Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:5]2=[N:6][CH:7]=1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[CH3:25][O:26][C:27](=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[N:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:5]3=[N:6][CH:7]=2)[CH:34]=1
Reactant: COCCOCn1nc(-c2ccccc2OC)c2cc(Br)cnc21
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COCCOCn1nc(-c2ccccc2OC)c2cc(-c3cccc(C(=O)OC)c3)cnc21
Yield: 100 %

Procedure:
A mixture of 5-bromo-1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (535 mg, 1.36 mmol), 3-methoxycarbonylphenylboronic acid (258 mg, 1.43 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (50 mg, 68 μmol) in acetonitrile (7 mL) and 2 M aqueous solution of sodium carbonate (7 mL) was irradiated in a Personal Chemistry Optimizer at 90° C. for 10 minutes. The resulting mixture was distributed between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by flash silica gel chromatography using a gradient of ethyl acetate and hexanes to afford 3-[1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (612 mg, 1.36 mmol, 100% yield) as a yellow oil. 1H-NMR (500 MHz, d6-DMSO) δ 8.96 (d, 1H), 8.43 (d, 1H), 8.28 (t, 1H), 8.07 (td, 1H), 7.99 (td, 1H), 7.67-7.69 (m, 2H), 7.51 (ddd, 1H), 7.25 (d, 1H), 7.12 (dt, 1H), 5.92 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.73-3.75 (m, 2H), 3.43-3.45 (m, 2H), 3.21 (s, 3H). MS: m/z 372 [MH+].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C=O)C.C(O)C.O.ClCCl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1cccc(-c2n[nH]c3ncnc(N)c23)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
To a solution of 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.522 g, 2.0 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml), 3-methoxyphenylboronic acid (0.395 g, 2.59 mmoles) and sodium carbonate (1.05 g, 10 mmoles) were added and the system is degassed for 30 min. Palladium tetrakis triphenylphosphine (0.455 g, 0.39 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture neutralised with 1.5N HCl, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.130 g, 27% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.57(s, 1H), 8.20(s, 1H), 7.46(t, J=7.8 Hz, 1H), 7.23(d, J=7.5 Hz, 1H), 7.18(d, J=2.4 Hz, 1H), 7.04 (dd, J=8.0,1.8 Hz, 1H), 3.81(s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[CH3:34][S:35]([CH2:38][C:39](O)=[O:40])(=[O:37])=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:39](=[O:40])[CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (79.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=4:1). Crystallization from ethyl acetate-diisopropyl ether gave the title compound (128 mg) as colorless powder crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([C:15]#[C:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>CN(C)C=O.C(O)(=O)C.[Pd]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([CH2:15][CH2:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(CCc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A suspension of 342 mg of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 12a)) and 70 mg of 10% palladium-on-charcoal in 35 ml of dimethylformamide and 35 ml of acetic acid is hydrogenated at normal hydrogen pressure. After 6 hrs. the reaction mixture is filtered and the filtrate is concentrated in a high vacuum at 50°. The yellow residue is treated with 100 ml of 1N aqueous sodium hydroxide solution and extracted three times with 50 ml of methylene chloride each time. The combined organic phases are washed with 50 ml of water, dried over magnesium sulphate and concentrated. The crude product is triturated with 10 ml of hot ethyl acetate and filtered off under suction. 275 mg (80%) of ethyl 1-cyclopropyl-7-[2-[5-(2,4-diamino-pyrimidin-5-yl-methyl)-2,3-dimethoxy-phenyl]ethyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a yellowish solid. M.p. 218°-220°.
Reaction SMILES: C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=CC=CC=1C1C=C(NC2C=CC(F)=CN=2)C(=O)N(C)C=1)(=O)C.[C:42]([O:45][CH2:46][C:47]1[C:52](B2OC(C)(C)C(C)(C)O2)=[CH:51][C:50]([F:62])=[CH:49][C:48]=1[N:63]1[CH2:74][CH2:73][C:72]2[C:71]3[CH2:70][C:69]([CH3:76])([CH3:75])[CH2:68][C:67]=3[S:66][C:65]=2[C:64]1=[O:77])(=[O:44])[CH3:43].Br[C:79]1[N:80]=[C:81]([NH:87][C:88]2[CH:89]=[C:90]3[C:95](=[CH:96][CH:97]=2)[CH2:94][N:93]([CH:98]2[CH2:101][O:100][CH2:99]2)[CH2:92][CH2:91]3)[C:82](=[O:86])[N:83]([CH3:85])[CH:84]=1>>[C:42]([O:45][CH2:46][C:47]1[C:52]([C:79]2[N:80]=[C:81]([NH:87][C:88]3[CH:89]=[C:90]4[C:95](=[CH:96][CH:97]=3)[CH2:94][N:93]([CH:98]3[CH2:99][O:100][CH2:101]3)[CH2:92][CH2:91]4)[C:82](=[O:86])[N:83]([CH3:85])[CH:84]=2)=[CH:51][C:50]([F:62])=[CH:49][C:48]=1[N:63]1[CH2:74][CH2:73][C:72]2[C:71]3[CH2:70][C:69]([CH3:75])([CH3:76])[CH2:68][C:67]=3[S:66][C:65]=2[C:64]1=[O:77])(=[O:44])[CH3:43]
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C2COC2)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: CC(=O)OCc1c(-c2cc(Nc3ccc(F)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C3COC3)C4)n2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O

