1H NMR (CDCl3) δ 2.07 (s, 3H), 2.37 (s, 3H), 3.81 (s, 2H), 6.38 (s, 1H), 7.00-7.40 (m, 5H); MS (CI) m/z 214.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Br
Yield: 57 %

Procedure:
This reaction was carried out similarly to Example 1, with 2-bromo-5-nitrobenzaldehyde and malonic acid in pyridine and with piperidine. The product of melting point 185° C. was obtained in 57% yield.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:28])=O>>[CH2:1]([O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:28])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Nonyloxylpyrimidine-2-yl)benzoic acid (1.78 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-nonyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10]Br)[C:4]=1[O:12][CH3:13].[CH3:14][N:15]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:18]([CH3:24])[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:24][N:18]1[CH2:17][CH2:16][N:15]([CH3:14])[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][N:21]3[CH2:22][CH2:23][N:15]([CH3:14])[CH2:16][CH2:17][N:18]([CH3:24])[CH2:19][CH2:20]3)[C:4]=2[O:12][CH3:13])[CH2:20][CH2:19]1
Reactant: CN1CCNCCN(C)CC1
Reactant: COc1c(CBr)cc(C)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1c(CN2CCN(C)CCN(C)CC2)cc(C)cc1CN1CCN(C)CCN(C)CC1

Procedure:
0.31 g (1 mmol) of 2,6-bis bromomethyl-4-methylanisole are added over the course of 30 min to a solution of 0.31 g (2 mmol) of 1,4-dimethyl-1,4,7-triazacyclononane, 0.14 g of K2CO3 (1 mmol) in 10 ml of toluene, and the reaction mixture is refluxed under a protective gas for 2 days.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([NH2:36])=[N:28]1.N1C=CC=CC=1>O1CCCC1.O.CN(C)C=O>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([NH:36][C:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:17][CH2:16]2)=[O:20])=[N:28]1
Reactant: O=C(O)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Reactant: Nc1noc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1noc2ccccc12)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperidine-4-carboxylic acid (289 mg, 1.00 mmol) and N,N-dimethylformamide (0.010 ml) in tetrahydrofuran (5 ml) was added in water-bath, oxalyl chloride (0.174 ml, 2.00 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was added to a solution of 1,2-benzisoxazol-3-amine (134 mg, 1.00 mmol) in pyridine (0.404 ml, 5.00 mmol) under ice-cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of hexane and ethyl acetate to give 60.3 mg (14.9%) of the desired product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:32]([C:37]1[CH:38]=[N:39]C(Br)=[N:41][CH:42]=1)[CH2:33][CH2:34][CH2:35][CH3:36]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:41]=[CH:42][C:37]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:38][N:39]=4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:30][CH:31]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reactant: CCCCCc1cnc(Br)nc1
Product: CCCCCc1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (50 mg, 0.11 mmol) and 5-pentyl-2-bromopyrimidine (37 μL, 0.22 mmol) following a procedure analogous to that in Example 48 as a white crystal (35 mg, yield 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.[CH2:22]([N:24]([CH:27](O)[CH2:28][CH3:29])[CH2:25][CH3:26])[CH3:23]>CN(C=O)C.O>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:23]
Reactant: CCC(O)N(CC)CC
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a stirred solution of 3-nitrophenol (2 mmol) in DMF (6 mL) at rt, solid potassium carbonate (4 mmol) was added. A solution of the mesylate of N,N-diethylaminopropanol (2.2 mmol) in DMF (2 mL) was then added to the reaction mixture and heated to 80° C. until completion, according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was then treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine. The crude product was used directly for further transformation.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=4)[CH2:9][C@@H:4]3[CH2:3]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: Fc1ccc(CO[C@H]2C[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A solution of 0.23 g (0.91 mmol) of (7S,8aS)-7-hydroxy-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 18) in 10 mL of dry THF was treated with 40 mg (1.0 mmol) of sodium hydride (60% oil dispersion), followed by 0.125 mL (1.0 mmol) of 4-fluorobenzyl bromide and 17 mg (0.05 mmol) of tetra-n-butylammonium iodide. The mixture was stirred at ambient temperature for 16 hours, and warmed to 50° C. for 4 hours. The suspension was cooled, the solvent was evaporated, and the residue partitioned between ethyl acetate and water. The layers were separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 chloroform: methanol gave 0.135 g (41%) of the title compound. Mp (.HCl) 165-168° C. HRMS calc'd for C19H22ClFN3O (MH+): 362.1435, found: 362.1451.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([N:31](CC)CC)C.CN>CCOCC.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:31][CH3:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CNC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (from the previous step) (Example 5) and triethylamine (2.5 eq.) in ether (0.05 M) was added methanamine (5.0 eq.). The reaction mixture was stirred for overnight. Then the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N,3-dimethylbenzamide as a white solid. 1H NMR (CDCl3): δ 8.62 (s, 1H), 8.32 (s, 1H), 8.04 (d, 1H), 7.60 (s, 1H), 7.46-7.52 (m, 2H), 7.09-7.11 (m, 2H), 6.05 (br, 2H), 3.09-3.17 (m, 4H), 3.00 (d, 3H), 2.52 (s, 3H), 2.33 (s, 3H). LRMS [M+H]=385.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:43][O:44][CH2:45][CH2:46]Br>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:46][CH2:45][O:44][CH3:43])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCCBr
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Potassium carbonate (246 mg, 1.78 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 310 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL) at room temperature and the mixture was then stirred at room temperature for 30 min and then treated with 2-bromoethyl methyl ether (0.06 mL, 0.59 mmol). The mixture was then heated at 80° C. for 1 h. The resulting reaction mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine (343 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C30H32N2O6S2 [M+H]+ 581.73, observed 581.1.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH2:14][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
4-Cyclohexylaniline (8.0 g, 53 mmol) was dissolved in methanol (200 mL) and a suspension of 4-formylbenzoic acid (9.4 g, 53 mmol) in glacial acetic acid (12 mL) was added in portions and the resulting mixture was heated at reflux temperature for 1.5 hour. After cooling to room temperature a mixture of sodium cyano borohydride (5.0 g, 80 mmol) in methanol (100 mL) was added in portions, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered and washed thoroughly with water and dried in vacuo at 50° C. for 3 days to afford 12.8 g (78%) of 4-[(4-cyclohexylphenylamino)methyl]benzoic acid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=416.9 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[F-].[K+].Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl>CN(C=O)C.O.CCOC(C)=O>[N+:27]([C:26]1[C:21]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]3)=[N:22][CH:23]=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reaction time: 0.5 h

