Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=3)[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Br)cc1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc(Br)cc2)nc(N)n1
Yield: 91 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-bromo-phenylamine provided the title compound (91% yield). 1H NMR (DMSO-d6) δ 2.34 (s, 3H, CH3), 6.37 (s, 1H, Ar), 7.40 (d, 1H, J=8.9 Hz, Ar), 7.59 (d, 2H, J=8.7 Hz, Ar), 7.70-7.71 (m, 2H, Ar), 7.82-7.84 (m, 2H, Ar), 10.89 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:21][O:22][C:23](=[O:43])[CH:24]([NH2:42])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>>[CH3:21][O:22][C:23](=[O:43])[CH:24]([NH:42][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:19])=[CH:8][N:7]=2)=[CH:18][CH:17]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)C(N)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: COC(=O)C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid (283 mg, 1.0 mmol) and 2-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester (360 mg, 1.0 mmol) following general procedure A. (580 mg) 1H-NMR(400 MHz, CD3COCD3): 3.24 (dd, 1H), 3.39 (dd, 1H), 3.74 (s, 3H), 4.98 (m, 1H), 6.64 (d, 1H), 7.50 (m, 2H), 7.60 (m, 2H), 7.69 (m, 3H), 7.78 (d, 2H), 7.88 (d, 2H), 7.98(m, 2H), 8.15 (m, 2H); LC/MS (m/z): 589 (M+1)+.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:17](=O)(O)[O-].[Na+].CI>CN(C)C=O.CCOC(C)=O>[CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([O:11][CH3:17])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([O-])O
Reactant: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)c(C2CCC2)cc1C

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 82.4, 500 mg, 2.29 mmol) in N,N-dimethylformamide (10 mL) and sodium bicarbonate (390 mg, 4.64 mmol). With stirring, methyl iodide (430 μL, 6.90 mmol) was added drop-wise and the resulting mixture was stirred for 5 h at room temperature. The reaction was then diluted with EtOAc (50 mL) and the mixture was washed with brine (4×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 0.40 g (crude) of the title compound as a brown oil
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:34])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][N:15](C(OCC3C=CC=CC=3)=O)[C@H:16]([C:21]([O-:23])=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18])[C:9]=2[N:10]=1.[ClH:35]>CO.O1CCCC1.[Pd]>[ClH:35].[NH2:1][C:2]1[NH:3][C:4](=[O:34])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][NH:15][C@H:16]([C:21]([OH:23])=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18])[C:9]=2[N:10]=1
Reactant: CC[C@H](C)[C@@H](C(=O)[O-])N(CCOCn1cnc2c(=O)[nH]c(N)nc21)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NCCOCn1cnc2c(=O)[nH]c(N)nc21)C(=O)O
Reaction time: 11 h
Yield: 92 %

Procedure:
A solution of 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-methoxy]-ethyl-N-[(benzyloxy)carbonyl]-L-isoleucinate (1.11 g, 2.2 mmol) in methanol-tetrahydro furan (1:1, 50 ml) was treated with 0.5N hydrochloric acid (5 ml) and 5% palladium on charcoal (0.30 g; MCB Reagents). The mixture was hydrogenated on a Parr hydrogenator at 50 psi for 11 hours, filtered through a Celite pad and the filtrate was concentrated in vacuo to give 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl-L-isoleucinate hydrochloride (0.86 g, 92%) as an off-white solid; mp 180°-182° C. (effervescent softening ca. 150° C.):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[Cl:12].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].[F-].[K+].FC(F)(F)C(O)=O>O.CC#N.O.O1CCOCC1>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([O:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
1,2-Dichloro-4-fluoro-5-nitrobenzene (50 g, 0.238 mol), ethyl glycolate (90.1 mL, 0.952 mol), and potassium fluoride (76.1 g, 1.31 mol) were added to a 1 L round-bottom flask containing 200 mL of anhydrous dioxane. The mixture was magnetically stirred and heated to 100° C. in an oil bath. After two hours, HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=7.5 min) was gone and that one major peak (Rt=7.8 min) had formed. The reaction mixture was poured into 4 L of water, which resulted in precipitation of the product. The solid was filtered off and dried under vacuum to give ethyl [(4,5-dichloro-2-nitrophenyl)oxy]acetate (67.4 g, 0.229 mol, 96%) as a tan solid. MS (ES) m/e 294 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[CH2:19][C:18]3([CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)[O:17][C:14]2=[N:15][CH:16]=1>O1CCCC1>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]3[CH2:19][C:18]4([CH:24]5[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]5)[CH2:20]4)[O:17][C:14]3=[N:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reaction time: 12 h
Yield: 86 %

