Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[OH-].[K+].C(O)C.[C:33](=S)=[S:34]>C(O)C>[SH:34][C:33]1[O:21][C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:27]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:26]=[CH:25][CH:24]=2)=[N:22][N:23]=1
Reactant: S=C=S
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(S)o3)c1)C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (50 mg, 0.13 mmol) obtained in Step 2 of Example 56 was suspended in ethanol (1.0 mL), and the mixture was stirred at 40° C. for 3 hours after adding a 0.25 mol/L potassium hydroxide/ethanol solution (0.52 mL, 0.13 mmol) and carbon disulfide (0.11 mL, 1.80 mmol). After concentrating the mixture under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 4 by addition of a 6 mol/L aqueous hydrochloric acid solution. The precipitated white solid was filtered off to give (S)-5-[3-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (37 mg, 66%).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[C:20]([OH:25])(=[O:26])[CH2:21][CH2:22][C:23]([OH:6])=[O:24]
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)O
Reaction time: 0.08 h

Procedure:
AZT (1.068 g, 4 mmol), succinic anhydride (0.440 g, 4.4 mmol) and DMAP (0.015 g) were weighed into a 25 ml flask fitted with a condenser. DMF (10 ml) was added and the mixture stirred for 5 min and immersed into an oil bath preheated to 90° C. for 1.5 h until HPLC assay indicated completion of reaction. DMF was evaporated under vacuum (<40° C.) and the residue used directly for the subsequent reaction. The residue can be purified by chromatography on silica gel and the product isolated in >87% yield and 97% purity if required.
Reaction SMILES: Br.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].Cl>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[N:13]=2)(=[O:29])=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1nc(-c2ccc3ccccc3c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccc4ccccc4c3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10 g of 4-(2-naphthyl)-thiazol-2-ylamine hydrobromide with 8.5 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred for 18 hours with 40 ml of pyridine. The resulting, red colored suspension was poured into 400 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and (sic) concentrated. The residue was dissolved in a mixture of 500 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 10 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 11.1 g of 3,4-dimethoxy-N-(4-naphthalen-2-yl-thiazol-2-yl)-benzenesulfonamide separated upon neutralization with concentrated hydrochloric acid in the form of colorless crystals, which were recrystallized from ethanol/water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([C:9]([OH:11])=[O:10])[N:3]=1.[CH3:12][NH2:13]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=[O:10])[C:5]([NH:13][CH3:12])=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)c1nc(Cl)ccc1F
Solvent: C1COCCO1
Product: CNc1ccc(Cl)nc1C(=O)O
Temperature: 125 °C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5-fluoropyridine-6-carboxylic acid (2.00 g, 11.4 mmol), 41% aq. methylamine solution (8 mL) and 1,4-dioxane (8 mL) was heated at 125° C. under microwave irradiation for 60 min. After cooling, volatile material was distilled off, and the residue was dissolved in water (20 mL) and acidified to pH 3 by addition of 37% aq. hydrochloric acid solution. The precipitate was collected by filtration to produce the title compound (1.85 g, 87%). Light yellow solid, MS (ISP): 185.1 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=O.[CH:19]12[N:25]([C:26]3[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([NH2:36])=[CH:28][CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:22]12[N:25]([C:26]3[N:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[C:29]([NH:36][C:16]([C:3]4[C:2](=[O:1])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][C:10]=5[C:12]([F:13])([F:14])[F:15])[NH:5][CH:4]=4)=[O:18])=[CH:28][CH:27]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:24][CH2:23]2
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Reactant: Nc1ccc(N2C3CCC2CC3)nc1C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: O=C(Nc1ccc(N2C3CCC2CC3)nc1C(F)(F)F)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid (100 mg, 0.3889 mmol) and 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)pyridin-3-amine (110.1 mg, 0.4278 mmol) in 2-methyltetrahydrofuran (1.0 mL) was added propyl phosphonic acid cyclic anhydride (50% solution in ethyl acetate, 495.0 μL, 0.7778 mmol) and pyridine (61.52 mg, 62.90 μL, 0.7778 mmol). The reaction was capped and heated at 60° C. for 16 h. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL) and quenched with saturated Na2CO3 solution (6 mL). After stirring for 20 min the organic layer was separated, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate in dichloromethane) provided N-(6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)pyridin-3-yl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (137 mg, 71% yield). LC/MS m/z 497.5 [M+H]+, retention time 1.92 min (RP—C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1>>[F:8][C:6]1[CH:7]=[C:2]([C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:3]=[N:4][CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1cncc(Br)c1
