Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].CN(C)C=O.Br[CH2:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:40]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:38][C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:40])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(CC(=O)c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (0.7 g), potassium tert-butoxide (1.0 M tetrahydrofuran solution, 1.75 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromo-1-(4-fluorophenyl)ethanone (0.35 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH3:25])=C[CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(OC2C=[N:45]C(C(O)=O)=NC=2)C2CC(C)(C)OC=2C=1)=O.CN>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[N:45][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[N:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2
Agent: CN
Product: CNC(=O)c1ncc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid (171c) (72.3 mg, 0.21 mmol) and methyl amine (2 mL, 2.0 M solution in THF) to give a white solid (45 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 2 H) 7.88 (d, J=3.79 Hz, 1 H) 7.28 (d, J=10.11 Hz, 1 H) 7.19 (s, 1 H) 3.88 (s, 3 H) 3.08 (d, J=5.05 Hz, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C18H19N3O5 m/z 358.20 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2:13][C:14]1[NH:18][C:17]([CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=2)=[N:16][C:15]=1[C:30](=[O:32])[NH2:31].C(=O)([O-])O.[Na+].O>C1COCC1>[C:30]([C:15]1[N:16]=[C:17]([CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=2)[NH:18][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)(=[O:32])[NH2:31]
Reactant: CCOC(=O)c1ccc(Cc2nc(C(N)=O)c(N)[nH]2)o1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2[nH]c(Cc3ccc(C(=O)OCC)o3)nc2C(N)=O)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
4-Propylbenzoyl chloride (2 ml; 11.9 mM) are added dropwise to 3 g (10.8 mM) of ethyl 5-(5-amino-4-carbamoyl-1H-imidazol-2-ylmethyl)furan-2-carboxylate and 1.8 g of sodium hydrogen carbonate (21.6 mM) in 15 ml of THF. The reaction medium is then stirred at 20° C. for 20 hours. After addition of water, a solid precipitate is formed, which is isolated and purified by chromatography on silica, first using a dichloromethane/acetone mixture (90/10) as eluent, and then a dichloromethane/methanol mixture (90/10) to give 2.9 g of ethyl 5-[4-carbamoyl-5-(4-propylbenzoylamino)-1H-imidazol-2-ylmethyl]furan-2-carboxylate in the form of a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20]C(=O)C)=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:24]([O:26]CC)=[O:25])=[CH:6][C:5]=1[C:29]#[C:30][Si](C)(C)C>CO.O.C(OCC)(=O)C.CCCC(C)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:24]([OH:26])=[O:25])=[CH:6][C:5]=1[CH2:29][CH3:30]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(C#C[Si](C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCCC(C)C
Product: CCc1cc(Cn2c(C(=O)O)cc3cc(O)ccc32)ccc1Cl
Reaction time: 3 h
Yield: 65.9 %

Procedure:
Sodium hydroxide (2M, 1.8 ml) was added to a solution of ethyl N-[(4-chloro-3-trimethylsilylethynylphenyl)methyl]-5-acetoxyindole-2-carboxylate (0.14 g) in methanol (5 ml) and the mixture was stirred for 3 hours. The methanol was removed and the residue obtained was diluted with water (20 ml) and extracted twice with ethyl acetate (20 ml each time). The aqueous layer was acidified with aqueous hydrochloric acid (2M) and extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extracts were washed with water (30 ml) and brine (30 ml) and dried (MgSO4). The residue obtained on removal of the solvent was dissolved in a mixture of ethyl acetate and iso-hexane (1:1) and passed down a 5 g silica Isolute column eluting with an ethyl acetate iso-hexane mixture (1:1) to give the title compound (65 mg). NMR (CD3SOCD3): d 4.5 (s, 1H), 5.7 (s, 2H), 6.8 (m, 1H), 6.9 (m, 2H), 7.1 (m, 1H), 7.2 (s, 1H), 7.35 (m, 1H), 7.4 (m, 2H), 9.0 (s, 1H); m/z 324.4 (M−H).