Procedure:
Following the procedures as described for 148b and starting with 247b and 305 mg of 222a, 277 mg of 249a was obtained as a yellow solid (51%). MS: [M+H]+ 698.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.[C-:25]#[N:26].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)[C:25]#[N:26]
Reactant: [C-]#N
Reactant: N#Cc1ccc(C(Cl)=NNc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55 g of solid 4-{1-[(2,6-dichloro-4-trifluoromethylphenyl)hydrazono]chloromethyl}benzonitrile are added in portions in the course of approximately one hour to 11.4 g of sodium cyanide in 270 ml of water and 400 ml of ethanol. After the mixture has been stirred for three hours at room temperature, 200 ml of ethanol and 135 ml of water are added and the mixture is stirred for a further 5 hours. 100 ml of water are added slowly, the precipitate is filtered off and washed with water, and the filter residue is dried in vacuo at 40°. This gives the title compound of melting point 186-187° (compound no. 3.4).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Product: N#Cc1ccc(N2CCOCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and morpholine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>>[Si:21]([O:20][C:19]1[CH:18]=[C:17]([CH:30]=[CH:29][CH:28]=1)[CH2:16][O:14][C:13]1[C:8]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1csc(Nc2ncccc2O)n1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccc(O[Si](C)(C)C(C)(C)C)c2)n1
Yield: 52.6 %