Product: Fc1cncc(-c2ccncc2)c1

Procedure:
Prepared from 3-bromo-5-fluoropyridine (439.0 mg, 2.50 mmol) and pyridin-4-ylboronic acid (509.9 mg, 3.73 mmol) according to Method K, except the product was purified by silica gel chromatography (ethyl acetate, Rf=0.21) instead of preparative HPLC; 1H NMR (300 MHz, chloroform-D) δ ppm 7.50-7.51 (m, 2H), 7.65 (dt, J=9.1, 2.4 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.73-8.76 (m, 3H). MS (DCI/NH3) m/z=175 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([S:9][C:10]1[N:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:13]=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO>[CH3:8][C:2]([S:9][C:10]1[N:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:13]=[CH:12][CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Sc1ccnn1-c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccnn1-c1cccc2ccccc12)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-ylthio)propanoate (124 mg, 0.36 mmol), aqueous sodium hydroxide solution (10%, 5 mL) and methanol (5 mL) was stirred at reflux for 2 hours. The reaction was then cooled to room temperature and the methanol removed. Water was added, neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-ylthio)propanoic acid as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C(B(CC)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C(OCC)(=O)C.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>[Br:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Brc1cccc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 70.2 %

Procedure:
A mixture of 1,3-dibromobenzene (105.0 g, 0.45 mol), diethyl(3-pyridyl)borane (30.0 g, 0.204 mol) and tetrabutylammonium hydroxide (2 ml of a 40 wt % solution in water) in 1,2-dimethoxyethane (200 ml) and sodium carbonate (100 ml of a 2M solution) was degassed with nitrogen for 15 min before addition of tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.9 mmol). The mixture was heated at 80° C. for 18 h, cooled to room temperature, diluted with ethyl acetate and extracted with 1M hydrochloric acid (4×250 ml). The combined aqueous phases were made basic with solid sodium hydroxide and then extracted with diethyl ether. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated to give a yellow oil. Purification by silica gel chromatography eluting with isohexane on a gradient of diethyl ether (10% to 50%) gave 3-(3-bromophenyl)pyridine (33.5 g, 70%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δH 7.28-7.40 (2H, m), 7.48-7.57 (2H, m), 7.73 (1H, t, J 2), 7.82-7.87 (1H, m), 8.62 (1H, s), 8.80 (1H, s).
Reaction SMILES: ClCCl.[Br:4][C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[N:7](COCC[Si](C)(C)C)[C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)[CH:24]=1.Cl.N>CO.O1CCOCC1>[Br:4][C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[NH:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:33][CH2:34]2)[CH:24]=1
Reactant: COc1ccc(-c2c(Br)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CC1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2[nH]c3cn[nH]c(=O)c3c2Br)cc1OC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To 1 ml of dichloromethane solution containing 186 mg (0.367 mmol) of 3-bromo-2-(3-cyclopropoxy-4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 43-(a) was added 6 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the solid obtained from the reaction suspension by filtration was washed with diisopropyl ether. To the obtained crude solid were added methanol and 28% aqueous ammonia, and the mixture was stirred at room temperature for 5 hours. Then, the solution was concentrated under reduced pressure and the obtained solid was washed with ethyl acetate and dried under reduced pressure to obtain 85 mg of the title compound as a white solid. (Yield: 62%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5](Cl)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>CN(C)C=O.O.C(#N)C>[NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5]([C:27]2[CH:28]=[CH:29][C:24]([N:23]([CH3:33])[CH3:22])=[CH:25][CH:26]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(N)c(C(=O)O)nc2Cl)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)c1ccc(-c2nc(C(=O)O)c(N)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 3-amino-6-chloro-5-[4-(methylsulfonyl)phenyl]pyrazine-2-carboxylic acid (0.18 mmol, 60 mg,), 4-(dimethylamino)phenyl boronic acid (0.24 mmol, 40 mg), tetrakis(triphenylphosphine) Pd(0) (0.033 mmol, 38 mg), cesium carbonate (2.1 mmol, 297 mg) in dimethylformamide (2 ml) and deionized water (0.4 ml) was mixed under argon at room temperature. The reaction was heated in a microwave reactor at 120° C. for 15 min. The product was characterized by LC-MS (5-50 acetonitrile with 0.1% trifluoroacetic acid, positive ion [M+H]+=413).
