Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:24]1([N:27]2[CH2:32][C:31]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[O:30][CH2:29][C:28]2=[O:38])[CH2:26][CH2:25]1>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH:6]([C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])[N:35]1[CH2:36][CH2:37][C:31]2([O:30][CH2:29][C:28](=[O:38])[N:27]([CH:24]3[CH2:25][CH2:26]3)[CH2:32]2)[CH2:33][CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(Br)c1c(F)cc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC(c1c(F)cc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2,6-difluorophenyl)ethyl acetate (1.013 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (3.04 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (1.115 mmol). The reaction was stirred at room temperature overnight. The reaction solution was diluted with water (100 mL) and was extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound as a yellow solid (405 mg of 80% pure material as estimated by 1H NMR, 65% yield). MS(ES)+ m/e 487.2/489.3 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].C(N(CC)CC)C>[Pd].CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1c2cc(N)ccc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of isopropyl (S)-4-acetyl-7-bromo-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.23 g, 0.575 mmol), methanol (23 mL), triethylamine (0.80 mL, 0.575 mmol) and palladium on carbon (10 wt %, 23 mg) was added to a Parr bottle, and the mixture was shaken at room temperature for 3 h under a hydrogen atmosphere (30 psi). The mixture was filtered through Celite and the filter cake was washed with methanol. The filtrate was concentrated to afford isopropyl (S)-4-acetyl-6-amino-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.167 g, 100%). MS (ESI, pos. ion) m/z 314 [M+Na]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:35][CH3:36])=[C:7]([CH:24]=[C:25]([N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:26]=1)/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[H-].C(O[Al+2])(C)(C)C.[Li+].[H-].[H-]>C1COCC1>[C:1]([C:5]1[C:6]([O:35][CH3:36])=[C:7]([CH:24]=[C:25]([N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:26]=1)/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][C:11]=1[CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)Cl)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: CC(C)(C)O[Al+2]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CO)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of the product from Example 27, Part A (375 mg, 0.705 mmol) in anhydrous THF (5 ml) at 0° C. under N2 gas was added a 1.0 M solution of lithium tert-butoxyaluminiumhydride (1.8 ml, 1.8 mmol) dropwise. The resulting mixture was stirred at 0° C. for 30 min, and then allowed to warm to room temperature and was stirred for 1 h. The mixture was partitioned between 1 N aq. HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (220 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.41 (s, 1H) 9.82 (s, 1H) 7.73 (t, J=8.27 Hz, 2H) 7.66 (d, J=2.57 Hz, 1H) 7.31-7.39 (m, 2H) 7.20 (d, J=2.57 Hz, 1H) 7.12-7.19 (m, 2H) 5.65 (d, J=8.09 Hz, 1H) 5.28 (t, J=5.52 Hz, 1H) 4.65 (d, J=5.52 Hz, 2H) 3.79 (s, 3H) 3.00 (s, 3H) 1.38 (s, 9H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=O>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[CH2:23][N:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1CCCNc2ncccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(Cc2ccc([N+](=O)[O-])cc2Cl)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-5-one and 0.234 g of triethylamine in 6 ml of dichloromethane is added 0.506 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred at room temperature overnight under argon. The solution is washed with H2O, 10% NaHCO3 and dried (MgSO4). The solvent is removed to give a brown oil which crystallizes. The mixture is chromatographed on silica with a waters Prep-500 instrument with ethyl acetate-hexane (1:1) as solvent to Give 2.4 g of off-white crystals, m.p. 162°-164 C. (identified as O-2-chloro-4-nitrobenzoyl derivative (2-chloro-4-nitro-benzoyl enolate of product) and 0.80 g of product as crystals, m.p. slowly decomposes 160°-220° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:16][CH2:15]2)[N:5]=1>C(Cl)Cl>[OH:22][CH:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1)[CH2:20][N:17]1[CH2:18][CH2:19][N:14]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]3)[CH2:15][CH2:16]1
Reactant: CC(=O)Nc1cccc(C(=O)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C(O)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
Sodium borohydride (0.015 g, 1.6 eq) was added to a stirred solution of N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]acetyl}phenyl)acetamide (0.102 g, 1 eq) in dry DCM (2 mL) cooled to 0° C. under an inert atmosphere. The reaction was warmed to room temperature and stirred for 18 hours. The mixture was diluted with DCM (10 mL) and washed with water (2×10 mL). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (Silica) using as eluant DCM-methanol (97:3), affording the title compound in 42% yield (0.104 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([CH3:10])=[CH:8][S:7][CH:6]=1.C[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([CH3:10])=[CH:8][S:7][CH:6]=1.[NH+:12]1[CH:16]=[CH:15][NH:14][CH:13]=1
Reactant: Cn1ccnc1
Agent: Cc1cscc1OCCBr
Product: c1c[nH+]c[nH]1

