Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C([Li])CCC.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([NH:33][C:34]([C:10]2[N:11]([CH3:21])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C=NC1CCCCC1
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (50 mg, 0.15 mmol) from Example 32, Step C in THF (3 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.11 mL, 0.18 mmol). The reaction was stirred for 1 hr and then cyclohexyl isocyanate (0.040 mL, 30 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (1 mm, silica) (100% methylene chloride) to afford the title compound.
Reaction SMILES: C(OC(=O)[C@H](CO)N[C:9](=[O:29])[CH2:10][N:11]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[C@@H:27]2[C@@H:22]([NH:23][C:24]([NH:26]2)=[O:25])[CH2:21][S:20]1)[CH3:12])(C)(C)C.C(N(CC)CC)C.C1(=O)O[C:43](=[O:44])CC1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:43][O:44][C:9](=[O:29])[CH2:10][N:11]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[C@@H:27]2[C@@H:22]([NH:23][C:24]([NH:26]2)=[O:25])[CH2:21][S:20]1)[CH3:12]
Reactant: CN(CC(=O)N[C@@H](CO)C(=O)OC(C)(C)C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 12.5 °C
Reaction time: 22 h

Procedure:
To a solution of biotinamido-N-methylglycyl-serine t-butyl ester (6) in anhydrous dimethylformamide is added 3 equivalents of triethylamine, 0.01-0.1 equivalents of 4-dimethylaminopyridine and 1.1 equivalents of succinic anhydride. The mixture is stirred at 0-25° C. for 20-24 h and then concentrated via reduced pressure rotary evaporation. The residue is diluted with ethyl acetate and 1 N aqueous hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed on reverse phase C-18 silica gel, eluting with methanol/water. The fractions containing the product are combined and concentrated to give the final product (4).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)cc(F)c2)c1
Yield: 45 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (180 mg, yield: 45.0%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:16])(=[O:3])[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:18]([Cl:17])(=[O:20])=[O:19])[C:7]=1[OH:16])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc(C(C)(C)C)ccc1O
Reactant: O=S(=O)(O)Cl
Product: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15.5 g (0.059 mole) of 2-acetamidomethyl-4-(1,1-dimethylethyl)-phenol are introduced at room temperature into 100 ml of chlorosulfonic acid. Stirring is continued for a further 15 minutes and the solution is stirred into ice water. The precipitate is filtered off with suction and recrystallized from toluene.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][CH:14]([OH:29])[C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)=[CH:8][CH:7]=1)(=O)C.C1COCC1.[OH-].[Na+]>O>[OH:29][CH:14]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:13]#[C:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1
Reactant: CC(=O)OCc1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(CO)cc3)ccc21
Reaction time: 0.5 h

Procedure:
780 mg (2 mmol) of 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzyl acetate and 30 ml of THF were introduced into a round-bottomed flask. 5 ml of a 2N methanolic sodium hydroxide solution were added and stirring was carried out for 30 min. 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 triturated in heptane and filtered, 419 mg (60%) of the expected compound, with a melting point of 85°-86° C., were recovered.
Reaction SMILES: C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:33])/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:14][C:15](O)=[O:16].C(OCC)(=O)C>O>[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:33])/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:14][CH2:15][OH:16]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CCO
Temperature: 10 °C

Procedure:
To 150 ml. of anhydrous diethyl ether there was added 1.9 g. of lithium aluminum hydride. To the mixture was dropwise added, under stirring and at 10° C., 1.53 g. of the carboxylic acid compound obtained in Example 1. The resulting mixture was then stirred at room temperature for 1 hour, and 1 ml. of ethyl acetate and 1 ml. of water were then added thereto. The mixture was subsequently washed with water and dried. The solvent was removed by evaporation and the resulting residual oil was purified by silica gel column chromatography to obtain 13.8 g. of the desired oily product.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[H-].[Na+].[N+:7]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:18]=1)[C:15](Cl)=[O:16])([O-:9])=[O:8]>CN(C)C=O>[C:1]([NH:4][C:15](=[O:16])[C:14]1[CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[N:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=C(Cl)c1cncc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)c1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.8 %

