Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[O:31]C.Cl.N1C=CC=CC=1.[NH4+].[OH-]>O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[OH:31]
Reactant: COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 190 °C
Reaction time: 1.33 h
Yield: 69 %

Procedure:
A mixture of 6-(2-(4-fluoro-3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline (Example 80, prepared according to the method described in US 2008/0319012 A1) (948 mg, 2.23 mmol) and pyridine hydrochloride (95 g) was stirred at 190° C. for 80 min. Then the hot reaction mixture was poured into H2O (60 mL) and added NH4OH solution to pH 5. The aqueous solution was extracted with CH2Cl2 (30 mL, 7 times) and then the organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:30 (v/v) to 1:15 (v/v)) to afford the solid, which was recrystallized from CH2Cl2/Et2O to give the title compound (635 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 2.34 (3H, s), 3.95 (2H, s), 6.50 (1H, d), 6.56-6.57 (1H, m), 6.79 (1H, dd), 6.91 (1H, d), 7.25-7.33 (2H, m), 7.78 (1H, m), 7.91-7.97 (2H, m), 8.03 (1H, s), 8.81 (1H, d), 10.80 (1H, bs), 11.48 (1H, bs). MS (ESI) m/z 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:6](Cl)=[C:5]([CH:8]=[O:9])[S:4][N:3]=1.[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O>O>[C:11]1([S:17]([C:6]2[C:2]([Cl:1])=[N:3][S:4][C:5]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1snc(Cl)c1Cl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1snc(Cl)c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
A mixture of 3,4-dichloroisothiazole-5-carbaldehyde (0.087 g), benzenesulfinic acid sodium salt (0.078 g) and dimethyl sulfoxide (3.0 mL) was stirred at room temperature for 3.5 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a colourless oil (0.093 g).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: C=Cc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.7 %

Procedure:
N-tert-Butyl-3-(1-(2,3-difluoro-4-vinylphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1081, 260 mg) was dissolved in 30 ml of ethyl acetate. 10% Palladium on carbon was added to the mixture and the reaction flask was charged with hydrogen (1 atm). After stirring at RT for 12 hours, the reaction was filtered through diatomaceous earth, concentrated in vacuo, and the residue purified by column chromatography (SiO2), eluting with 0-20% EtOAc/Hexane, to afford 130 mg of N-tert-Butyl-3-(1-(4-ethyl-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1082); MS (M+1)=359.4.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1cccc2ccccc12
Product: BrCCCCCCOCCc1cccc2ccccc12
Yield: 74 %

Procedure:
1-Naphthaleneethanol (3.00 g) and 1,6-dibromohexane (12.73 g) were treated according to the method of Intermediate 1. FCC eluting with cyclohexane followed by ethyl acetate-cyclohexane (1:20, then 1:4) gave the title compound (4.32 g) as a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 4 h
Yield: 19.7 %

