Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[N:25]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([C:31]([NH2:33])=[O:32])[CH2:26][CH2:27]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: NC(=O)N1CCNCC1
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C(N)=O)CC3)nn12

Procedure:
The title compound was prepared in analogy to Example 3 using (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C) and piperazine-1-carboxamide instead of piperazin-2-one (tR 3.16 min (conditions 1), MH+=438, 1H-NMR in DMSO-d6: 8.95 (d, 1H); 8.46 (d, 1H); 7.80 (d, 1H); 7.65 (d, 1H); 7.61 (s, 1H); 7.60 (m, 1H); 7.08 (d, 1H); 6.07 (s, 2H); 4.98 (m, 1H); 3.15-3.40 (m, 8H); 1.88 (d, 3H)).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:12]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: ClC(c1ccccc1)c1ccccc1
Product: O=Cc1cccc2c1ccn2C(c1ccccc1)c1ccccc1

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-4-carbaldehyde and benzhydryl chloride instead of the benzyl bromide used in Example 1 to give 1.14 g of 1-benzhydrylindole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 61%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[CH2:42]([S:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])=[O:45])[CH3:43]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([N:50]2[CH2:49][CH2:48][N:47]([S:44]([CH2:42][CH3:43])(=[O:45])=[O:46])[CH2:52][CH2:51]2)=[O:40])[CH:34]=1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCS(=O)(=O)N1CCN(C(=O)c2cccc(-c3cc(-c4nnnn4CCCOC)c(O)cc3O)c2)CC1

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and 1-ethylsulfonyl piperazine as described in general procedure D. LCMS: 531 [M+H].
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[C:26]#[N:27])=[CH:21][CH:20]=4)=[C:14]([CH2:32][CH2:33][CH3:34])[N:13]4[N:35]=[CH:36][N:37]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]#[N:27])=[CH:21][CH:20]=3)=[C:14]([CH2:32][CH2:33][CH3:34])[N:13]3[N:35]=[CH:36][N:37]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(5-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile (0.69 g), 3N hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), sodium borohydride (0.076 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.41 g, 63%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([NH:23][C:24]4[S:25][C:26]5[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:33].[ClH:33].[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([NH:23][C:24]4[S:25][C:26]5[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCNC3)ccc21
Yield: 248.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (S)-pyrrolidin-3-ylamide dihydrochloride (51 mg) was prepared by following General Procedure L starting from (S)-3-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg) in 4M HCl in dioxane (1 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[CH3:1]
Reactant: CO
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C
Temperature: 70 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
To a solution of 2-methyl-4-nitro-benzoic acid (3 g, 16.56 mmole) in 30 ml methanol was added at 0° C. sulfuric acid (95-98%, 10 ml) slowly for ½ hr. The reaction mixture was stirred at 70° C. for 24 hrs. Mixture was cooled down, a solid precipitated out, then the mixture was concentrated, diluted with 50 ml water, stirred for 10 minutes, filtered off, the solid was washed with water, dried to afford 3.08 g of brown solid, 95.3% yield, pure by H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([CH3:14])([OH:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: Oc1ccccc1Br
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccccc1Br
Temperature: 90 °C
Yield: 0.6 %

Procedure:
To a solution of 2-bromophenol (3.0 g, 1.745 mmol, Aldrich) and 1-chloro-2-methylpropan-2-ol (2.8 g, 6.397 mmol, Spectrochem) in DMF (15 mL) was added sodium carbonate (1.23 g, 11.63 mmol). The reaction mixture was heated at 90° C. for 12 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material that was purified by combiflash silica gel column chromatography (column size: 12 g; elution: 0-5% ethyl acetate in hexane) to yield 1-(2-bromophenoxy)-2-methylpropan-2-ol (2.7 mg, 64.2%) as a transparent liquid. m/z (ESI) 243.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+:17]>C1COCC1.O>[C:1]([C:5]1[S:9][C:8]([C:10]([O-:12])=[O:11])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3].[Li+:17]
Reactant: CCOC(=O)c1nnc(C(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc(C(=O)[O-])s1
Yield: 104.1 %

Procedure:
A solution of ethyl 5-tert-butyl-1,3,4-thiadiazole-2-carboxylate (0.21 g, 1.0 mmol) and lithium hydroxide hydrate (42 mg, 1.0 mmol) in THF (2 mL) and water (2 mL) was stirred at room temperature for 18 hours. The solvent was removed under vacuum to give lithium 5-tert-butyl-1,3,4-thiadiazole-2-carboxylate (0.2 g) as a white solid which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[Br:15]Br.O>[N+](C)([O-])=O.[Fe](Cl)(Cl)Cl>[Br:15][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:13])([F:14])[F:1])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: BrBr
Agent: Cl[Fe](Cl)Cl
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Temperature: 110 °C
Yield: 54.3 %