Procedure:
In 10 ml of dimethylformamide was dissolved 0.29 g of acetamide, and to this solution was added 0.24 g of NaH (mineral oil 50%). The mixture was then stirred at room temperature for 2 hours. To the mixture was added 0.93 g of 5-nitronicotinic acid chloride, and this was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The obtained residue was, after addition of water, extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated to remove the solvent. The obtained product was purified on a silica gel column and recrystallized from ethyl acetate - petroleum ether to give 0.07 g of the desired compound melting at 162° - 163° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.[BH3-]C#N.[Na+].[CH3:19][C:20](OC(C)=O)=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:21])[CH3:19]
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1c2cccc(C(F)(F)F)c2CC1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-4-(trifluoromethyl)-1H-indole (Example 114D) (0.48 g, 2.41 mmol) was dissolved in HOAC (3.0 mL), cooled to 0° C. and NaBH3CN (0.454 g, 7.23 mmol) was added in one portion. After 5 min the mixture was removed from the cooling bath and stirred at rt for 14 h. The mixture cooled to 0° C. and the pH was adjusted to ca. 13 by addition of 1 N NaOH (20 mL) and further addition of solid NaOH pellets. The mixture was extracted with Et2O (×3), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry CH2Cl2 (10 mL) and treated with DMAP (0.884 g, 7.23 mmol). The mixture was cooled to 0° C. and Ac2O (0.455 mL, 4.81 mmol) was added dropwise via syringe. The mixture was stirred overnight, slowly warming to rt, diluted with CH2Cl2, washed (10% HCl, H2O, brine), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.25 g of the title compound as a pale yellow oil: MS (ES) m/z 244 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=1>Cl.[Fe]>[Br:12][C:5]1[C:6]([CH3:11])=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Cc1c(Br)cnc(N)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: Cc1c(Br)cnc(N)c1N
Temperature: 25 °C

Procedure:
2-Amino-5-bromo-4-methyl-3-nitropyridine (5 g) was dissolved in 6M HCl (50 mL) and iron powder was slowly added. The reaction was then heated to reflux until no starting material was seen via HPLC. The reaction was then cooled to room temperature and filtered. The bis-HCl salt was dried to a cream solid which was then taken up in EtOAc, neutralized with 50% NaOH solution to yield 5-bromo-4-methylpyridine-2,3-diamine as a free base.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[F:49]C1C=CC(N)=CC=1>C(O)(=O)C>[F:49][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc(F)cc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(F)cc1
Yield: 64 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (76 mg, 0.33 mmol), triethyl orthoformate (0.66 ml), 4-fluoroaniline (0.058 mg, 0.61 mmol), and acetic acid (0.08 ml) were used to give 68.5 mg (0.021 mmol, 64% yield) of the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[N:18]=[CH:17][C:16]=1[CH2:34][C:35]([NH2:37])=[O:36])C1C=CC=CC=1.Cl.[H][H]>C(O)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]>[O:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:16]([CH2:34][C:35]([NH2:37])=[O:36])=[C:15]([NH:14][CH2:13][CH:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)[CH:20]=3)=[CH:23][CH:24]=2)[CH2:33][CH2:32]1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCC1CCCN1Cc1ccccc1
Reactant: [H][H]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCC1CCCN1
Yield: 49.5 %

Procedure:
143.2 mg of 4-{[(1-benzylpyrrolidin-2-yl)methyl]amino}-6-[(4-morpholinophenyl)amino]pyridine-3-carboxyamide crude product (the compound of Example 357) was dissolved in 3 mL of ethanol, to which 103.1 mg of palladium hydroxide (II) and 0.3 mL of 2 mol/L hydrochloric acid in water were sequentially added, and stirred in a sealed tube at 40° C. in a hydrogen atmosphere at an initial pressure of 1 MPa for 12 hours. After cooling, the insoluble substances were filtered with celite, and the solvent was evaporated. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate in water and saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol-ammonia=8:1) to obtain 58.1 mg of the title compound as a light yellow crystalline powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH4+:18].[OH-]>C1COCC1>[Cl:8][C:6]1([NH2:18])[N:7]=[CH:2][N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[NH:5]1
Reactant: [NH4+]
Reactant: C[C@H](Nc1nc(Cl)nc(Cl)n1)c1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC1=NC=NC(N)(Cl)N1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of 4,6-Dichloro-N2-[(1S)-1-phenylethyl]-1,3,5-triazine-2-amine, (Compound of Example 14), in THF (500 mL) was added conc. NH4OH (50 mL). The reaction mixture was stirred at ambient temperature for 48 h then was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (500 mL) and was washed with H2O (2×250 mL). The organic layer was filtered through a cotton plug then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4-Chloro-N2-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4-diamine as a white solid (29.7 g, 90%) MP 163-164° C., 1H (CDCl3) δ 7.78 (m, 5H), 6.1-6.2 (m, 4H), 1.52 (d, 3H), MS (ESI+) (M+) 249.7 obs.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=O.[BH4-].[Li+]>C1COCC1.C1(C)C=CC=CC=1>[OH:2][CH2:3][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(CO)nccc12
Temperature: 60 °C
Yield: 12.2 %