Reaction SMILES: C([Li])CCC.CCCCCC.[N+]([O-])(OCCC)=O.[Li][Li].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:32]([N+:36]([O-:38])=[O:37])C(O)=O)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].Cl.C(=O)=O>O1CCCC1.O>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][N+:36]([O-:38])=[O:37])=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(SC(C(=O)O)[N+](=O)[O-])cc1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCO[N+](=O)[O-]
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(SC[N+](=O)[O-])cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A 1.6 M solution of butyllithium in hexane (51.25 ml, 82 mmol) was added dropwise to a stirred solution of B (9.07 g, 40.5 mmol) in anhydrous tetrahydrofuran (150 ml) maintained a -40° C. under an atmosphere of argon. When the addition was complete, the mixture was stirred for 1 hour at -5° C. Propyl nitrate (12.92 g, 123 mmol) was added dropwise to the stirred mixture at -5° C., which was then stirred for a further 2 hours, maintaining the temperature below 0° C. throughout. The mixture [containing the dilithium salt of 2-(4-t-butylphenylthio) 2-nitroacetic acid]was acidified to pH 2 by addition of 2M hydrochloric acid. The mixture was allowed to stand for 30 minutes at ambient temperature after which time evolution of carbon dioxide [obtained from decarboxylation of 2-(4-t-butylphenylthio) 2-nitroacetic acid] had ceased. Water (300 ml) was then added and the mixture was extracted with ethyl acetate. The combined extracts were washed successively with an aqueous solution of sodium hydrogen carbonate, water and brine, and then dried (MgSO4) and the solvent removed by evaporation. The residual oil was purified by chromatography on silica, eluting with (3:20 v/v) ethyl acetate/hexane, to give (4-t-butylphenylthio)nitromethane (A) as an orange oil (4.76 g), NMR spectrum (200 MHz, d6DMSO): 1.27 (s, 9H), 6.02 (s, 2H), 7.42 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.[CH2:17]([O:19][C:20](=[O:40])[CH:21](P(OCC)(OCC)=O)[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)[CH3:18].O.[OH-].[Li+].[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[CH2:17]([O:19][C:20](=[O:40])/[C:21](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)[CH3:18]
Reactant: CCOC(=O)C(CCCOC1CCCCO1)P(=O)(OCC)OCC
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 19 h
Yield: 33.2 %

Procedure:
To a THF (5 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (283 mg) obtained in Example 1 and 2-(diethoxyphosphoryl)-5-(tetrahydropyran-2-yloxy)valeric acid ethyl ester (480 mg), lithium hydroxide monohydrate (110 mg) was added, and the reaction solution was agitated at room temperature for 19 hours. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH and elution solvent: hexane:ethyl acetate=1:1→ethyl acetate), and 186 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]2[O:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=4)=[CH:29][C:26]=3[C:27]=2[CH3:28])[CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:23]2[O:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=4)=[CH:29][C:26]=3[C:27]=2[CH3:28])[CH:20]([CH3:22])[CH3:21])=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
