Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH:48]([C:52](O)=[O:53])[CH2:47]3)=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:28][C:52]([CH:48]2[O:49][CH2:50][CH2:51][N:46]([C:44]([O:43][CH2:42][CH:40]3[C:39]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:33]4[C:41]3=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:45])[CH2:47]2)=[O:53])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=C(O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCO1
Reaction time: 2 h

Procedure:
HATU (1.17 g, 3.0 mmol) and cyclopropylamine (0.17 g, 3.0 mmol) were added to a solution of 4-[(9H-fluoren-9-ylmethoxy)carbonyl]morpholine-2-carboxylic acid (1.0 g, 2.9 mmol) and DIPEA (0.56 mL, 3.2 mmol) in DMF (50 mL). The reaction mixture was stirred for 2 hrs. at ambient temperature and the solvent was concentrated. The product was recovered in EtOAc and washed with water, saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous MgSO4 and the solvent was concentrated to provide the title compound that was used for the next step without further purification. MS (ESI) (M+H)+=393.0.
Reaction SMILES: [C:1]([NH2:5])(=O)[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:9])=[O:8].[CH3:10][C:11]([CH3:13])=[O:12].Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>O>[C:1](=[N:15][OH:16])([NH2:5])[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:9])=[O:8].[CH3:10][C:11]([CH3:13])=[O:12]
Reactant: C=CC(N)=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CC(N)=NO
Yield: 82 %

Procedure:
To a solution of 408 g. (2.4 moles) of diacetone acrylamide ##STR12## and 200 g. (2.88 moles; 20% molar excess) of hydroxylamine hydrochloride in 1.5 l. of distilled water was added a solution of 200 g. (1.44 moles) of potassium carbonate in 250 ml. of water at room temperature of about 25° C. over a period of 15 min. A precipitate formed after about 15 minutes. Stirring was continued until a thick paste formed and the mixture was then allowed to stand for another hour. The solid product was isolated by filtration, washed with small portions of water (amounting to a total of 500 ml.) and dried at 40° C. in a vacuum oven. Yield of 365 g. of a white crystalline powder (82% yield), m.p. 103° C. The material was of sufficient purity to be directly employed in polymerization and was employed in the polymerization described in Example 2 hereinafter. If desired, further purification can be attained through recrystallization from benzene or toluene.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][C:3]=1[NH:11]C(=O)CCCC.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][C:3]=1[NH2:11]
Reactant: CCCCC(=O)Nc1cc2nc[nH]c2nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2[nH]cnc2cc1N
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a solution of 2-butyl-3-[2'-(1,1-dimethylethyl)aminosulfonyl][1,1'-biphenyl]-4-yl]methyl]-5-methyl-6-[(1-oxopentyl)amino]-3H-imidazo[4,5-b]pyridine (347 mg, 0.589 mmol) in MeOH (3 mL) was added conc. HCl (2 mL). After the solution was stirred at rt for 42 h, the solution was diluted with EtOAc, neutralized by saturated aq. NaHCO3, washed with brine, and dried over anhydrous MgSO4. Concentration followed by flash chromatography (100% EtOAc, 10% MeOH/EtOAc) afforded 2-butyl-3-[2'-(1,1-dimethylethyl)aminosulfonyl][1,1'-biphenyl]4-yl]methyl]-5-methyl-6-amino-3H-imidazo[4,5-b] pyridine as a solid. To this solid (100 mg, 0.198 mmol) and DMAP (10 mg, 0.08 mmol) in pyridine (2 mL) was added iso-propylisocyanate (24 mL, 0.24 mmol). After the solution was stirred at rt for 18 h, the solution was quenched with MeOH, and stirred at rt for additional 2 h. Concentration gave a brown glass, which was dissolved in TFA (2 mL) and stirred at rt for 18 h. After TFA was removed in vacuo, the residue was dissolved in EtOAc and washed with saturated aq. NaHCO3. The aqueous layer was extracted with EtOAc (2X). The combined organic layer was washed with brine, and dried over anhydrous MgSO4. Concentration followed by flash chromatography (hexanes: EtOAc=1:1, 100% EtOAc, 10% MeOH/EtOAc) afforded the title compound as a foamy powder.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].[C:5]1([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O>[CH3:1][CH:2]([NH:4][CH2:18][CH:17]([OH:19])[CH2:16][O:15][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC(C)N
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: O
Product: CC(C)NCC(O)COc1cccc2ccccc12