Procedure:
N-[1-(Methoxycarbonyl)isoquinolin-5-yl]-N′-[4-(trifiluoromethyl)benzyl]urea (Example 116, 70 mg, 0.174 mmol) was suspended in a mixture of THF (5 ml) and toluene (5 ml). Lithium borohydride (50 mg, 2.27 mmol) was added and the reaction mixture heated at 60° C. for 1 hour. The reaction was cooled to room temperature and allowed to stand for 1 week. The crystalline product was collected by filtration, washed with toluene (2 ml), then triturated with 1:1 TBF-dichloromethane (2 ml), triturated again with THF (2 ml) and dried under vacuum to give the title compound (8 mg, 12%). m/z (ES+) 376 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2OS(C(F)(F)F)(=O)=O)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:13]1[C:8]2[C:6](=[O:7])[CH:1]3[CH2:5][CH:4]([CH:3]=[CH:2]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(OS(=O)(=O)C(F)(F)F)c1C(=O)C1CC=CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1C(=O)C1C=CC2C1
Temperature: 130 °C
Yield: 46.5 %

Procedure:
Trifluoro-methanesulfonic acid 2-(cyclopent-3-enecarbonyl)-3-methoxy-phenyl ester (45.0 g, 129 mmol) was dissolved in DMF (100 mL) under a N2 atmosphere and treated with triethylamine (19.5 g, 193 mmol), potassium acetate (1.89 g, 19.0 mmol) and 1,3-bis(diphenylphosphino)propane (5.30 g, 12.9 mmol). This mixture was stirred and degassed (3 vacuum/N2 purge cycles) then treated wlth palladium acetate (1.16 g, 5.14 mmol). After 20 min. the mixture was warmed to 130° C. for 1 hour, cooled and poured into brine (300 mL). The resulting mixture was extracted with EtOAc (4×100 mL) and the combined organic layer was washed with sat. aq. NaHCO3 soln. (100 mL), H2O (100 mL), and brine (100 mL), dried (MgSO4), filtered and evaporated to an oil. (55 g). The oil was chromatographed on silica gel to provide product as a white solid (12.0 g, 47%). (TLC 25%EtOAc/hexanes Rf 0.27). 1H NMR (CDCl3) δ7.29 (t, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.63 (dd, J=5.0,3.0 Hz, 1H), 6.15 (dd, J=5.0,3.0 Hz, 1H), 3.87 (s, 3H), 3.60 (br s, 1H), 3.39 (br s, 1H), 2.56 (AB m, 2H). 13C NMR 195.38, 161.61, 149.82, 143.47, 133.77, 131.84, 131.80, 117.51, 111.46, 57.63, 55.96, 47.63, 47.51. GSMS m/e 200 (M+). mp 135-136° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.[CH3:17][C:18]1[O:19]CC[N:22]=1.P(=O)(O)(O)O.[OH-].[Na+]>O>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O:19][CH:18]([NH2:22])[CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CC1=NCCO1
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCc1ccccc1OC(C)N
Temperature: 200 °C