Procedure:
Following the method according to Example 3, Steps B and C, 5, 2-(4-methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 5.0 g, 24 mmol), (3-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane (7.3 g, 24 mmol) [J. Med. Chem. (1992), 35, 3498] and potassium carbonate (8.3 g, 60 mmol) were combined to provide 3-(3-(tert-butyldimethylsilyloxy)benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (5.4 g, 48% yield) as a clear and colorless oil. 1H NMR (CDCl3) δ 8.61 (bs, 1H), 7.94 (dd, 1H), 7.26 (m, 1H), 7.06 (dd, 1H), 7.00 (m, 1H), 6.84 (m, 2H), 6.79 (dd, 1H), 6.38 (s, 1H), 5.06 (s, 2H), 2.33 (s, 3H), 0.97 (s, 9H), 0.20 (s, 6H). Mass spectrum (apci) m/z=428.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=3[NH:16][C:15](=[O:25])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](I)[CH3:29]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=3[N:16]([CH2:28][CH3:29])[C:15](=[O:25])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2CC(=O)Nc3cc(Cl)ccc3C2)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)CN([C@@H]2CCN(C(=O)OC(C)(C)C)C2)Cc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
(R)-3-(8-Chloro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.258 g, 0.70 mmol) was dissolved in THF (7 mL) and cooled to 0° C. To the solution was added NaH (0.042 g, 1.0 mmol) and stirred for 15 min, followed by ethyl iodide (0.085 mL, 1.0 mmol). The solution was allowed to warm to room temperature slowly and stir at room temperature for 14 h. The reaction was quenched with water and extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (75% ethyl acetate/25% ethyl acetate to 100% ethyl acetate) to yield the title compound (0.130 g, 47%). 1H-NMR (CDCl3): δ 1.16 (t, 3H), 1.43 (s, 9H), 1.75 (sextet, 1H), 2.18 (pentet, 1H), 3.05–3.9 (m, 1H), 7.20 (m, 3H). ESI-MS m/z: 394 (M+1), retention time 2.25.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[N:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]3[N:26]=[CH:27][C:22]([F:21])=[CH:23][N:24]=3)[CH3:29])[N:7]=2)[CH:13]=1)[CH3:16]
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCOc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26, 0.35 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.20 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.37 g of the title compound. MS (electrospray): 389 (M+1) for C16H17FN8O3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[C:14]([CH3:26])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:26])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O

Procedure:
4-Chloro-1-(4-benzyloxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (20 g) was boiled in 200 ml of trifluoroacetic acid for 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 300 ml of diethyl ether and washed with two 300-ml portions of water. The diethyl ether layer was extracted with six 150-ml portions of 0.3 N-sodium hydroxide. The aqueous layers containing the desired product were combined, adjusted to pH 2 with hydrochloric acid and extracted with four 200-ml portions of ethyl acetate. The ethyl acetate layer was evaporated to dryness under reduced pressure and the residue was dissolved in 20 ml of acetone, followed by addition of 30 ml of diethyl ether to give 10 g or 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 193°-195° C. (decompn.).
Reaction SMILES: OC1C=CN2C(C(NC)=O)=C(C)N=C2C=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1.Cl[CH:26]([C:32](=O)[CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:32]([CH3:33])[N:24]=[C:20]2[CH:19]=1
Reactant: COc1ccnc(N)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CNC(=O)c1c(C)nc2cc(O)ccn12
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2cc(OC)ccn12

Procedure:
Note that 7-hydroxy-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide 111-B was obtained by the following procedure. To a solution of 4-methoxypyridin-2-amine (prepared as in Org. Prep. & Proc. Int., 29, 1, 117-122, 1997) 2.8 g, 22.6 mmol in ethanol (100 ml) was added ethyl 2-chloro-3-oxobutanoate (6.2 ml, 45.2 mmol) and the resulting solution heated to reflux for 16 hours under a nitrogen atmosphere. The solvents were removed in-vacuo and the yellow solid was titrated with dichloromethane to extract the crude product. The dichloromethane extracts were concentrated and purified by flash chromatography (eluting with ethyl acetate) to yield ethyl 7-methoxy-2-methylimidazo[1,2-α]pyridine-3-carboxylate, 2 g, 38%, as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[CH2:10][CH:9]1[CH3:25])=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][CH:9]1[CH2:10][C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)=[CH:12][CH2:13][NH:8]1
Reactant: CC1CC(c2cc(F)c(F)c3ccoc23)=CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1CC(c2cc(F)c(F)c3ccoc23)=CCN1
Yield: 86 %