Procedure:
Under a nitrogen atmosphere, phenyl isocyanate (0.056 mL, 0.515 mmol) was added to a suspension of 5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (119 mg, 0.514 mmol) in anhydrous tetrahydrofuran (5 mL) and stirred for 12 hours. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography through silica gel, eluting with ammoniated chloroform/methanol (92.5:7.5), to obtain the title compound (155 mg, 0.442 mmol, 86%) as an off-white solid: electrospray MS (m/z, relative intensity) 351 ([MH]+, 100).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].S(Cl)([Cl:24])=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([Cl:24])=[O:17]
Reactant: O=C(O)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 15.6 g (0.1 mol) of 3-(2-quinolinylmethyloxy)benzoic acid and 11.9 g (0.1 mol) of thionyl chloride is refluxed for 4 hours. The reaction mixture is then evaporated to dryness at room temperature and used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[C@H:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][O:3]1.[OH-].[Na+].Cl.[CH3:27][C:28]1[C:29]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO.O1CCOCC1.O>[CH3:27][C:28]1[C:29]([N:35]2[CH2:36][CH2:37][N:38]([C:11]([C:10]3[CH:16]=[CH:17][C:7]([N:6]4[C@H:5]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:4][O:3][C:2]4=[O:1])=[CH:8][CH:9]=3)=[O:13])[CH2:39][CH2:40]2)=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2C(=O)OC[C@H]2c2ccccc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4c4ccccc4)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
Ethyl (R)-4-(2-oxo-4-phenyl-oxazolidin-3-yl)benzoate (623 mg) described in Preparation Example 75 was dissolve in methanol (3 mL) and 1,4-dioxane (3 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The mixture was neutralized with 1N hydrochloric acid (5 mL), 1-(3,5-dimethylpyridin-2-yl)piperazine (383 mg) described in Preparation Example 47 and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (829 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (144 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30]([O:33][Si](C(C)(C)C)(C)C)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of [(1S,2S)-1-({[4-(t-butyl-dimethyl-silanyloxy)-phenyl]-[(1R,2R)-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid tert-butyl ester (190 mg) in THF (3 mL) was added TBAF in THF (1M, 1 mL) the resulting solution was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with H2O (2×15 mL) and brine (15 mL). The EtOAc layer was dried (Na2SO4) and concentrated to give the titled compound (102 mg). MS (MH+ 472).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH:8]([N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=2)=[CH:23][C:22]1=[O:37])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(N(C)C)=O.O>[CH:8]([N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:28]=2)=[CH:23][C:22]1=[O:37])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccn(C(c3ccccc3)c3ccccc3)c(=O)c2)n1
Reactant: NC1CCOCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 55.2 %

Procedure:
Tetrahydro-2H-pyran-4-amine (0.20 g, 2.0 mmol) was added to 1-benzhydryl-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.12 g, 0.29 mmol) in DMA (3 mL) in a microwave vial. The mixture was heated at 120° C. for 1 hour in a microwave. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc was washed with water, twice with brine, dried over MgSO4, filtered, and evaporated to yield a crude product (0.09 g) as a film. This was chromatographed on a 10 g Biotage SNAP column with EtOAc. Fractions 9-20 contained a film (0.0764 g). This was triturated with water, dried, then triturated with hexane and dried to afford the desired 1-benzhydryl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.072 g, 0.16 mmol, 57% yield) as a film. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 7.52 (s, 1H), 7.40-7.15 (m, 9H), 6.91 (d, 1H), 6.76-6.72 (m, 1H), 5.25-5.21 (m, 1H), 4.15-4.06 (m, 1H), 4.02-3.96 (m, 2H), 3.59-3.51 (m, 2H), 2.09-2.03 (m, 2H), 1.62-1.52 (m, 2H); m/z (APCI-pos) M+1=439.2.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([O:14][S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(O[Si](C)(C)C(C)(C)C)C2)cc1
Yield: 98.1 %

Procedure:
3-(tert-Butyldimethylsilyloxy)cyclopentanol (4.8 g, 0.022 mol) and 4.22 g (0.022 mol) of tosyl chloride were mixed with 45 mL of pyridine and stinted at room temperature over night. TLC revealed the completion of the reaction. The pyridine was removed in vacuo and the residue was dissolved in ethyl acetate, washed with 1 N HCl and brine, and dried over Na2SO4. The filtrate was concentrated under vacuum to dryness to obtain 8.0 g of crude desired product as a light pink residue. The crude product was purified over SiO2 using 3% EtOAc in hexanes as eluant to give two lots material. The first lot contained 2.50 g of product approximately 90% pure. The second lot contained 2.66 g of desired product with greater than 98% purity. The combined yield was approximately 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=O.CCN(C(C)C)C(C)C.[NH2:27][NH2:28]>C(O)C.C1COCC1>[Cl:16][C:13]1[N:12]=[C:11]2[NH:27][N:28]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:10]2=[CH:15][CH:14]=1
Reactant: NN
Reactant: O=C(c1ccccc1Cl)c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1ccc2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.7 %

Procedure:
(2-Chloro-phenyl)-(2,6-dichloro-pyridin-3-yl)-methanone (3.0 g, 10.47 mmol) was dissolved in 25 mL of ethanol/THF (4:1) and cooled in an ice bath. Hunig's base (N,N-diisopropylethylamine, 1.8 mL, 10.47 mmol) was added to the reaction mixture, followed by dropwise addition of 0.36 mL (11.52 mmol) of hydrazine. The reaction mixture was stirred at 0° C. for five minutes, then heated to 70° C. for 1.5 hours. Volatiles were removed under reduced pressure, and the residue was taken up in 150 mL of EtOAc, 10 mL of THF and 10 mL of MeOH. To this mixture was added 20 mL of saturated ammonium chloride and 110 mL of water. The organic phase was collected, and the aqueous phase was wahsed with an additional 100 mL of EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and solvent was removed to to yield 1.18 g of 6-chloro-3-(2-chloro-phenyl)-1H-pyrazolo[3,4-b]pyridine as a yellow solid. Mass Spec. M−H=262.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C