Procedure:
Similarly, monomer 2 is prepared from 3-(2-bromoethoxy)-4-methylthiophene (compound 4) and 1-methylimidazole (Aldrich Co.) (see Scheme 2). Compound 4 is prepared according to the procedure developed by Leclerc et al. (Faïd, K.; Leclerc, M. J. Chem. Soc., Chem. Commun., 2761, (1996)). The quaternization reaction between 1-methylimidazole and compound 4, provides the desired monomer imidazolium salt 2. (Lucas, P.; Mehdi, N. E.; Ho, H. A.; Belanger, D.; Breau, L. Synthesis, 9, 1253, (2000)).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1
Reactant: COc1ccc([N+](=O)[O-])c(N2C(C)CCC2C)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(N)c(N2C(C)CCC2C)n1

Procedure:
4.2 g (0.017 mol) of the product 2-(2,5-dimethylpyrrolidin-1-yl)-6-methoxy-3-nitropyridine synthesized according to the above procedure, 40 ml of ethanol, 10 ml of cyclohexene and 1.5 g of palladium-on-charcoal were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1OC)[CH:6]=[O:7].B(Br)(Br)Br.[OH2:23]>ClCCl>[OH:23][C:4]1[C:3]([C:2]([F:18])([F:17])[F:1])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O
Reactant: COc1c(C(F)(F)F)cc(C=O)cc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1O
Temperature: -78 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
3,5-Bis(trifluoromethyl)anisaldehyde (prepared as in Sui and Macielag, Synth. Commun. 1997, 27, 3581-3590, which is expressly incorporated by reference herein; 2.0 grams (g), 7.7 millimoles (mmol)) was dissolved in dry dichloromethane (CH2Cl2; 15 milliliters (mL)), cooled to −78° C. and treated in portions with boron tribromide (BBr3, 1 M solution in CH2Cl2; 8.0 mL, 8.0 mmol). The mixture was stirred and allowed to warm to 25° C. After 20 hours (h), the mixture was cooled to −40° C., carefully treated with H2O (10 mL) and warmed to room temperature. The separated organic phase was washed with water (H2O; 10 mL), saturated (satd) sodium chloride (NaCl) solution (5 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with a 0 to 20% gradient of ethyl acetate (EtOAc) in hexane to give the purified aldehyde (1.4 g, 70%) as an oil: 1H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 10.02 (s, 1H), 8.07 (s, 2H). EIMS m/z 258.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].CS(C)=O.[BH4-].[Na+]>C(O)(=O)C>[N+:1]([CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
To a solution of 2-(4-((E)-nitro-vinyl)-phenoxymethyl)-pyridine (33.9 g, 132 mmol) described in Manufacturing Example 203-1-2 in acetic acid (34 mL) and dimethyl sulfoxide (576 mL) was added sodium borohydride (7.99 g, 211 mmol) at room temperature while cooling appropriately. This mixture was stirred for 5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was recrystallized from heptane and ethyl acetate to obtain the title compound (6.81 g, 20%).
Reaction SMILES: [NH2:1][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][Si:18]([CH3:21])([CH3:20])Cl>C1COCC1>[CH3:17][Si:18]([CH3:21])([CH3:20])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CO)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 945.1 %