Procedure:
A mixture of 0.5 gm (2.53 mMol) 4,5-difluorobenzofur-7-ylboronic acid, 0.872 gm (2.53 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine, 0.806 gm (3.8 mMol) potassium phosphate, and 0.146 gm (0.127 mMol) tetrakis(triphenylphosphino)palladium in 10 mL tetrahydrofuran was placed under vacuum and pressurized with nitrogen three times to exclude oxygen. The reaction mixture was heated at reflux for 3 hours and was then poured into 250 mL diethyl ether and filtered through a pad of celite. The filter pad was washed with 200 mL diethyl ether and the combined filtrates were concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane followed by 9% ethyl acetate in hexane. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.65 gm (74%) 1-(tert-butoxycarbonyl)-2-methyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine. A solution of 0.62 gm (1.77 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine in 10 mL 4 M hydrogen chloride in dioxane was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue slurried in diethyl ether to provide 0.44 gm (86%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:11]([NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:26])[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:11]([NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:26])[CH:10]=1
Reactant: CCOc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccccc1-c1ccc(CN)cc1NC(=O)c1c[nH]c2ccccc2c1=O

Procedure:
{2′-Ethoxy-2-[(4-oxo-1,4-dihydroquinoline-3-carbonyl)-amino]-biphenyl-4-ylmethyl}-carbamic acid tert-butyl ester (304) (40 mg, 0.078 mmol) was stirred in a CH2Cl2/TFA mixture (3:1, 20 mL) at room temperature for 1 h. The volatiles were removed on a rotary evaporator. The crude product was purified by preparative HPLC to afford 4-oxo-1,4-dihydroquinoline-3-carboxylix acid (4-aminomethyl-2′-ethoxybiphenyl-2-yl)amine (163) as a tan solid (14 mg. 43%). 1H NMR (300 MHz, DMSO-d6) δ 12.87 (d, J=6.3 Hz, 1H), 11.83 (s, 1H), 8.76 (d, J=6.3 Hz, 1H), 8.40 (s, 1H), 8.26 (br s, 2H), 8.01 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 7.75 (dt, J=8.1 Hz, J=1.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.24 (s, 2H), 7.15 (dd, J=7.5 Hz, J=1.8 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.02 (dt, J=7.5 Hz, J=0.9 Hz, 1H), 4.09 (m, 2H), 4.04 (q, J=6.9 Hz, 2H), 1.09 (t, J=6.9 Hz, 3H); HPLC ret. time 1.71 min, 10-100% CH3CN, 5 min gradient; ESI-MS 414.1 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:12]=[N:13][O:14][C:15]=1[CH3:16].CO.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([C:15](=[O:14])[CH3:16])[C:12]#[N:13]
Reactant: COc1ccc(-c2cnoc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C#N)C(C)=O)c(OC)c1
Temperature: 60 °C

Procedure:
Slurry 4-(2,4-dimethoxyphenyl)-5-methyl-isoxazole (4.4 g) in 1.0 N NaOH (35 mL) and add 35 mL MeOH to dissolve. Heat at 60° C. under N2 for 1 hour, then cool to clear brown solution. Add 1.0 N HCl to acidify to pH 1, then filter the resulting white solid precipitate. Dissolve solid in EtOAc, dry over Na2SO4, filter and concentrate to red oil. Use without further purification. LCMS=220.2 (MH+); 218.2 (M−).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17](OC)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCC.O1CCCC1>[O:27]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCCCCCCC(=O)OC
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g. (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml. dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml. of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 36.3 g. (0.20 mole) methyl decanoate is added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 25 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, to give dimethyl 2-oxo-undecylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:18](O)(=O)C.C(N)=N>C(O)C>[Cl:8][C:5]1[N:4]=[C:3]2[N:9]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])[CH:18]=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(Nc2nc(Cl)ccc2N)c1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: N#Cc1cccc(-n2cnc3ccc(Cl)nc32)c1

Procedure:
In step 1-3, a solution of 3-(3-amino-6-chloropyridin-2-ylamino)benzonitrile (1.07 g, 4.38 mmol) and foramidine acetate (1.37 g, 13.1 mmol) in ethanol was refluxed for 3 hours. The reaction mixture was concentrated and purified to afford 3-(5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile (1-3) as a yellow solid.