Procedure:
Under a nitrogen atmosphere, 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 2.3 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (0.64 mL, 4.6 mmol) using mild heat and vigorous stirring. The solution was chilled in an ice-water bath and 4-morpholinecarbonyl chloride (0.27 mL, 2.3 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for an additional 4 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (25 mL). The phases were separated and the organic layer was washed with water (3×25 ml), brine (25 mL), dried (Na2SO4), filtered and concentrated to yield a yellow foam. The product was recrystallized from dichloromethane and ethyl acetate. The crystals were triturated with ether (2×5 mL) to remove residual solvent. The final product was dried in a vacuum oven to provide 200 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide as a tan crystalline solid, m.p. 164-166° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[CH3:27].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[C:9]([C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[O:16])[CH:8]=4)=[CH:31][CH:30]=1)[CH3:27]
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: CCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 17.6 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (57 mg, 0.142 mmol), 4-ethoxyphenylboronic acid (35.3 mg, 0.213 mmol), Pd(Ph3P)4 (16.37 mg, 0.014 mmol) and aqueous Na2CO3 (2M) (0.177 mL, 0.354 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and filled with N2. then stirred at 100° C. for 12 hrs. The reaction mixture was concentrated and purified using preparative HPLC to give 11.1 mg of titled product. MS (ESI) m/z 444.21 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.53 (s, 1H), 8.64 (s, 1H), 8.37 (bs, 1H), 8.29 (m, 2H), 7.81 (m, 3H), 7.56 (bs, 1H), 7.22 (d, 1H, J=8), 7.07(m, 2H), 4.10 (q, 2H, J=6.9), 3.64 (bm, 8H), 1.37 (t, 3H, J=6.9).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].C[Sn+](C)C.ClCCl.CC(O)=O>ClCCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cn(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2c(c1)c(CC(=O)O)cn2C(=O)c1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
In a microwave process vial methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetate (10 mg, 0.028 mmol) was dissolved in 1,2-dichloro ethane (1 mL) and after addition of trimethyltin hydroxide (25 mg, 0.14 mmol) the reaction mixture was heated for 30 min at 130° C. in a microwave (TLC analysis indicated complete reaction). Dichloromethane (1 mL) and 50% AcOH (2 mL) were added to the cold reaction solution and the resulting biphasic mixture was agitated until both layers were clear. The organic phase was collected, washed with brine, dried over Na2SO4 and filtered (using a phase separator syringe with drying cartridge). Removal of the solvent (dichloromethane) in vacuo and following silica gel chromatography using an ethyl acetate/hexane gradient (0.5% AcOH) afforded the pure title compound quantitatively. C18H14ClNO4, Mr=343.76; 1H NMR (400 MHz, DMSO-d6) d: 3.67 (s, 2H), 3.81 (s, 3H), 6.99 (dd, J=2.4/9.2 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.32 (s, 1H), 7.65-7.77 (m, 4H), 8.17 (d, J=9.2 Hz, 1H); LCMS (ESI) tR: 2.60 min (>99%, ELSD), m/z: 344.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN1C(=O)N(C)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 25 °C

Procedure:
5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazole (D4) (200 mg) was dissolved in DMPU (2.8 ml) and treated with Cs2CO3 (367 mg) followed by ethyl 3-bromopropionate (145 ul). The resultant mixture was heated to 140° C. in a microwave reactor for 1.5 hours. The reaction mixture was then cooled to RT, evaporated to dryness and dissolved in H2O. This solution was extracted with EtOAc (×3) and the combined extracts washed with brine and evaporated to give the title compound (240 mg) as a brown oil. MS (ES): C23H2335ClN4O4 requires 454; found 455 (MH+).
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[CH:26]=[CH:27][C:28]2[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]3[C@@H:31]([CH3:35])[CH2:32][O:33][C:34]=1[C:29]=23>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[CH:26]=[CH:27][C:28]4[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]5[C@@H:31]([CH3:35])[CH2:32][O:33][C:34]=3[C:29]=45)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N3CC[C@@H](C4(N)CC4)C3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 36.5 %

Procedure:
After adding 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (252 mg, 1.12 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (3 ml), 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (244 mg, 928 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 18 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduce pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (6 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 4 ml of water to the reaction solution and washing this acidic aqueous solution with chloroform (10 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from ethanol and then dried under a reduced pressure. 125 mg (36.5%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [S-][C:2]#[N:3].[Na+].[Cl:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[CH:33][CH:34]=3)[N:23]=2)[CH:17]=1.Cl.C(N=C=NCCCN(C)C)C>CC(C)=O>[Cl:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:3][C:2]2[NH:36][C:31]3[CH:30]=[C:29]([O:28][C:24]4[N:23]=[C:22]([C:18]5[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=5)[CH:27]=[CH:26][N:25]=4)[CH:34]=[CH:33][C:32]=3[N:35]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2nccc(-c3cccnc3)n2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Nc1nc2ccc(Oc3nccc(-c4cccnc4)n3)cc2[nH]1)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of sodium thiocyanate (1 eq) in acetone was added slowly in to a solution of 4-(chloromethyl)benzoylchloride (1 eq) in acetone at 0° C. The mixture was then filtered in to a solution of 4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine (1 eq) in acetone. Formation of N-acylthiourea was followed by LC/MS. The mixture was concentrated and taken in tetrahydrofuran and to it was added 1-ethyl-(3-dimethylaminopropyl)carbodimidehydrochloride (2 eq) and stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was then dried and concentrated to yield [4-(chloromethyl)phenyl]-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide. It was taken in tetrahydrofuran and added methylpiperazine (4 eq) and stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified on preparative chromatography to yield {4-[(4-methylpiperazinyl)methyl]phenyl}-N-[5-(4-(3-pyridyl)pyrimidin-2-yloxy)benzimidazol-2-yl]carboxamide. MS: MH+=520.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O.O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCCC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (123.7 mg, 0.208 mmol) in N,N-dimethylformamide (2.5 mL) was added pyrrolidine (86.8 μL, 1.04 mmol). The reaction mixture was stirred at 80° C. for 2.5 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (94.6 mg, 0.183 mmol, 88%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][CH:34]=[CH:33][C:16]=1[CH2:17][O:18]/[N:19]=[C:20](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)\[CH2:21][CH2:22][C:23]([O:25]C)=[O:24].CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][CH:34]=[CH:33][C:16]=1[CH2:17][O:18]/[N:19]=[C:20](/[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)\[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC/C(=N\OCc1ccccc1OCc1nc(-c2ccccc2)oc1C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CO/N=C(\CCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of methyl E4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.60 g), methanol (5 ml), tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated to give E-4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (1.42 g, yield 91%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles. m.p. 116-117° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH:6]=[N:7][C:2]([NH:36][CH:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[CH2:31][CH2:32]3)=[N:3][C:4]2=[O:16])=[CH:10][CH:11]=1
Reactant: NC1CCN(c2ccc(F)cc2)CC1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1nc(NC2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 52.5 %

