Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:16][CH:17]2[CH2:31][CH:20]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:19]3[CH2:18]2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)=[N:7][CH:8]=1)#[N:2].Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:15][N:13]1[CH:14]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([NH:16][CH:17]3[CH2:31][CH:20]4[CH2:21][NH:22][CH2:23][CH:19]4[CH2:18]3)[C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:11]=[N:12]1
Reactant: Cn1cc(Nc2ncc(C#N)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(Nc2ncc(C#N)c(NC3CC4CNCC4C3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of tert-butyl 5-((5-cyano-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (425 mg, 1.001 mmol) in dichloromethane (30 mL) was added the solution of HCl in EtOAc (10 mL, 40 mmol), and the mixture was stirred at rt for 1 h. The mixture was diluted with water (20 mL) and adjust to pH=8-9 with saturated NaHCO3 solution and then extracted with DCM (30 mL×3). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=5/1) to give the title product as a white solid (185.2 mg, 57.02%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:7]2[C:2]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: CSc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Temperature: 130 °C

Procedure:
A resealable pressure bottle was charged with 4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (6.00 g, 25.2 mmol), 4-aminophenol (2.89 g, 26.5 mmol), and cesium carbonate (16.4 g, 50.5 mmol). These reagents were suspended in DMSO (50.5 ml, 0.50 M). The vessel was sealed and heated to 130° C. for 48 hrs. Reaction mixture was allowed to cool to RT, diluted with water and extracted with EtOAc. The organic layer was collected, dried with Na2SO4, filtered, and concentrated to give a light brown residue, which was purified by silica gel chromatography (ISCO, 10% to 50% Ethyl Acetate/Hexanes) to afford clean material as light yellow solid. MS m/z=311 [M+H]+. Calc'd for C16H14N4OS: 310.37.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)(C(F)(F)F)=O.ClCCl.CO.C(OCC)C>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:30])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccncc2Nc2ccc(I)cc2F)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: NC1CCN(C(=O)c2ccncc2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[(4-aminopiperidin-1-yl)carbonyl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine was synthesized from tert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)carbamate (described below) by deprotection of the Boc group with TFA/DCM: 0.33 mmol of tert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)carbamate was dissolved in 4 ml of 50:50 mixture of TFA/dichloromethane. After 2 hours of stirring at room temperature the volatiles were stripped and the residue was re-dissolved in 2 ml of methanol. 1.0N HCl in diethylether was added and the product precipitated. LC/MS [2.01 min; 441 (free base, M+1)]
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:36][CH3:37])[C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH2:29]([NH:28][C:26](=[O:27])[N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:7]=1)[CH2:36][CH3:37])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1