Reaction SMILES: [Cl-].[Li+].[CH3:3][Mg]Cl.[CH3:6]/[C:7](=[CH:22]\[CH2:23][CH3:24])/[C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:12][C:11]1=[O:21])=[O:9]>O.O1CCCC1.C(O)(=O)C>[CH3:6][C@H:7]([C@H:22]([CH3:3])[CH2:23][CH3:24])[C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:12][C:11]1=[O:21])=[O:9]
Reactant: C[Mg]Cl
Reactant: CC/C=C(\C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A 20 L jacketed reactor was fit with a gas inlet and a 2 L dripping funnel. A nitrogen sweep was begun over the reactor and maintained throughout the process. To the reactor was charged 392 g (9.26 mol) of lithium chloride, 1332 g (6.479 mol) of copper bromide dimethylsulfide complex and 11 L of tetrahydrofuran. The reaction was stirred for 30 minutes at room temperature and then cooled to −15° C. To the reaction mixture was added 4.268 L (12.80 mol) of 3.0M methyl magnesium chloride at a rate such that the reaction temperature did not exceed −10° C. Upon completion of the addition, the cuprate solution was allowed to stir at −5° C. overnight. To the cuprate solution was added 500 g (3.09 mol) of (S)-3-((E)-2-methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one as a solid. The reaction was stirred at −3° C. for 2 hours. The reaction solution was charged to a 22 L round bottom flask containing 800 mL of acetic acid and 2 L of tetrahydrofuran at a rate such that the temperature of the quench solution did not exceed 25° C. To the quenched solution was added 6 L water. The resulting emulsion was filtered and the layers were separated. The organic layer was extracted with 9 L of 4.8 M NH4OH followed by 9 L of saturated NH4Cl. The organic layer was clarified through a plug of magnesol. The organic layer was concentrated to give 822 g of a crude solid. The crude solid was recrystallized from 8 L of 20% H2O in MeOH, filtered and dried in a vacuum oven to give 550 g of a white solid. The white solid was recrystallized from 5 L of 20% H2O in MeOH, filtered and dried in a vacuum oven to give 475 g of the titled compound: 1H-NMR (DMSO) 7.338-7.224 (m, 5H), 5.431-5.399 (q, 1H, J=4.288), 4.696-4.652 (t, 1H, J=8.773), 4.120-4.087 (m, 1H), 3.622-3.556 (m, 1H), 1.648-1.584 (m, 1H), 1.047-0.968 (m, 1H), 0.900-0.883 (d, 3H, J=6.823), 0.738-0.721 (d, 3H, J=6.628), 0.693-0.656 (t, 3H, J=7.408); Anal Calc'd for C16H21N1O3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.81; H, 7.61; N, 5.07; MS (Ion Mode: APCI) m/z=276 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C(NC(C)C)(C)C.[Li].[Cl:20][C:21]1[CH:32]=[CH:31]C(C(N(OC)C)=O)=[CH:23][CH:22]=1.OS(O)(=O)=O>C1COCC1>[Cl:20][C:21]1[CH:32]=[CH:31][C:11]([C:10]2[O:9][C:3](=[O:8])[CH:4]=[C:5]([OH:6])[CH:7]=2)=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=c1cc(O)cc(-c2ccc(Cl)cc2)o1
Yield: 31 %

Procedure:
The title compound (1.56 g, m.p. 247-249° C.) was prepared in a similar manner as that demonstrated in the preparation of Example N using the following: 60% NaH (0.904 g, 22.6 mmol), THF (50 mL), ethyl acetoacetate (3.00 g, 22.6 mmol), lithium diisopropylamine in THF (39.8 mL, 24 mmol), 4-chloro-N-methoxy-N-methylbenzamide (3.73 g, 22.6 mmol), 90% H2SO4 (20 mL). H NMR (300 MHz, DMSO-d6) δ11.950 (bs, 1 H), 7.878 (d, 1 H, J=9 Hz), 7.584 (d, 1 H, J=9 Hz), 6.812 (d, 1 H, J=2 Hz), 5.409 (d, 1 H, J=2 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[NH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
t-Butyl trans-4-aminomethylcyclohexylcarbamate (344 mg, 1.5 mmol) was dissolved in CH2Cl2 (7 mL) and cooled in an ice-bath. Triethylamine (0.21 mL, 1.5 mmol) was added, followed by benzyl chloroformate (0.22 mL, 1.5 mmol) dropwise. The mixture was stirred at rt under N2 for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with water and brine, dried over Na2SO4, filtered, and concentrated to a white solid. This solid was dissolved in 10 mL of 4 N HCl-dioxane and stirred at rt for 10 min. The solvent was removed. The residue was dried under vacuum to give 350 mg of the desired product as a white solid (78%). MS 263.36 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].C1COCC1.C([Li])CCC>O>[CH3:14][C:7]1([CH3:15])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:3]#[CH:2])[CH:5]=2)[S:10][CH2:9][CH2:8]1
Reactant: CC1(C)CCSc2ccc(C=C(Br)Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C

Procedure:
7.7 g (21.2 mmol) of 2,2-dibromo-1-(4,4-dimethylthiochroman-6-yl) ethylene and 80 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 17 ml (26.6 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at −78° C. and the mixture was permitted to heat to room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with heptane. 3.9 g (90%) of the expected acetylene derivative were recovered in the form of a yellow oil.
