Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(C)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 77.5 °C
Yield: 52.2 %

Procedure:
To a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, ethyl ester (0.76 g, 3.47 mmol) and potassium carbonate (0.92 g, 6.67 mmol) in acetonitrile (10 ml) was added benzyl bromide (1.0 ml, 1.4 g, 8.4 mmol). The mixture was heated at 75-80° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to yield 5-benzyloxy-2-methyl-1H-indole-3-carboxylic acid, ethyl ester (Compound 53) as a yellow solid (0.56 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]2[CH2:27]O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:40]([NH2:43])[C:41]#[CH:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]2[CH2:27][NH:43][CH2:40][C:41]#[CH:42])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reactant: C#CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: C#CCNCc1nnc(CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 47, 5-chloro-2',6'-difluoro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with p-toluenesulfonyl chloride followed by propargylamine, to give 5-chloro-2',6'-difluoro-2-[3-[[(2-propynyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12](=O)([O-])[O-:13].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:13][CH3:12])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: [K+]
Solvent: CO
Product: COc1cc(Cl)nc(Cl)c1
Temperature: 70 °C
Yield: 88 %

Procedure:
A mixture of 2,6-dichloro-4-nitropyridine (1.0 equiv.), potassium carbonate (3 equiv.) and methanol (20 equiv.) were heated to 70° C. for 25 min in the microwave. The reaction mixture was diluted with methanol and was decanted from remaining solids. After concentration, the mixture was partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give 2,6-dichloro-4-methoxypyridine in 88% yield. LCMS (m/z) (M+H)=177.9/179.9, Rt=0.72 min.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.ClC(Cl)C(O)=O>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([Pb+3:17])=[CH:20][CH:19]=1
Reactant: [Pb+4]
Reactant: COc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C(O)C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc([Pb+3])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of lead tetraacetate (0.73 equiv) in chloroform and dichloroacetic acid was added anisole (1.0 equiv.). The reaction mixture was allowed to stir at room temperature for 90 min. After this period the solution was washed with water and the organic layer was treated with hexane. The product precipitated out and was collected by filtration. The solid was taken up in chloroform and acetic acid. The resultant solution was stirred for 1 h and then washed with water. The later 2 steps were repeated and the chloroform layer was treated with hexane. This mixture was cooled to 2° C. for 24 h. The material that precipitated was collected by filtration and dried under vacuum to afford p-methoxyphenyllead triacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(OC(F)(F)F)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: -20 °C
Reaction time: 15 h
Yield: 34 %

Procedure:
4-hydroxy-4-(4-(trifluoromethoxy)phenyl)piperidine-1-formic acid tert-butyl ester (1.85 g, 5 mmol) was dissolved in dry dichloromethane (30 mL), cooled to −20° C., added dropwise triethyl silicane (696 mg, 6 mmol), added slowly until completed, slowly resumed to stir for 15 h at room temperature. After the reaction was finished, added ice water to quench reaction, partitioned, organic phases were washed by saturated saline, followed by sodium sulphate drying, concentration, column chromatography (PE: EA=20:1) to give 0.6 g light yellow gel-like substance, yield: 34%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5ccccc5)nc43)cc2)CCC1
Temperature: 100 °C

Procedure:
To a suspension of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (20 g) in toluene (200 mL) and ethanol (200 mL) was added saturated aqueous sodium bicarbonate (150 mL) and phenyl boronic acid (9.9 g). The reaction was degassed for 5 minutes and the Pd (PPh3)4 (1.0 g) was added. The reaction was again degassed for 5 minutes and then heated to 100° C. for 2 days or until reaction is complete by LCMS. The reaction mixture was cooled to room temperature, and dichloromethane (250 ml×3) and water (100 mL) were added to the reaction. The organics were washed with saturated sodium bicarbonate (1×250 mL) and water (1×250 mL), dried over sodium sulfate and concentrated. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product with some impurities. The solid was re-crystallized with ethyl acetate affording an off-white solid (7.2 g). 400 M Hz 1H NMR (DMSO-d6) δ: 8.23 (d, J=8.0 Hz, 1H), 8.04-7.98 (m, 3H), 7.94 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.46-7.35 (m, 6H), 7.18-7.14 (m, 1H), 6.90 (bs, 1H), 6.33 (dd, J=7.6 Hz and 4.4 Hz, 1H), 2.48-2.40 (m, 4H), 2.09-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.30 (m, 9H); LCMS: 533 [M+H].
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][N:29]([C:1]([Cl:4])=[O:2])[CH2:28][CH2:27]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Cl)Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Temperature: 0 °C
Yield: 51 %