Procedure:
To a stirred solution of 4-amino benzyl alcohol (16.0 g, 13.0 mmol, 1.0 eq) in THF (400 mL), was added triethylamine (18.9 mL, 13.6 mmol, 1.05 eq) followed by trimethylchlorosilane (17.2 mL, 13.6 mmol, 1.05 eq). The reaction mixture was stirred under a nitrogen atmosphere overnight at room temperature. THF was evaporated under vacuum and the mixture partitioned with ethyl acetate (300 mL) and water (300 mL). The organic phase was isolated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (2×150 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as a yellow oil (24.0 g, 95% yield) and used in stage 4 without further purification.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][CH2:25]Cl)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(#N)C>[C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[CH:17]=[C:18]3[C:21](=[O:22])[NH:23][CH2:24][CH2:25][N:19]3[N:20]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(-c3cc(C(=O)NCCCl)n[nH]3)c2nc1NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4n(n3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 85 °C
Yield: 35.3 %

Procedure:
To a 10-mL reaction vial was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-N-(2-chloroethyl)-1H-pyrazole-3-carboxamide (471a) (82 mg, 0.21 mmol), K2CO3 (88 mg, 0.64 mmol), DMF (1 mL), and ACN (1 mL). The vial was closed and the reaction mixture was heated at 85° C. for 5 h. The reaction mixture was cooled to RT and partitioned between water (5 mL) and EtOAc (5 mL). The organic extract was taken and washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-3% 2 M NH3/MeOH in DCM to provide 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (471) (26 mg, 35% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 7.86 (dd, J=1.27, 7.34 Hz, 1H), 7.75 (dd, J=1.08, 7.92 Hz, 1H), 7.36-7.42 (m, 2H), 6.07 (s, 1H), 4.36 (t, J=9.49 Hz, 2H), 3.90-3.97 (m, 2H), 2.56 (s, 3H), 1.51 (s, 9H). m/z (ESI, +ve) 351.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)=[CH:7]2.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OC(=O)C)C>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:11]2[C:2]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=3)=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:5]=[CH:4]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 95 °C
Reaction time: 0.08 h

Procedure:
(R)-4-[5-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.2079 g, 0.0004516 mol), 4-trifluoromethoxy phenylboronic acid (0.130 g, 0.000632 mol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.00002 mol) and sodium carbonate (0.191 g, 0.00181 mol) were added to a capped 40 mL EPA vial equipped with a magnetic stir bar. The vial was degassed and purged with nitrogen. 1,2-Dimethoxyethane (5.00 mL, 0.0481 mol) was added and the mixture was stirred for 5 minutes. Water (3.00 mL, 0.166 mol) was then added and the mixture was heated at 95° C. After 3 h, HPLC analysis showed that the reaction was complete. Ethylacetate (5 mL) and water (5 mL) were added and the layers were separated. The combined organic phase was then dried over MgSO4, filtered, concentrated and purified by flash chromatography (0-55% EtOAc in hexane) to give 204.1 mg of the title compound (83% yield).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].NC(OCC)=O.C[O:13][C:14]([O:29]C)([C:21]([C:23]1C=CC=C[CH:24]=1)=O)[C:15]1[CH:20]=CC=[CH:17][CH:16]=1>>[C:1]([O:5][CH2:20][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:21][CH2:23][CH3:24])(=[O:4])[CH:2]=[CH2:3].[C:14]([OH:29])(=[O:13])[CH:15]=[CH2:16]
Reactant: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: C=CC(=O)O
Agent: CCOC(N)=O
Product: C=CC(=O)OCC(CC)CCCC

Procedure:
A pressure-sensitive adhesive A-3 was prepared by mixing 100 parts by weight of an acrylic polymer with 10 parts by weight of an ultraviolet-curable urethane acrylate oligomer (supplied by Nippon Synthetic Chemical Industry Co., Ltd. under the trade name “SHIKOH UV1700”), 3 parts by weight of an initiator for active-energy-ray-induced polymerization (supplied by Ciba Japan (now part of BASF Japan Ltd.) under the trade name “IRGACURE 651”), and 3 parts by weight of a crosslinking agent (supplied by Nippon Polyurethane Industry Co., Ltd. under the trade name “CORONATE L”). The acrylic polymer was a copolymer obtained from 90 parts by weight of 2-ethylhexyl acrylate and 10 parts by weight of acrylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].O[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N(C(OCC)=O)(C(OCC)=O)N>C(OCC)(=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:2]([O:1][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:3]=1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: CCOC(=O)N(N)C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c(OCCN2CCOCC2)c1
Reaction time: 8 h