Procedure:
2.55 ml of (1-methylethyl)amine (0.0297 mol) are mixed with 1.25 ml of H2O and the mixture is then stirred with 5 g of 1-(1-naphthyloxy)-2,3-epoxypropane (0.0249 mol) and reacted at room temperature for 23 hours.
Reaction SMILES: [CH2:1]([N:10]1[C:15]([O:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[C:14]([CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[NH:12][C:11]1=[O:29])[CH:2]=[CH:3][C:4]1C=CC=CC=1.COC(C=CCN1C(OC2C=C(C)C=C(C)C=2)=C(C(C)C)C(=O)NC1=O)=O.C(N1C(OC2C=C(C)C=C(C)C=2)=C(C(C)C)C(=O)NC1=O)C#CC.C1(C#CCN2C(OC3C=C(C)C=C(C)C=3)=C(C(C)C)C(=O)NC2=O)C=CC=CC=1>>[CH2:1]([N:10]1[C:15]([O:16][C:17]2[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=2)=[C:14]([CH:25]([CH3:26])[CH3:27])[C:13](=[O:28])[NH:12][C:11]1=[O:29])[CH:2]=[CH:3][CH3:4]
Reactant: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC=Cc2ccccc2)c1
Agent: CC#CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: COC(=O)C=CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC#Cc2ccccc2)c1
Product: CC=CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
1-cinnamyl-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(methoxycarbonylallyl)-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(2-butynyl)-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; and 1-(3-phenyl-2-propynyl)-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:14]Br.C(=O)(O)[O-].[Na+]>ClS(O)(=O)=O.[I-].[K+]>[Br:14][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7](=[O:13])[C:6]=2[CH:5]=1
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S(=O)(O)Cl
Agent: [I-]
Product: Cc1cc(Br)cc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 155.1 %

Procedure:
To a solution of 8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione, (10.0 g, 56.5 mmol) and potassium iodide (0.36 g, 1.8 mmol) in chlorosulfonic acid (12 mL) was added bromine (4.6 g, 28.7 mmol). and the reaction was stirred overnight at room temperature. The reaction was then slowly poured onto ice water and neutralized with sodium bicarbonate powder to a pH of 7. The solids were filtered, rinsed with water and to afford the desired intermediate as a white solid (11.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([CH3:19])=[CH:7][C:6]=2[CH3:20].C([O:24][C:25]1[CH:35]=[CH:34][C:28]([CH:29]=[CH:30][C:31](Cl)=[O:32])=[CH:27][CH:26]=1)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[C:6]([CH3:20])[CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[CH:30]=[CH:29][C:28]1[CH:34]=[CH:35][C:25]([OH:24])=[CH:26][CH:27]=1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2ncc(NC(=O)C=Cc3ccc(O)cc3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
A mixture of 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (282 mg), 4-acetoxycinnamoyl chloride (250 mg) and tetrahydrofuran (5 ml) was stirred at room temperature for 6 hours. After being diluted with water and made neutral with a sodium hydrogen carbonate saturated solution, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was dissolved in tetrahydrofuran-methanol solution (1:1, 6 ml). Then, 2N-hydrochloric acid was added to the solution which was thereafter stirred at room temperature for 1.5 hours. The resultant solution was diluted with water, adjusted to pH 4 by addition of 2N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The resultant was removed to give crystals of 4-(2-chlorophenyl)-3-(4-hydroxycinnamoylamino)-6,8-dimethylquinoline (335 mg, 78.3%). The obtained crystals were recrystallized from ethanol to afford colorless needles.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:16]4[C:11]([C:12]([CH3:30])=[CH:13][CH:14]=[N:15]4)=[CH:10][C:9]=3[CH2:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:31][CH2:30][C:12]1[C:11]2[C:16](=[C:17]([O:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18]3[C:19](=[O:20])[N:7]([CH2:6][CH:1]4[CH2:5][CH:4]=[CH:3][CH2:2]4)[CH2:8][C:9]=3[CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc2c(OC(=O)c3ccccc3)c3c(cc12)CN(CC1CC=CC1)C3=O
Solvent: CCOC(C)=O
Product: O=C(Oc1c2c(cc3c(CBr)ccnc13)CN(CC1CC=CC1)C2=O)c1ccccc1

Procedure:
For example, benzoic acid 7-cyclopent-3-enylmethyl-4-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-9-yl ester A17.12 is reacted with N-bromosuccinimide in refluxing ethyl acetate to afford benzoic acid 4-bromomethyl-7-cyclopent-3-enylmethyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-9-yl ester A17.13. This compound is heated to 120° C. with an excess of a trialkyl phosphite to give after deprotection the phenolic phosphonate ester A17.14.
Reaction SMILES: [C:1]([NH2:12])(=[S:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[C:13]1([C:19]([CH:21](Cl)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:6]1[O:7][C:8]2[CH:9]=[CH:10][C:2]([C:1]3[S:11][C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:12]=3)=[CH:3][C:4]=2[O:5]1
Reactant: NC(=S)c1ccc2c(c1)OCO2
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccc4c(c3)OCO4)sc2-c2ccccc2)cc1
Yield: 67.1 %