Procedure:
To a −78° C. solution of 1.85 M phosgene in toluene (15.8 mL, 29.3 mmol) and DCM (32 mL) was added 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (4.00 g, 14.6 mmol), prepared as described in Example 1d, in one portion with stirring, followed immediately by the rapid addition of DIEA (2.66 mL, 16.1 mmol) along the walls of the flask over ˜5 sec. The flask was sealed and stirred at −78° C. for another 5 min before placing the flask in an ice bath with stirring at 0° C. for 30 min. The opaque easily stirred slurry was then poured into a mixture of DCM (70 mL), 0.5 M trisodium citrate (60 mL), and ice (60 mL), and partitioned. The aqueous layer was extracted with DCM (1×50 mL) and the organic layers combined, dried (Na2SO4), and concentrated under reduced pressure to give the crude title compound as an orange solid. Purification by flash chromatography (7:1→4:1 DCM/acetone) afforded the title compound as a beige solid (2.50 g, 51%). 1H-NMR (300 MHz, CDCl3) 9.07 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 4.58-4.47 (m, 2H), 4.072 (s, 3H), 4.068 (s, 3H), 3.65 (tt, J=10.9 Hz, 4.0 Hz, 1H), 3.46-3.33 (m, 1H), 3.28-3.14 (m, 1H), 2.30-2.06 (m, 2H), 2.06-1.95 (m, 2H). LC/MS (ESI): calcd mass 335.1, found 336.1 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)[C:18]2=[O:25].FC1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[C:19](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:18]2=[O:25]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: Cc1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Yield: 36 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-methylisatin for 5-fluoroisatin gave the title compound in 36% yield: mp 282.8°-284.8° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28-8.38 (m, 2H) 7.94 (d, 2H) 7.64-7.78 (m, 3H) 3.34 (s, 3H); MS (M+H)+ 263.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C:28]3[CH2:29][NH:30][CH2:31][C:24]=3[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CC3=C(CNC3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
0.4 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 0.6 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 40 ml of acetonitrile and the suspension was refluxed in 100° C. oil bath for 7 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and washed with methanol. 0.3 g of the titled compound was obtained (yield 57%).
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[BrH:30]>C(O)(=O)C.O.[Cu]Br>[Br:30][C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(Cc2c(Cl)cc(Br)cc2Cl)n[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (46) (0.9 g, 2.88 mmol) in glacial acetic acid (16 mL) at room temperature was treated with concentrated sulfuric acid (4 mL). A solution of sodium nitrite (480 mg, 6.96 mmol) in water (5 mL) was added below the surface of the reaction slowly over 10 min. The reaction mixture was heated to 60° C. for 1 h. The reaction was cooled to room temperature and a mixture of copper(I)bromide (450 mg, 3.14 mmol) and 48% hydrogen bromide in water (2 mL, 17.68 mmol) was added dropwise. The reaction was heated to 100° C. where vigorous gas evolution occurred. After 1 h, the reaction was cooled to room temperature, poured onto ice water (100 mL) and was extracted with ether (3×75 mL). The ether layer was cautiously washed with a saturated aqueous sodium bicarbonate solution (150 mL). The organic layer was separated, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was purified by flash chromatography using silica gel eluted with a gradient of 4:1 to 2:1 ethyl acetate:hexanes. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 6-(4-bromo-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (51) (553 mg, 51%) as an off-white solid; LRMS-ES(+) for C14H13BrCl2N2O (M+H) m/z=375. MW=376.0825, Exact Mass=373.9588
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][O:27][CH3:28])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Reactant: COCCBr
Product: COCCn1ccc(-n2c(C)nc(C#Cc3cccc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=382.3, 384.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-bromoethyl-methylether.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([O:73][CH3:74])=[CH:71][CH:72]=2)[C:56]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([O:73][CH3:74])=[CH:71][CH:72]=4)[C:56]=3[CH3:75])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: COc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)cn1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.050 mmol), 2,5-dimorpholinopyridin-3-amine (0.099 g, 0.37 mmol), 4-chloro-5,7-difluoro-2-(6-methoxypyridin-3-yl)-3-methylquinoline (0.1 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.075 g, 0.78 mmol) in toluene (3.1 mL) at 120° C. for 3.2 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-2-(6-methoxypyridin-3-yl)-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (1H, d, J=2.4 Hz), 7.92 (1H, dd, J=8.5, 2.4 Hz), 7.72 (1H, br d, J=11.2 Hz), 7.66 (1H, d, J=2.5 Hz), 7.60 (1H, br d, J=8.0 Hz), 7.00 (1H, ddd, J=8.5, 0.7 Hz), 6.92 (1H, d, J=13.5, 8.6, 2.7 Hz), 6.35 (3H, d, J=2.3 Hz), 4.03 (3H, s), 3.91 (4H, t, J=4.7 Hz), 3.82 (4H, app t, J=4.7 Hz), 3.25 (4H, br. s.), 3.04 (4H, app t, J=4.9 Hz), 2.21 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Oc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Solvent: CSC
Solvent: C1CCOC1
Product: CCc1cc(Oc2ccc(CCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetate (0.075 g, 0.20 mmol) in THF (1.3 mL) at 0° C. was added BH3.SMe2 (0.031 g, 0.39 mmol). The mixture was warmed to rt and stirred overnight. After this time, the reaction was quenched with 0.5M HCl, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, methanol/dichloromethane) to afford the title compound as a white solid (0.052 g, 69%). MW=354.83. 1H NMR (DMSO-do, 500 MHz) δ 8.17-8.10 (m, 2H), 7.59-7.54 (m, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.37-7.32 (m, 2H), 7.22-7.17 (m, 2H), 6.88 (s, 1H), 4.67 (t, J=5.2 Hz, 1H), 3.68-3.62 (m, 2H), 2.79 (q, J=7.3 Hz, 4H), 1.28 (t, J=7.6 Hz, 3H); APCI MS m/z 355 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OC1C=CC=CC=1/C=N/O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[Cl:8][C:6]1[CH:7]=[C:2]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncc(Cl)cc1Br
Agent: O=[Cu-]
Agent: O/N=C/c1ccccc1O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc(Cl)cc1Oc1ccccc1
Temperature: 110 °C
Yield: 15 %