Procedure:
To a 250-ml three-necked flask equipped with a thermometer, stirrer, condenser and nitrogen inlet were charged 66 g. of nonylphenol and 30 g. of 2-methyl-2-oxazoline. The mixture was heated to 200° C. for six hours. About 80 g. of 85% phosphoric acid and 20 g. of water were then added. The mixture was heated to reflux for eight hours. The resulting reaction mixture was neutralized with sodium hydroxide solution. The resulting product was washed with water and then dried. 2-Nonylphenoxyethanamine was obtained in quantitative yield and the product purity by NMR spectroscopy analysis was found to be about 98%.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH2:30][C:31]1[C:40]2[N:41]=[C:42]([CH2:49][O:50][CH2:51][CH3:52])[N:43]([CH2:44][C:45]([CH3:48])([OH:47])[CH3:46])[C:39]=2[C:38]2[CH:37]=[CH:36][C:35](Br)=[CH:34][C:33]=2[N:32]=1.[C:54]([O:58][CH3:59])(=[O:57])[CH:55]=[CH2:56]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:30][C:31]1[C:40]2[N:41]=[C:42]([CH2:49][O:50][CH2:51][CH3:52])[N:43]([CH2:44][C:45]([OH:47])([CH3:48])[CH3:46])[C:39]=2[C:38]2[CH:37]=[CH:36][C:35](/[CH:56]=[CH:55]/[C:54]([O:58][CH3:59])=[O:57])=[CH:34][C:33]=2[N:32]=1
Reactant: C=CC(=O)OC
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 120 °C

Procedure:
A thick walled glass reaction vessel was charged with anhydrous DMF (2 mL), palladium (II) Acetate (0.01 equivalents (eq)), tri-o-tolylphosphine (0.02 eq) and triethylamine (3 eq). To this orange solution was added a solution of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol in 50 mL anhydrous DMF followed by the addition of methyl acrylate (1.0 eq). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. overnight, and slowly cooled to room temperature. The reaction mixture was concentrated to dryness and then slurried in water (50 mL). Saturated potassium carbonate solution (25 mL) was added. The mixture was extracted with dichloromethane (4×50 mL). The combined extracts were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-25% CMA in chloroform) to provide Methyl(2E)-3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12.C1(C)C=CC=CC=1.[NH3:29].CO.[Cl-].[Na+]>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:7]([C:8]([NH2:29])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12
Reactant: N
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C(=O)O)cnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C(N)=O)cnc21
Reaction time: 1 h
Yield: 96.2 %

Procedure:
4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (480 mg, 1.47 mmol) in thionyl chloride (3 mL) was stirred at room temperature for 2 hours. After addition of toluene, the reaction mixture was concentrated under reduced pressure, and after addition of toluene, concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and ammonia-methanol solution (7.0 M, 1.0 mL, 7.0 mmol) was added dropwise, and the resulting reaction mixture was stirred for 1 hour. After addition of saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (461 mg, yield 96%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:9](C)[CH2:10][CH2:11][CH2:12]OC2C=CC=CC=2)[CH:5]=[C:6](O)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:26]=[CH:25][C:24]=1[OH:44].[OH:45][CH:46]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][C:51](C(C)CCCOC3C=CC=CC=3)=[CH:52][CH:53]=2)[O:48][C:47]1([CH3:70])[CH3:69]>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:26]=[CH:25][C:24]=1[OH:44].[OH:45][CH:46]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][C:51]([CH:12]([CH3:21])[CH2:11][CH2:10][CH2:9][C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)=[CH:52][CH:53]=2)[O:48][C:47]1([CH3:70])[CH3:69]
Reactant: CC(CCCOc1ccccc1)c1ccc2c(c1)OC(C)(C)C(O)C2=O
Reactant: CC(CCCOc1ccccc1)c1cc(O)cc(O)c1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Product: CC(CCCc1ccccc1)c1ccc2c(c1)OC(C)(C)C(O)C2=O

Procedure:
4-(3,5-dihydroxyphenyl)-1-phenoxypentane is converted to dl-5-hydroxy-2,2-dimethyl-7-(1-methyl-4-phenoxybutyl)-4-chromanone, a light yellow oil:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:22][NH:23]C>C(O)C>[CH3:22][NH:23][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Reactant: CNC
Solvent: CCO
Product: CNCc1cccc(-c2nc3cccc(C(=O)OC)c3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 135 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and dimethylamine (50 mg, 1.6 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated under reduced pressure to obtain methyl 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (80 mg, yield 76%). LC-MS (ESI) m/z 297 [M+1]+.