Procedure:
Thiopiperonylamide (18.1g, 0.10 mole) and desyl chloride (23.1g, 0.10 mole) are heated under reflux in 95% ethanol (100 ml) for two hours. An oil precipitates which solidifies when the reaction mixture is cooled. The solid is collected and recrystallized from ethanolethyl acetate to give 24.0g (67% yield) of 2-(3,4-methylenedioxyphenyl)-4,5-diphenylthiazole, m.p. 121°-124° C. Thiopiperonylamide is also prepared from the corresponding nitrile by the method of Fairfull et al., J. Chem. Soc. 1952, 742.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][CH:18]([CH3:21])[C:19]#[CH:20]>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:17][CH:18]([CH3:21])[C:19]#[C:20][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: OCc1ccc(I)cc1
Reactant: C#CC(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1ccc(CO)cc1
Reaction time: 0.17 h

Procedure:
4-Iodobenzyl alcohol (1.00 g) was dissolved in DMF (17 mL), added with copper (1) iodide (97.7 mg), triethylamine (0.89 mL), and 3-methyl-1-butyne (1.27 mL), and stirred for 10 minutes in argon atmosphere. Subsequently, it was added with bis(triphenylphosphine)palladium (II) chloride (300 mg) and stirred for 4.3 hours at room temperature in argon atmosphere. After filtration through Celite, it was washed with ethyl acetate and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (6 to 40% ethyl acetate/hexane) to obtain the title compound as a yellow oil.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:36]=[CH:35][C:24]([O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=2)=[CH:23][CH:22]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:2]1([C:8]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][N:10]([CH2:19][C:21]3[CH:36]=[CH:35][C:24]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)(c4ccccc4)C3)cc2)nc1
Yield: 105.8 %