Procedure:
3-Bromo-5-chloropyridin-2-amine (50.0 g, 241 mmol), phenol (45.4 g, 482 mmol), copper(I)oxide (1.72 g, 12.1 mmol), (E)-2-hydroxybenzaldehyde oxime (6.61 g, 48.2 mmol), Cs2CO3 (157 g, 482 mmol), and 3A powdered molecular (72.3 g) sieves were placed in DMF (300 mL) and heated at 110° C. for 3 days. Reaction was cooled, then filtered through celite. Reaction was then partitioned between water and ether. An emulsion was formed and was filtered through a plug of celite. Water was extracted with ether then dried, filtered, and concentrated. Crude material was purified on a first silica gel chromatography (5-10% EtOAc in hexanes), and then on a second column to provide the title compound (8.00 g, 15.0% yield). 1H NMR (CDCl3) δ 7.80 (d, 1H), 7.39 (t, 2H), 7.19 (t, 1H), 7.03 (d, 2H), 6.94 (d, 1H), 4.76 (bs, 2H); Mass spectrum (apci) m/z=221 (100).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]2[CH:16]=[C:17]([C:32]([O:34]C)=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH:7]=[CH:8][CH:9]=1.Cl>C1COCC1.CO>[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]2[CH:16]=[C:17]([C:32]([OH:34])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
NaOH 2N (0.398 mL, 0.80 mmol) was added to methyl 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylate (120 mg, 0.27 mmol) in a mixture of THF (2.4 mL) and MeOH (2.4 mL). The resulting solution was stirred at 25° C. over the weekend. HCl aq was added until pH ˜2. The solvents were removed under vacuum and the yellow solid was collected by filtration, washed with Diethyl ether to give 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (100 mg, 86%). Mass Spectrum: m/z [M+H]+=439.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[Cl:20]CCl>>[Cl:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2c(Cl)c(N)ncc2c1
Yield: 85 %

Procedure:
A solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (60.8 mg, 241 μmol) in dichloromethane (2.0 mL) was treated with N-chlorosuccinimde (35.2 mg, 264 μmol) at ambient temperature. After 24 h the mixture was absorbed directly onto silica gel in vacuo and purified by flash chromatography (silica, ISCO, 0-6% methanol in dichloromethane) to yield the title compound as a pale orange solid (59.0 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.30-7.20 (m, 2H), 7.00 (t, J=8.3 Hz, 2H), 4.95 (s, 2H), 2.25 (s, 3H). 1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 7.93 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.40-7.34 (m, 1H), 7.18-7.12 (m, 2H), 6.40 (s, 2H), 2.24 (s, 3H). LCMS (Method E): RT=5.508 min, M+H+=287.0 & 289.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([O:16]C)=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:19][CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[NH2:18].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:18][C:12]1[N:11]=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[N:9]=[C:8]2[C:13]=1[NH:14][C:15](=[O:16])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCCCl
Product: CC(C)Oc1nc(N)c2[nH]c(=O)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(5-chloropentyl)-2-[(1-methylethyl)oxy]-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:5][C:6]1([C:29]([O:31]CC)=O)[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.C([NH2:40])=O.C[O-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:5][C:6]1([C:29]([NH2:40])=[O:31])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: NC=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(N)=O)ccc1-c1cnc(C)o1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (100 mg), formamide (78.5 μL), sodium methoxide (28% methanol solution, 200 μL) and DMF (1 mL) was stirred at 70° C. for 30 min, and allowed to cool to room temperature. Saturated aqueous ammonium chloride solution was added. The precipitate was collected by filtration, washed with water and IPE, and dried under reduced pressure to give the title compound (80.4 mg).