Procedure:
To stirred solution of methyl 3-hydroxy-4-methoxybenzoate (2.00 g, 11.0 mmol), 4-(2-hydroxyethyl)morpholine (1.58 g, 12.0 mmol) and triphenylphosphine (3.17 g, 12.1 mmol) in ethyl acetate (60 mL) was added, dropwise, diethyl azodicarboxylate (1.9 mL, 12.1 mmol). The reaction was allowed to proceed overnight and then diluted with additional ethyl acetate and extracted with 1 N aqueous hydrochloric acid. The aqueous layer was washed with ethyl acetate, basified with concentrated ammonium hydroxide and then extracted with ethyl acetate. The organic extract was dried (sodium sulfate) and concentrated to afford 3.25 g of a 92:8 mixture of product (95%) and diethyl hydrazinedicarboxylate as an amber oil. This material was used without further purification in the next step: 1H NMR (CDCl3) δ 7.69 (dd, J=8.4, 2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.77-3.72 (m, 4H), 2.87 (t, J=6.0 Hz, 2H), 2.65-2.57 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([CH:33]([N:35]=[C:36]=[O:37])[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:36]([NH:35][CH:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH3:34])=[O:37])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(N=C=O)c1cccc2ccccc12
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4cccc5ccccc45)cc3)c2cc1OC
Yield: 72 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in toluene (5 ml) with heat, 1-(1-naphthyl)ethyl isocyanate (0.05 ml) was added, and the admixture was refluxed with heat for 100 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 65 mg of the title compound (yield: 72%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:11][CH:10]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(OCc2ccncc2)c2ccccc12

Procedure:
4-tert-Butyloxycarbonylamino-1-naphthol (41) can be alkylated with 4-chloromethylpyridine hydrochloride in a non-protic solvent, such as acetonitrile, with a base, such as powdered potassium carbonate, at temperatures between 60-80° C. Purification of the product 4-tert-butyloxycarbonylamino-1-(pyridin-4-yl-methyl)naphthalene (44) can be accomplished by silica gel chromatography. Removal of the BOC-protecting group can be accomplished with HCl in a non-protic solvent, such as dioxane, to provide 1-amino-4-(pyridin-4-yl-methoxy)naphthalene (43) as the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C:11]3[N:15]=[CH:16][C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)=[CH:18][C:10]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C:11]3[N:15]=[CH:16][C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:36]5[CH2:37][CH2:38][CH:33]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)[CH2:34][CH2:35]5)=[O:25])=[CH:21][CH:20]=4)=[CH:18][C:10]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cccnc2Cl)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cccnc2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 20 %

Procedure:
4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (38 mg) was reacted with 4-(1-pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (20% yield). LCMS: m/z=516.89 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.50 (1H, m), 1.80 (5H, m), 1.97 (2H, m), 2.27 (1H, m), 2.58 (4H, m), 3.01 (2H, m), 3.50 (2H, m), 3.67 (2H, m), 3.79 (1H, m), 4.54 (2H, s), 4.95 (1H, bs), 6.58 (1H, d, J=1.5 Hz), 7.23 (1H, m), 7.36 (4H, m), 7.62 (1H, dd, J=7.6, 1.8 Hz), 7.73 (1H, d, J=1.8 Hz), 8.34 (1H, dd, J=4.8, 1.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].CI.[C:23](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1Cl
Yield: 132.5 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.62 g, 2.0 mmol), methyliodide (0.25 mL, 4 mmol) and potassium carbonate (0.21 g, 1.5 mmol) was stirred for 2 hours under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by crystallization from dichloromethane to obtain a white solid of 2-(2,4-dichloro-5-methyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.65 g, yield:100%).