Procedure:
To a chloroform solution (1.1 mL) of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (59 mg, 0.23 mmol) synthesized in Reference Synthesis Example 11, potassium carbonate (80 mg, 0.58 mmol) and 1-(4-fluorophenyl)piperidine-4-amine (66 mg, 0.34 mmol) synthesized in Reference Synthesis Example 83 were added and the resultant mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, water was added to the reaction solution and extraction with chloroform from the resultant reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/5→0/1 and next, ethyl acetate/methanol=19/1 (v/v)) to obtain the title compound (50 mg, yield: 52%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:12]2[C:13]3[C:18](=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:10]([C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:28])=[O:4])=[CH:11]2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCC(=O)c1cn(Cc2ccc(Br)cc2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCC(=O)c1cn(Cc2ccc(Br)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 95.1 %

Procedure:
2N Sodium hydroxide solution (0.21 mL, 0.42 mmol) was added dropwise to a stirred solution of methyl-4-[1-(4-bromobenzyl)-5-chloro-1H-indol-3-yl]-4-oxo-butyrate (59 mg, 0.14 mmol) in tetrahydrofuran (5 mL) and methanol (1 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a white solid (56 mg, 95%): Rf: 0.30 (5% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 12.1 (1H, br s, OH), 8.67 (1H, s, ArH), 8.13 (1H, d, J=2 Hz, ArH), 7.52 (3H, m, ArH), 7.24 (3H, m, ArH), 5.48 (2H, s, CH2N), 3.12 (2H, t, J=7 Hz, CH2CO), 2.57 (2H, t, J=7 Hz, CH2CO).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([C:15]=2[C:16](Cl)=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.Cl.NO.[OH-:30].[K+].[CH3:32]O>>[NH2:3][OH:4].[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([C:15]=2[C:16]([O:30][CH3:32])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(C(=O)Cl)c2ccccc2n1-c1ccc(O)cc1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: NO
Agent: [K+]
Product: COC(=O)c1c(-c2c(C)noc2C)n(-c2ccc(O)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carbonyl chloride was dissolved in 0.5 ml of dry MeOH and the mixture was cooled on an ice-bath. Fresh hydroxylamine was prepared by pouring a MeOH solution (0.3 ml) of hydroxylamine hydrochloride (12 mg, 0.17 mmol) into a MeOH solution (0.3 ml) of KOH (19 mg, 0.33 mmol). The mixture was filtered through a syringe filter into the cooled acid chloride solution. After 5 min, the cooling bath was removed and the reaction was allowed to warm to RT and was stirred for 10 min Water, 1M HCl and EtOAc were added and the phases were separated. After evaporation of the solvents, the residue was purified by preparative HPLC to provide methyl 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylate in 16% yield. ES/MS m/z: 363.11 (M+H), 361.13 (M−H); 1H NMR (methanol-d4, 500 MHz): 8.21 (m, 1H), 7.32-7.26 (m, 2H), 7.20 (m, 1H), 7.13 (br s, 1H), 7.01 (br s, 1H), 6.88 (m, 2H), 3.83 (s, 3H), 2.12 (s, 3H) and 2.03 (s, 3H).