Procedure:
4-(Trifluoromethoxy)benzoic acid (2 g, 9.70 mmol) and iron(III) chloride (1.574 g, 9.70 mmol) were suspended in nitromethane (20 mL). To this mixture was added bromine (0.497 mL, 9.70 mmol) at 0° C. The solution was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was added to cold water (100 mL) and extracted with ethylacetate (2×100 mL). The organic phase was washed with an aqueous solution of sodium thiosulfate pentahydrate and brine. The organic layer was concentrated and the residue was purified by HPLC to give the title compound as a white solid (1.5 g). LCMS m/z=287.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67 (d, 1H), 8.06 (d, 1H), 8.29 (s, 1H), 13.47 (s, 1H).
Reaction SMILES: [C:1]12([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=[CH:3][CH2:2]2.C(=O)(O)[O-:18].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[O:18]1[CH:4]2[CH:3]1[CH2:2][C:1]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: O=C1NC(=O)C2(CC=Cc3ccccc32)N1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C2(CC3OC3c3ccccc32)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a slurry of 2.7 g. (0.013 mole) of spiro[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione in 50 ml. of chloroform and 125 ml. of a 5% sodium bicarbonate solution was added 3.4 g. (0.016 mole) of m-chloroperbenzoic acid and the reaction mixture allowed to stir at room temperature for 3 hours. The reaction mixture was poured into 100 ml. of a 5% sodium bicarbonate solution and the product extracted with chloroform (2×75 ml.) and ethylacetate (2×75 ml.). The combined extracts were washed with a sodium bicarbonate solution and a brine solution, dried over sodium sulfate and concentrated to a yellow solid. Trituration with diethyl ether gave 1.6 g. (55% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Cl:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([S:28]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc(Cl)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.3 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3-chlorobenzene-1-sulfonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification using preparative HPLC/UV (System B) afforded the title product (3 mg, 10%) as a white solid. MS (ESI+) for C18H19ClN2O3S m/z 379 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=2[F:24])=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[F:24][C:16]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:26])=[O:2])[C:10](=[O:25])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2c(F)ccc(OC)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a solution containing (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.254 g, 0.001 mol) in tetrahydrofuran (10 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 3 mL, 0.002 mol). The mixture was stirred at 5° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid, (0.212 g, 87%), as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]1[CH2:27][CH2:28]1
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1cnc2ccccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (48 mg, 0.128 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (35 mg). MS 392.3 (M+H); UV 202.9, 223.0, 246.8, 296.0, 351.7 nm; t 0.437 min.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26](O)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>>[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: O=C(NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with biphenyl-2-carboxylic acid.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.CS[C:14]1[N:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][N:15]=1.[CH3:32][NH:33][CH3:34].O>O1CCCC1>[CH3:32][N:33]([CH3:34])[C:14]1[N:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][N:15]=1
Reactant: CSc1ncc(-c2nc3cccc(C(=O)O)c3o2)cn1
Reactant: CNC
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ncc(-c2nc3cccc(C(=O)O)c3o2)cn1
Reaction time: 0.25 h
Yield: 83 %

Procedure:
77% m-Chloroperbenzoic acid (476 mg, 2.12 mmol) was added to a suspension of methyl ester of 2-(2-methylthiopyrimidin-5-yl)benzoxazole-7-carboxylic acid (400 mg, 1.33 mmol) in tetrahydrofuran (10 ml) under ice cooling and the mixture was stirred for 15 min. and then at room temperature for 3 hrs. To the reaction mixture was added dropwise 50% aqueous solution of dimethylamine at room temperature and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled with ice and water (25 ml) was added thereto. The mixture was stirred for 15 min. and extracted with ethyl acetate. The organic layer was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=4) to give methyl ester of 2-(2-dimethylaminopyrimidin-5-yl)benzoxazole-7-carboxylic acid (328 mg, 83%) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([F:28])=[CH:7][C:8]([N+:25]([O-])=O)=[C:9]([CH:24]=1)[NH:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]>[Fe].C(O)(=O)C>[C:1]([NH:4][C:5]1[C:6]([F:28])=[CH:7][C:8]([NH2:25])=[C:9]([CH:24]=1)[NH:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)Oc1ccc(Nc2cc(NC(C)=O)c(F)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ccc(Nc2cc(NC(C)=O)c(F)cc2N)cc1
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
Methyl 2-[p-(5-acetamido-4-fluoro-2-nitroanilino) -phenoxy]propionate (8.2 g, 0.021 mol) is added to a mixture of iron dust (3.51 g, 0.063 mol) in a 5% acetic acid solution at 65° C. The reaction mixture is stirred at 65° C. for 2.5 hours, treated with additional iron dust (0.5 g), stirred at 65° C. for 30 minutes, cooled to room temperature and filtered through diatomaceous earth. The resultant filtrate is poured into water and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a brown-black solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.CCCCCC>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CC)C2CCCCC2)cc1
Solvent: CCCCCC
Solvent: CCO
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (880 mg) which is a synthetic intermediate in Example 10 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 12 min were collected, and concentrated. The obtained amorphous compound (359 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (330 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[NH2:40])=[N:29][CH:30]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=1)=[O:41])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Product: CSc1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
2-[2-(3-tert-Butoxycarbonylaminopropoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was prepared by methods described in Example 4-E from 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide (1.53 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:3]1[N:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc(Cl)c1Cl
Product: Clc1cnnc(Cl)c1Cl

Procedure:
A stirred solution of 4,5-dichloro-2,3-dihydro-3-pyridazinone (15.00 g, 90.92 mmol) in POCl3 (100 mL) was refluxed for 1.5 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (400 mL), washed with water (100 mL), dried over Na2SO4, filtered and concentrated to give 3,4,5-trichloropyridazine. M.S.(M+1):185.00
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.ClCCl.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2cccc(C)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C(=O)c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 265.2 %

Procedure:
(4-Methoxyphenyl)(3-methylphenyl)methanone (603 mg) was dissolved in dichloromethane (3 ml) to prepare a solution. A boron tribromide-dichloromethane solution (1.0 M) (11 ml) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was poured into ice-cooled water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane/ethyl acetate as a solvent to give (4-hydroxyphenyl)(3-methylphenyl)methanone (1.50 g, yield 56%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(F)cc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3OC)cccc2c1N
Yield: 81.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 5-fluoro-2-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (140 mg, 81% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.89 (m, 1H), 7.75-7.67 (m, 2H), 7.14-7.04 (m, 2H), 6.99-6.92 (m, 1H), 3.67 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.67 min.