Procedure:
4-Iodoaniline (10.0 g, 45.7 mmol), (2,4-dichlorophenyl)boronic acid (10.5 g, 54.8 mmol), Pd(dppf)Cl2 (3.7 g, 4.6 mmol), and K2CO3 (12.6 g, 91.3 mmol) were dissolved in 1,4-dioxane (200 mL) and water (50 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:31])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:21])=[C:16]([CH:20]=2)[C:17](O)=[O:18])=[C:8]([C:22]2[S:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:26]=2)[CH:7]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:36][N:37]([CH3:45])[CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(N(CC)CC)C.C([O-])(=O)C=C>C1(C)C=CC=CC=1.CN(C=O)C.C1COCC1.CCOC(C)=O.O>[CH3:36][N:37]([CH3:45])[CH:38]=[C:39]([C:17](=[O:18])[C:16]1[CH:20]=[C:12]([C:9]2[CH:10]=[N:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:31])=[CH:7][C:8]=2[C:22]2[S:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:26]=2)[CH:13]=[CH:14][C:15]=1[F:21])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C=CN(C)C
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc(F)c(C(=O)O)c2)cn1
Agent: C=CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc(F)c(C(=O)C(=CN(C)C)C(=O)OCC)c2)cn1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
5-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-2-fluorobenzoic acid (0.180 g, 0.40 mmol, Intermediate 124) was suspended in toluene (3 mL). Thionyl chloride (0.145 mL, 1.98 mmol, Aldrich) and 1drop of DMF were added and the mixture was heated to 45° C. for 15 min After cooling to room temperature, the mixture was concentrated in vacuo, and toluene was added, then the mixture was concentrated in vacuo again to give a dark yellow residue. After drying under high vacuum overnight the oil turned into a dark yellow film. This film was taken up in THF (2 mL). In separate flask ethyl 3-(dimethylamino)acrylate (0.074 g, 0.51 mmol, Acros) and triethylamine (0.082 mL, 0.59 mmol, Acros) were dissolved in THF (5 ml). The solution of the acid chloride in THF (2 ml) was added dropwise to acrylate solution, then the flask was placed in an oil bath preheated to 72° C. and stirred for 1 h. After cooling to room temperature, the mixture was diluted with EtOAc(10 mL) and water (10 mL). The layers were separated and the organic layer was washed with 1 N HCl, twice with water, once with brine, then dry over Na2SO4, filter and concentrated in vacuo to give crude product as an orange oil.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>CN(C=O)C.O.C(N(CC)CC)C>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]4)[CH2:3][CH2:4]2)=[O:47])=[CH:44][CH:43]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (3.5 g) was suspended in 40 ml of DMF. After adding 960 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 6-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 2.34 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.5 g of 4-chlorobenzoyl chloride. After completion of addition the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogen carbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.7 g of 6-[4-(4-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 233°-235° C., pale yellow needles.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Br[C@@:10]1([O:33][C@H:32]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]1[O:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)O>C(#N)C>[C:14]([O:13][C@H:12]1[C@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:32]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:33][C@H:10]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OC[C@H]1O[C@@](O)(Br)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccnc2[N+](=O)[O-])[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The coupling procedure of Sakaguchi (17) (12) was modified to give a higher yield and selective formation of the β-anomer. 2-Nitroimidazole (118 mg; 1.05 mmol) was added to a stirred solution of 1-bromo-2,3,5-tri-O-benzoyl-α-D-arabinofuranose (500 mg; 0.95 mmol) and mercuric cyanide (600 mg; 2.04 mmol) in dry acetonitrile (50 mL). The mixture was stirred for 6 hours at room temperature, after which the solvent was removed under vacuum. The residue was dissolved in dichloromethane (200 mL) and filtered. The filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution, 30% aqueous potassium iodide, and water, then dried over anhydrous magnesium sulfate. The solvent was evaporated under vacuum and the residue applied to a silica gel column and eluted with ethyl acetate:toluene=90:10 (v/v). The coupled product was recovered in 69% chemical yield (367 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(F)c(N)cc23)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (310 mg, 1 mmol) and SnCl2.2H2O (171 mg, 4.5 mmol) in ethyl acetate (35 mL) was refluxed for 2 h. After cooled to room temperature, the mixture was treated with 5% aqueous NaHCO3 to adjust its pH value to 9-10. It was then subjected to extraction with EtOAc. The combined organic layers were washed with saturated brine and H2O and dried. The solvent was removed under reduced pressure to give 225 mg (81%) N4-(3-ethynylphenyl)-7-fluoroquinazoline-4,6-diamine as a yellow solid.