Procedure:
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (46.57 g) in THF (470 mL) and ethanol (370 mL) was treated with 1N aqueous NaOH (2 mL) for 45 minutes at room temperature. The mixture was acidified with 1N aqueous HCl (270 mL) and extracted three times with dichloromethane, the organics were dried with magnesium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to give [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[C:11]=[O:12]>O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:11]([NH:10][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Isoindoline (1.693 ml, 14.47 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to 0° C.; and methyl 4-isocyanatobenzoate (2.18 g, 12.06 mmol) was added by syringe and the resulting mixture was warmed to ambient temperature, and then stirred overnight. The solution was concentrated to a slurry, diluted with ether, and filtered to provide the title compound.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]4[CH2:26][N:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:24]4)[CH:15]=3)[C@@:11]([C@H:34]([OH:36])[CH3:35])([CH3:33])[CH2:10]2)=[O:8])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:36][C@@H:34]([C@@:11]1([CH3:33])[C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26]3)[CH:15]=2)[CH2:13][N:9]([C:7](=[O:8])[C@@H:5]([OH:6])[CH2:4][OH:3])[CH2:10]1)[CH3:35]
Reactant: COc1ccc([C@@H]2CN(C(=O)[C@@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1OC1CN(c2ccccn2)C1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CN(C(=O)[C@@H](O)CO)C[C@@]2(C)[C@@H](C)O)cc1OC1CN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of (1R)-1-[(3S,4S)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-4-(4-methoxy-3-{[1-pyridin-2-ylazetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol (22.1 mg) in tetrahydrofuran (2 mL) is added aqueous 1.0 M HCl (1 mL). Stir overnight at room temperature. Add aqueous 1.0 M HCl (1 mL) and stir for additional 8 hours. Neutralize with aqueous 1.0 M NaOH, extract with ethyl acetate, dry and evaporate to provide the title compound (18.2 mg). MS (ES+)=472 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].[H-].[Na+]>CN(C=O)C>[CH3:28][O:27][C:25](=[O:26])[C@@H:24]([O:23][C:22]1[CH:21]=[C:20]([CH:32]=[CH:31][CH:30]=1)[CH2:19][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2)[C:10]([CH3:11])=[C:2]1[CH3:1])[CH3:29]
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: COC(=O)[C@H](C)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(O[C@@H](C)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of allyl 2,3-dimethyl-1H-indole-5-carboxylate (1.0 g, 4.4 mmol, 1 equiv) and (S)-methyl 2-(3-(bromomethyl)phenoxy)propanoate (1.30 g, 4.84 mmol, 1.1 equiv) in anhydrous DMF (30 mL) under argon atmosphere was added sodium hydride (211 mg, 8.8 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then quenched slowly with a solution of HCl 0.5 N. The residue was dissolved in AcOEt, washed with a saturated NaHCO3 solution and brine, dried over MgSO4. The crude was purified by flash chromatography (AcOEt/Hexane 0->60%) to afford the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([NH:24]C(=O)OC(C)(C)C)[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(O)(=O)C(O)=O>C(#N)C>[CH3:1][C@@H:2]([NH2:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: C[C@H](Cc1c[nH]c2c(O[C@@H](C)C(=O)N3CCOCC3)cccc12)NC(=O)OC(C)(C)C
Agent: O=C(O)C(=O)O
Solvent: CC#N
Product: C[C@H](Oc1cccc2c(C[C@@H](C)N)c[nH]c12)C(=O)N1CCOCC1
Yield: 79 %

Procedure:
To a solution of tert-butyl (1R)-1-methyl-2-(7-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}-1H-indol-3-yl)ethylcarbamate (1.03 g, 2.39 mmol) in acetonitrile (10 mL) is added oxalic acid (860 mg, 9.55 mmol), and the mixture is refluxed for 5 hours. The reaction solution is evaporated under reduced pressure to remove the solvent, and to the residue are added a 10% aqueous potassium carbonate solution and a mixture of chloroform:methanol (10:1) for separation. The organic layer is dried over anhydrous potassium carbonate, and the solvent is removed by distillation to give the title compound (626 mg, yield: 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:27][CH:26]5[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH:25]5[CH2:24]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:24][CH:25]5[CH:26]([CH2:28][NH:29][CH2:30]5)[CH2:27]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.14 g) in DCM (30 mL) was added a solution of HCl in EtOAc. The reaction mixture was stirred for 6 h at room temperature and filtered to give crude product. The crude product was recrystallized from a mixture of MeOH and EA to give the title compound as a white solid (0.83 g, 89.50%), HPLC: 95.23%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 438.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.83-1.88 (m, 4H), 2.32-2.45 (m, 6H), 2.66-2.76 (m, 4H), 4.03 (s, 3H), 4.15 (t, J=7.2 Hz, 2H), 7.15 (s, 1H), 7.23 (s, 1H), 7.40 (s, 1H), 7.53-7.60 (m, 2H), 7.90-7.93 (m, 1H), 8.66 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Yield: 58 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem., 1983, 26, p. 1582 and J. Med. Chem., 1986, 29, p. 2194) (1.0 g, 4.6 mmol) in ethanol (4 ml) under argon was treated with phenylisocyanate (0.55 g, 4.6 mmol) and the reaction was heated at reflux temperature for 4 hours. The product precipitate out of the reaction. The reaction was then concentrated in vacuo and the residue was triturated with isopropylether to give the title compound as a colorless solid (0.9 g, 63%), m.p. 240-241° C.: 1H NMR (CDCl3 /DMSO) δ 8.3 (s, 1 H), 7.7 (s, 1 H), 7.4 (d, J=8.0 Hz, 3 H), 7.26 (t, J=8.0 Hz, 2 H), 7.0 (t, J=9.0 & 7.0 Hz, 1 H), 6.86 (d, J=9.0 Hz, 1 H), 6.4 (d, J=8.0 Hz, 1 H), 5.3 (d, J=5.0 Hz, 1 H), 4.9 (t, J=9.0 & 8.0 Hz, 1 H), 3.6 (dd, J=4.0 & 6.0 Hz, 1 H), 1.5 (s, 3 H), 1.3 (s, 3 H); 13C NMR (CDCl3 /DMSO) 157.0, 156.5, 139.1, 132.2, 132.1, 128.4, 123.9, 121.8, 118.2, 117.8, 80.0, 74.3, 49.9, 26.1, 18.4; IR (KBr) 1132, 1267, 1491, 1550, 1612, 1645, 2226, 2932, 2978, 3433 cm-1.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.[H-].[Na+]>O1CCOCC1>[C:19]([C:4]1[C:3]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[C:2]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(-n2cncn2)c1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 15.4 %