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]#[CH:23])[CH:15]=1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N+:33]([O-])=[O:34])[CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:23]=[C:22]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[O:34][N:33]=1)[CH3:25]
Reactant: CCOC(=O)CCCCC[N+](=O)[O-]
Reactant: C#Cc1cc(Cl)ccc1OC
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCc1cc(-c2cc(Cl)ccc2OC)on1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
Add 1,4-phenylenediisocyanate (8.41 g, 52.5 mmol) to a stirred solution of 4-chloro-2-ethynyl-1-methoxy-benzene (4.0 g, 30.3 mmol) and 6-nitro-hexanoic acid ethyl ester (8.6 g, 45.4 mmol) in toluene (300 mL, anhydrous) and stir at room temperature under N2. Add triethylamine (7.3 mL, 52.5 mmol) and heat to reflux under N2 overnight. Filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 6.6 g of a orange oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-40% EtOAc/hexanes to afford the title compound (4.51 g, 76%). MS (IS) 338 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.C([Li])(C)(C)C.C1C(=O)N([I:23])C(=O)C1>O1CCCC1>[I:23][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cnc2ccccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(I)nc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
In an oven dried nitrogen purged 3 neck 100 mL round bottom flask, 1.00 g (7.57 mmol) of 1-methylbenzimidazole in 20 mL of dry tetrahydrofuran is cooled to −78° C. 10.69 mL (18.17 mmol) of 1.7 M t-butyllithium in hexanes is added and the reaction mixture is stirred at −78° C. for 1 h. 2.55 g (11.36 mmol) of NIS in 20 mL of dry tetrahydrofuran is added. Reaction is removed from bath and stirred at room temperature for 1 hour, quenched with saturated aqueous solution of ammonium chloride, and diluted with dichloromethane. The layers are separated, the aqueous is extracted 3×100 mL dichloromethane, dried (MgSO4), and concentrated. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.400 g of the title compound, 21% yield. MS, ES+=259.0 (M+1); 1H NMR (DMSO-d6) δ 7.580-7.552 (m, 2H); 7.228-7.129 (m, 2H); 3.750 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[CH:4][C:3]=1[S:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]C)=[O:14].[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[CH:4][C:3]=1[S:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccccc1Sc1ccc(CCl)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(CCl)ccc1Sc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
8.16 g Methyl S-(2-amino-4-chloromethylphenyl)thiosalicylate was dissolved in THF (50 mL) and methanol (50 mL), and treated with 5N sodium hydroxide solution (20 mL) with stirring at room temperature for 17 h. The reaction mixture was concentrated in vacuo, diluted with water, and acidified to pH 1-2 with 6N hydrochloric acid. The resulting suspension was filtered, and recrystallized from n-heptane to provide S-(2-amino-4-chloromethylphenyl)thiosalicylic acid as a light gray solid, 1H NMR (300 MHz, CDCl3), δ 6.77 (dd, 1H, J=2.7 Hz, J=2.1 Hz), 6.83 (d, 1H, J=2.1 Hz), 7.18 (t, 1H), 7.367 (s, 1H), 7.32 (t, 1H), 7.38 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=1.8 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23]
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2ccc3c(O)c(C(=O)NCCCCC(=O)O)ncc3c2)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl 4-hydroxy-7-(4-methoxybenzylamino)isoquinoline-3-carboxylate (21.0 mg, 0.06 mmol), 5-aminovaleric acid (269.3 mg, 2.3 mmol, Sigma-Aldrich) and NaOMe in MeOH (3.0 mL, 1.5 mmol, 0.5 M solution, Sigma-Aldrich) was heated to reflux for 20 hours before cooling to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (10 mL) and EtOAc (10 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 14 mg. MS: (−) m/z 422.13 (M−1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=[O:30].C(N(CC)CC)C.O>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)=[O:30])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccccn4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.60 mmol) and picolinoyl chloride hydrochloride (0.29 g, 1.60 mmol) in N,N-dimethylformamide (20 mL), was added triethylamine (0.67 mL, 4.80 mmol) at room temperature under nitrogen. After 18 h, water (100 mL) was added and the product was extracted with CH2Cl2 (3×150 mL). The organic layers were combined, washed with water (3×150 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration, washed with Et2O (25 mL) and dried in vacuo to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.31 g, 51% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 5.52 min (97.80%); mp: 229-231° C.; 1H NMR (DMSO-d6) δ 1.86-2.11 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.59 (d, J=17.0 Hz, 1H, CHH), 2.79-3.06 (m, 1H, CHH), 4.30 (d, J=17.4 Hz, 1H, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 4.61 (d, J=6.4 Hz, 2H, CH2), 5.10 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.48 (d, J=7.7 Hz, 1H, Ar), 7.54 (s, 1H, Ar), 7.58-7.65 (m, 1H, Ar), 7.68 (d, J=7.9 Hz, 1H, Ar), 7.89-8.19 (m, 2H, Ar), 8.67 (d, J=4.5 Hz, 1H, Ar), 9.49 (t, J=6.3 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.51, 47.11, 51.58, 122.02, 122.18, 122.93, 126.62, 127.20, 130.36, 137.81, 142.35, 143.82, 148.47, 149.89, 164.07, 167.92, 170.98, 172.85; LCMS: MH=379; Anal Calcd for C20H18N4O4+0.1H2O: C, 63.18; H, 4.83; N, 14.74. Found: C, 62.80; H, 4.86; N, 14.69.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.C(O)(C)C>CC(O)CCC.Cl>[ClH:2].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:28]([F:33])[CH:27]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)cnnc2cc1OCCCN1CCOCC1
Temperature: 120 °C
Yield: 106.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnoline hydrochloride (150 mg, 0.36 mmol), (prepared as described for the starting material in Example 12), 4-chloro-2-fluoroaniline (77 mg, 0.53 mmol) in 2-pentanol (4 ml) and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for 1 hour. The mixture was allowed to cool and isopropanol was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnoline hydrochloride (185 mg, 98%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].[O:33]1CCC[CH2:34]1.CN(CCS(O)(=O)=O)C.[OH-].[Na+]>C(Cl)Cl>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([CH:34]=[O:33])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C1CCOC1
Agent: CN(C)CCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cn1c(N2CCN(C=O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 1.25 h
Yield: 75 %

Procedure:
5-[9-(Isobutyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (129.8 mg, 0.30 mmol) was added to a tetrahydrofuran solution (7.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (48.4 mg, 0.30 mmol) at room temperature and the resulting mixture was stirred for 75 minutes. Methylene chloride was added to the reaction mixture and the resulting mixture was poured into 2 N aqueous sodium hydroxide solution and extracted with methylene chloride-methanol (10:1). The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=49:1 to 32:1) to give the title compound (103.4 mg, 75%) as a pale yellow solid.
Reaction SMILES: FC1C=NC=CC=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14](C(F)(F)F)=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C#C>O>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[CH:8]1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: C#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc2ocnc2c1
Temperature: 100 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of 2-propyne-1-ol was stirred while heating at 100° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.20 g of 2-(3-(2-propyne-1-yloxy)pyridin-4-yl)-5-trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 73”).