Procedure:
Using a method similar to Example 345, using 3,3-diphenyl-pyrrolidine hydrochloride salt (0.107 g, 0.412 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.133 g, 0.628 mmol), and acetic acid (0.035 mL 0.611 mmol) in 1,2-dichloroethane (8.0 mL) provides 0.196 g (106%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C29H28N3O2 450.2182, found 450.2205; 1H NMR (methanol-d4): 8.68 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.46 (d, 2H, J=7.3 Hz), 7.35-7.26 (m, 8H), 7.21-7.12 (m, 4H), 7.04 (d, 1H, J=8.8 Hz), 3.75 (s, 2H), 3.38-3.24 (m, 2H), 2.98-2.91 (m, 2H), 2.71-2.64 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].CCOC(C)=O>C(Cl)Cl>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[O:1][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(C=O)c(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 82.2 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzaldehyde (30 g, 197 mmol) in DCM (anhydrous, 120 mL) was added pyridine (79 mL, 986 mmol) at room temperature. After the mixture was cooled to −10° C., the Tf2O (50 mL, 296 mmol) was slowly added to the reaction between −10° C. to 0° C. The addition took about 2.5 hours. After the addition, the stirring was kept for 30 minutes. The EtOAc (200 mL) was added. The organic layer was washed with 1 M HCl (3×80 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified over silica gel, eluting with 5% EtOAc/hexanes to give trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (2) 46 g in 82% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.13 (s, 1 H), 7.95 (d, J=8.99 Hz, 1 H), 7.03 (dd, J=8.60, 2.34 Hz, 1 H), 6.88 (d, J=2.34 Hz, 1 H), 3.93 (s, 3 H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccccc1OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred solution of 2′-hydroxyacetophenone (5.000 g, 36.724 mmol) in acetonitrile (200 mL) was added potassium carbonate (7.613 g, 55.086 mmol). The mixture was stirred at 50° C. for 30 min. 4-Nitrobenzyl bromide (8.727 g, 40.396 mmol) was added to the mixture, and the stirring was continued at 50° C. for 12 hrs. Potassium carbonate (0.508 g, 3.672 mmol) and 4-nitrobenzyl bromide (0.793 g, 3.672 mmol) were added to the mixture and the resulting mixture was stirred at 50° C. for 12 hrs. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated. The resulting residue was washed with hexane to give 1-{2-[(4-nitrobenzyl)oxy]phenyl}ethanone as a white solid. (8.900 g, yield; 89%)
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37](S(C)(=O)=O)[C:32]=2[S:31][CH:30]=1.[OH-].[NH4+]>CN(C)C=O>[F:18][C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:14][CH2:13]3)[C:32]=2[S:31][CH:30]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(S(C)(=O)=O)ncnc23)c(F)c1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(Oc3ncnc4c(-c5ccc(S(C)(=O)=O)cc5F)csc34)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (30 mg) was dissolved in N,N-dimethylformamide (2 mL) and cooled to an internal temperature of 0° C. Then, NaH (9 mg) was slowly added thereto and stirred for 30 min. 7-(2-fluoro-4-methanesulfonyl-phenyl)-4-methanesulfonyl-thieno[3,2-d]pyrimidine (50 mg) synthesized in Preparation Example 2 was slowly added thereto and heated to room temperature, followed by stirring for 2 hours. Then, the reaction mixture was mixed with a saturated solution of ammonium hydroxide, and extracted twice with ethyl acetate. The organic layer thus obtained was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a foamy residue. The residue was crystallized in the presence of diethyl ether to obtain the title compound (40 mg) as a whitish solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[CH2:20](N(CC)CC)[CH3:21].C([B-](F)(F)F)=C.[K+]>C(O)CC.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]>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([CH:20]=[CH2:21])[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCCO
Product: C=Cc1ccc2nc(N)c3ncn(CC(C)C)c3c2c1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (22.0 g, 68.9 mmol), triethylamine (19.20 mL, 137.8 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (1.00 g, 1.37 mmol), and potassium vinyltrifluoroborate (10.15 g, 75.81 mmol) were dissolved in n-propanol (20 mL/g). The amber colored solution was heated at reflux temperature for 18 hours and then cooled to ambient temperature. The reaction was concentrated under reduced pressure. The resulting solid was slurried in 1% aqueous sodium carbonate and a fine powder was collected by filtration. The powder was sequentially washed with acetonitrile (5 mL/g) and 10% sodium hydroxide (500 mL). A final purification using a HORIZON HPFC system (silica cartridge, eluting with 4% methanol/dichloromethane) provided 10 g of 1-isobutyl-8-vinyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, MS (APCI) m/z 267 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
Under ice-cooling, a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (1 g, 6.51 mmol) in THF (40 mL), was treated with NaH (60% in mineral oil; 438 mg, 10.95 mmol) and the mixture was stirred for 1 h. Trityl chloride (2.17 g, 7.81 mmol) was added and the mixture was stirred at the same temperature for 1 h and further stirred at room temperature for 3 h. The mixture was quenched with saturated NH4Cl and then extracted with EtOAc. The organic layer was washed with water, brine, dried (MgSO4) and concentrated in vacuo. To the residue was added 10 ml of DCM, some solid precipitated out. After filtration, some yellow solid was afforded. The filtrate was purified by chromatography on silica gel (0-30% EtOAc in hexane) to isolate 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.375 g, 3.47 mmol, 53% overall) as a yellow solid. MS ESI calc'd. for C25H19ClN3 [M+H]+ 396, found 396.
Reaction SMILES: [NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7]2)=[CH:4][N:3]=[CH:2]1.C(Cl)Cl.CO>O1CCOCC1.Cl>[NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1
Reactant: O=C(OCc1ccccc1)N1CCCC(c2cnc[nH]2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: c1ncc(C2CCCNC2)[nH]1
Temperature: 80 °C
Yield: 31.4 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of benzyl 3-(1H-imidazol-5-yl)piperidine-1-carboxylate (3 g, 10.53 mmol, 1.00 equiv) in 1,4-dioxane (30 mL) and conc. HCl (18 mL). The resulting mixture was heated to 80° C. in an oil bath for 16 hours. The reaction progress was monitored by TLC (DCM: MeOH=10:1). Upon completion, the resulting mixture was concentrated on a rotary evaporator. The resulting solution was diluted with water (60 mL) and treated with aqueous NaHCO3. The resulting mixture was then extracted with dichloromethane (4×40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording 3-(1H-imidazol-5-yl)piperidine as brown oil (0.5 g, 31%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=1)=[O:13])[CH2:6]2)#[N:2].C(C1C=C2C(=CC=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=[O:42])C2)#N>>[CH:24]1([CH2:23][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]([N:7]3[CH2:6][C:5]4[C:9](=[CH:10][CH:11]=[C:3]([C:1]([NH2:2])=[O:42])[CH:4]=4)[CH2:8]3)=[O:13])=[CH:16][CH:17]=2)=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C#N)cc3C2)cc1
Reactant: N#Cc1ccc2c(c1)CN(C(=O)Nc1ccc(NC(=O)CC3CCCC3)cc1)C2
Product: NC(=O)c1ccc2c(c1)CN(C(=O)Nc1ccc(NC(=O)CC3CCCC3)cc1)C2

Procedure:
The title compound was prepared as described in Example 132 substituting 5-cyano-N-{4-[(cyclopentylacetyl)amino]phenyl}-1,3-dihydro-2H-isoindole-2-carboxamide for 5-cyano-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.31 (s, 1H), 7.98 (s, 1H), 7.87-7.78 (m, 2H), 7.53-7.38 (m, 5H), 7.36 (brs, 1H), 4.78 (bs, 4H), 2.32-2.13 (m, 3H), 1.82-1.67 (m, 2H), 1.67-1.42 (m, 4H), 1.27-1.10 (m, 2H); MS (ESI(+)) m/e 407 (M+H)+.