Procedure:
To a solution of 5-bromo-3-cyano-1-(2,6-dichloro -4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (2.0 g) in dioxan (30 ml) was added 1,2, 4-triazole (0.74 g), and the mixture heated under reflux overnight. After cooling to ambient temperature, sodium hydride (0.125 g) was added and the mixture heated under reflux for 2 days. The solvent was evaporated in vacuo and the residue dissolved in dichloromethane (50 ml) and washed with water (50 ml). The aqueous layer was re-extracted with dichloromethane (50 ml) and the combined organics dried over anhydrous magnesium sulphate, then evaporated in vacuo to give a yellow oil. Purification by chromatography on silica, eluting with dichloromethane/hexane (1:1) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)- 5-(1,2,4-triazol-1-yl)-4-trifluoromethylsulphonylpyrazole (0.3 g) as a white solid, m.p. 172.3°-173.7° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Br)[N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1.[C:15]1(C)[CH:20]=CC=C[C:16]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C=O)C.[I-].C([Zn+])CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:16][CH2:15][CH3:20])[N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)Nc1cc(N)c(C#N)c(Br)n1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCC[Zn+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(NC(C)=O)cc(N)c1C#N
Temperature: 90 °C
Yield: 159 %

Procedure:
To 128 mg of N-(4-amino-6-bromo-5-cyano-pyridin-2-yl)-acetamide (Example 65A), 6 mg (0.027 mmol) of palladium(II)acetate, and 30 mg (0.098 mmol) of tri(o-tolyl)phosphine was added 0.5 mL of DMF. The mixture was put under N2 and stirred, then 2.0 mL of the n-propylzinc iodide solution was added via syringe. The mixture was heated at 90° C. for 10 minutes then poured into a stirred mixture of 10 mL water and 10 mL ethyl acetate. The metal salts were filtered away through diatomaceous earth, then the layers were separated. The organic layer was extracted with water (2×10 mL), and brine (1×10 mL), dried over MgSO4, filtered, and concentrated to a solid. This was purified via silica gel chromatography, eluting with 50:50 hexanes:ethyl acetate and loading as a solution in hot ethyl acetate to provide 34 mg (31%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.29 (s, 1H), 7.39 (s, 1H), 6.82 (s, 2H), 2.63 (m, 2H), 2.07 (m, 3H), 1.67 (m, 2H), 0.92 (t, 3H, J=7.5 Hz); MS (ESI) m/e 219 (M+H)+; m/e 217 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=C(C#N)[C:10](=[O:16])[NH:11]2.C(O)C.[OH-].[Na+].[C:24]([OH:27])(=[O:26])[CH3:25]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:25]([C:24]([OH:27])=[O:26])[C:10](=[O:16])[NH:11]2
Reactant: CC(=O)O
Reactant: N#Cc1cc2c(-c3cccs3)nccc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(-c3cccs3)nccc2[nH]c1=O