Ethyl 3-{methyl[(4-{[2-methyl-1-(3-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1-benzofuran-2-yl)propyl]amino}phenyl)carbonyl]amino}propanoate (425 mg) synthesized in Example A205 was dissolved in tetrahydrofuran (4.0 mL), 1N aqueous sodium hydroxide solution (1.4 mL) was added to the solution, and the mixture was stirred at 50° C. for 1.5 hr. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.4 mL) under ice-cooling and stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (378 mg, 94%) as a colorless amorphous form.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23])[C:13]([C:12]1[C:11]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:10]=2[O:9][CH:8]=1)=[O:26]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)coc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-benzofuran (30 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 μL, 0.076 mmol, 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (monitored by tlc), diluted with ethyl acetate (10 mL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 7:3) to afford the title product as a cream crystalline solid (19.3 mg, 86%); 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H, J=8.97 Hz), 8.01 (s, 1H, C2H), 7.14 (s, 2H, benzoyl Hs), 7.05 (d, 1H, J=2.11 Hz), 7.00 (dd, 1H, J=8.63, 2.11 Hz), 3.93 (s, 3H, OMe), 3.90 (s, 6H, 2×OMe), 3.87 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3) δ 188.71 (CO), 158.64, 156.31, 152.82, 150.22, 141.72, 133.97, 122.58, 120.87, 118.12, 113.11, 106.07, 95.53, 60.63, 55.99, 55.40.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:37]2[C:32]([CH:33]=[N:34][C:35](O)=[N:36]2)=[CH:31][CH:30]=1>>[N:15]1[CH:16]=[C:17]([NH:20][C:35]2[N:34]=[CH:33][C:32]3=[CH:31][CH:30]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[N:37]3[N:36]=2)[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C4CCNCC4)nc3)nn12

Procedure:
This example was prepared by using 5-Amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (WO2006/047277) and 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.0 (s, 1H), 8.8 (s, 1H), 8.6 (m, 1H), 8.3 (m, 1H), 8.1 (d, J=8.5 Hz, 1H), 7.7 (d, J=7.5 Hz, 1H), 7.5 (t, 1H), 7.2 (m, 2H), 7.1 (t, 1H), 7.0 (m, 2H), 3.8 (s, 3H), 3.4 (m, 2H), 3.0 (m, 3H), 2.0 (m, 2H), 1.85 (m, 2H); LC/MS (ESI+): 401 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:25]N)=[O:24])[O:20][N:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC([F:42])=CN3C=2CC2N=C(C(OCC)=O)ON=2)=CC=1.N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:42])=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH2:25])=[O:24])[O:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Reactant: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Agent: N
Solvent: CO
Product: NC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1

Procedure:
The title compound was prepared in the same fashion as that for compound 215 from ethyl 3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate and saturated ammonia in MeOH. (47 mg, 90.0%), as a white solid. m/e+=372 (M+H+). 1H NMR (300 MHz, in DMSO-d6): δ 8.68 (2H, D, brd, NH2), δ 8.39 (1H, D, s, ArH), δ 7.82-7.80 (2H, D, d, J=8.4 Hz, ArH), δ 7.75-7.71 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4 Hz, ArH), δ 7.47-7.44 (1H, D, m, ArH), and δ 4.74 (2H, D, s, CH2).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:19][CH:20]1[O:24][C:23](=[O:25])[NH:22][CH2:21]1>CN(C)C=O>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:19][CH:20]3[O:24][C:23](=[O:25])[NH:22][CH2:21]3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C1NCC(CCl)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCC(COc2cccc3c2CCC3=O)O1
Temperature: 200 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-hydroxy-1-indanone (500 mg, 3.37 mmol), cesium carbonate (2.0 g, 6.14 mmol) and 5-chloromethyl-2-oxazolidinone (503 mg, 3.71 mmol) in N,N-dimethylformamide (5 mL) was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer at about 200° C. for about 5 minutes. The reaction mixture was cooled, concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using dichloromethane/methanol (50:1) as the mobile phase to provide the desired product. MS (ESI): m/z 248 (M+H)+.