Procedure:
6-Hydroxyflavane (0.150 g) was dissolved in 3 ml of dry DMF under nitrogen. KF (0.117 g) was added and the solution was stirred for 30 minutes at +120° C. The solution was cooled a bit and 2-chloro-3-nitropyridine was added (0.212 g) and stirred for 7 hours at +120° C. and overnight at room temperature. The reaction mixture was taken up with EtOAc and 1M HCl and water were added and phases separated. Organic phase was washed with water and pH was adjusted to 7 with 1M NaOH. Organic phase was washed with water, brine and dried over Na2SO4. Product was purified by column chromatography (CH2Cl2:n-heptane/80:20). 1H-NMR (400 MHz; d6-DMSO): δ 8.55 (dd, 1H, J=7.9 Hz, J=1.7 Hz), 8.42 (dd, 1H, J=4.9 Hz, J=1.7 Hz), 7.51-7.29 (m, 6H), 7.02-6.92 (m, 2H), 6.88 (d, 1H, J=8.7 Hz), 5.14 (dd, 1H, J=10.0 Hz, J=2.1 Hz), 3.05-2.92 (m, 1H), 2.78-2.68 (m, 1H), 2.22-2.13 (m, 1H), 2.07-1.95 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[O:11][C:9](=[O:10])[C:8](=[C:12]=[O:13])[CH2:7]1.O.[NH2:15][NH2:16]>C(O)C>[OH2:10].[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[O:11][C:9](=[N:15][NH2:16])[C:8](=[C:12]=[O:13])[CH2:7]1
Reactant: O=C=C1CC(c2ccc[nH]2)OC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C1OC(c2ccc[nH]2)CC1=C=O

Procedure:
7.2 g (0.04 mol) of 4-(2-pyrrolyl)-carbonyl-γ-butyrolactone and 2.5 ml (0.05 mol) of hydrazine hydrate are stirred in ethanol at room temperature for 4 hours. The product which has crystallised out is filtered off with suction and rinsed with ethanol.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26]Cl)=[O:24].[Cl-].[NH4+]>CN(C)C=O>[Br:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(OCCl)c1cccc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.4 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.39 g of chloromethyl 3-bromobenzoate was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.25 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3-bromobenzoate (present compound (46)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].O.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:34])([F:33])[C:27]([F:32])([F:31])[C:28](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:28]([C:27]([F:32])([F:31])[C:26]([F:34])([F:33])[F:25])=[N:18][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(F)c1
Yield: 16 %

Procedure:
A solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in pentafluoropropanoic acid (2 ml) was stirred overnight at 80° C. Then the mixture was poured into water (100 ml), adjusted pH to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (24 mg, 16%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)[CH:4]=[CH2:5].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:3]([C:6]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)[CH:4]=[CH2:5]
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(O)ccc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)ccc2ncccc12
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.7 g, 16.8 mmol) in anhydrous N,N-dimethylformamide (80 ml) was added 5-allyl-quinolin-6-ol (intermediate 5) (2.68 g, 14 mmol) slowly at room temperature. The reaction mixture was stirred for 1 hour, then benzyl bromide (2.57 ml, 21 mmol) was added. The mixture was allowed to stir for 1.5 hrs at room temperature, quenched with water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (30% hexanes-ethyl acetate) afforded 3.6 g (92%) of 5-allyl-6-benzyloxy-quinoline as a light brown oil. MS ESI m/z 276 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[O:7])=[CH:4][C:3]=1[Br:24].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([O-:43])=[O:42].[Na+]>>[NH2:1][C:2]1[C:16]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:43][C:41](=[O:42])[CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:27]2[C:26]([Cl:25])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:32])=[O:7])=[CH:4][C:3]=1[Br:24]
Reactant: Nc1c(Br)cc(C(=O)OCCCCCCl)cc1CN1CCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCCCC1

Procedure:
This compound was prepared from 5-(4-amino-3-bromo-5-piperidinomethyl-benzoyloxy)-n-pentyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]1[CH:45]=[CH:44][CH:43]=[CH:42][C:19]=1[CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38](O)=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:17][C:18]1[CH:45]=[CH:44][CH:43]=[CH:42][C:19]=1[CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2F)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2F)c1

Procedure:
0.61 g of compound 58 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.99 g of ethyl 4-(2-aminophenoxy)butyrate and 0.86 g of 3-[1-(2-fluorobenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]5[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:35])([F:36])[F:37])[C:25]=5[F:24])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1F
Yield: 76.1 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), 2-fluoro-3-(trifluoromethyl)benzoic acid (312 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg, 1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (380 mg, 76%) was obtained as a white powder.