Procedure:
A mixture of 1,2-dihydro-5-(2-thienyl)-2-oxo-1,6-naphthyridine-3-carbonitrile (10.0 g), ethanol (300 ml) and 10N NaOH (300 ml) was refluxed overnight. After cooling, the reaction mixture was neutralized with acetic acid, and the precipitated crystals were separated by filtration, washed with water, isopropanol and diisopropyl ether in this order and then dried to give the title compound (Compound No. 44)(10.5 g) as pale yellow crystals. M.p. 2780° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][C:16]1[C:23]([CH3:24])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[CH3:25].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][C:16]1[C:23]([CH3:24])=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=3[N:1]=2)=[CH:18][C:17]=1[CH3:25]
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(O)c(C)c3)nc2n1
Temperature: 150 °C
Yield: 39.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.40 g, 7.1 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (1.07 g, 7.1 mmol) in N,N-dimethyl acetamide (20 mL), NaHSO3 (1.39 g, 7.81 mmol) and p-TSA (0.675 g, 3.55 mmol) were added and the reaction mixture was heated at 150° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected and further washed with methanol. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (0.92 g, 39.6%). Selected data: MS (ES) m/z: 328.07; MP 297-299° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[O:30])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[BH4-].[Na+]>CCO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(C=O)cc(C)c32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of (±)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole-5-carbaldehyde (221 mg, 0.52 mmol) and NaBH4 (98 mg, 2.6 mmol) in EtOH (5 mL) was stirred at 0° C. for 0.5 h. The reaction mixture was diluted with CH2Cl2. The mixture was washed with H2O, half satd. KHSO4 aqueous solution, H2O, and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=3.79 Hz, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 7.14 (s, 1H), 6.98 (d, J=3.79 Hz, 1H), 5.01 (t, J=5.56 Hz, 1H), 4.87 (d, J=11.37 Hz, 1H), 4.67 (d, J=11.37 Hz, 1H), 4.55-4.63 (m, 3H), 3.73-3.85 (m, 1H), 3.37-3.51 (m, 1H), 2.34 (s, 3H), 2.08 (s, 3H), 1.51-1.71 (m, 2H), 1.30-1.51 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:8]=[CH:7][C:6]=1Br.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:8]=[CH:7][C:6]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)Cc1cc(Oc2ccc(C(F)(F)F)cc2CN2CCOC2=O)ccc1Br
Reactant: OB(O)c1ccccc1
Product: COC(=O)Cc1cc(Oc2ccc(C(F)(F)F)cc2CN2CCOC2=O)ccc1-c1ccccc1

Procedure:
Prepared according to the procedure described in Example 7, Step 1, using the following starting materials: {2-bromo-5-[2-(2-oxo-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and phenylboronic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.CO.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:3]([C:9](=[O:11])[CH3:10])=[CH:4][C:5]([F:8])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)c1cc(F)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)c1cc(F)ccc1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
1-(2-Bromo-5-fluoro-phenyl)-ethanone (868 mg, 4 mmol), p-chlorophenylboronic acid (768 mg, 1.2 eq.), and tetrakis (triphenylphosphine)palladium(0) (473 mg, 0.1 eq.), were dissolved in 25 mL toluene, 6 mL methanol and 2.5 mL sat. sodium bicarbonate solution. After degassing/sonicating the solution, the sealed reaction vessel was heated to 80° C. overnight. The cooled solution was separated between ethyl acetate and water; the aqueous phase extracted two more times with ethyl acetate, and the organic fractions were combined, dried with sodium sulfate and evaporated. Silica gel chromatography (5:1 hexanes/ethyl acetate) gave 1-(4′-chloro-4-fluoro-biphen-2-yl)-ethanone (821 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C([Li])CCC.[Cl:18]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:18][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cn1cnc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole (0.600 g, 3.79 mmol) in 15 mL THF at −78° C. under nitrogen was added n-butyllithium 2.5 M in hexanes (1.67 ml, 4.17 mmol) dropwise over 3 min. The resulting orange-brown solution was allowed to stir for 30 min, at which time a solution of hexachloroethane (0.988 g, 4.17 mmol) in 5 mL THF was added slowly down the side of the flask. The orange-brown solution was allowed to stir for 1 h, and was quenched with sat'd aq. NH4Cl, warmed to ambient temperature, and stirred overnight. The mixture was extracted with EtOAc, the organic layers collected and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-chloro-1-methyl-4-phenyl-1H-imidazole as a brown solid. MS m/z=193 [M+H]+. Calc'd for C10H9N2Cl: 192.6.