Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=3)[C:10](=[O:24])[CH:9]=2)=[CH:2]1.P(Br)(Br)[Br:26]>C(Cl)Cl>[Br:26][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:9][C:10]2=[O:24])=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CO)cc1
Solvent: ClCCl
Product: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 220 mg (0.68 mmol) 4-(furan-3-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 5.1a) in 8.0 mL of DCM is added at 0° C. 44 μL (0.47 mmol) phosphorus tribromide. After warming to RT, the mixture is stirred 2 h at RT and is diluted with ice water. The layers are separated, the aqueous phase is extracted three times with DCM/MeOH. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]#N)=[C:6]([N+:11]([O-])=O)[CH:5]=[CH:4][CH:3]=1.C[OH:15].O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:11]2
Reactant: CO
Reactant: N#CCc1c(F)cccc1[N+](=O)[O-]
Solvent: O
Product: O=C1Cc2c(F)cccc2N1
Temperature: 25 °C

Procedure:
6-Fluoro-2-nitrobenzyl cyanide (23.10 g, 0.12 mole) (prepared according to A. Kalir, Synthesis (1987) 514-515) was dissolved in 10:1 MeOH/H2O (250 mL) and the solution was chilled in an ice water bath. HBr gas was bubbled into the cold mixture for 75 min. The solution was allowed to warm up to r.t. and then concentrated to half its volume under reduced pressure. THF (100 mL), water (100 mL) and conc. HCl (6 mL) were successively added at r.t. and stirring was maintained for 75 min. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, sat. aq. NaHCO3 and brine, then dried over sodium sulfate and concentrated under reduced pressure. This material (20.9 g) was dissolved in acetic acid (200 mL) and hydrogenated for 2 h in a Parr apparatus at 50 Psi, in the presence of 10% Pd/C (4.33 g). The reaction mixture was filtered through a cake of Celite®, and the cake was washed with acetic acid. The solution was concentrated under reduced pressure and dissolved in MeOH (300 mL) containing 1N NaOH (15 mL). This mixture was poured into 2:1 sat aq. NaCl/H2O (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was triturated with ether to afford 5.8 g (first crop) of pure 1,3-dihydro-4-fluoro-2H-indol-2-one. The mother liquor was chromatographed on Silica Gel (230-400 mesh, eluted with 40% ethyl acetate in hexanes) to yield1.6 g of product (overall yield from cyanide: 41%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[N:4]=1.C(OC(=O)C)(=O)C.[Br:18]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][S:2][C:3]1[C:8]([Br:18])=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[N:4]=1
Reactant: CSc1cc(C)[nH]c(=O)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSc1nc(=O)[nH]c(C)c1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35 %

Procedure:
4-Methylthio-6-methylpyrimid-2-one (see Wheeler, L. H. and MacFarland, F. D. J. Amer. Chem. Soc. 42 (1909) (43) (0.01 mol) was dissolved in acetic acid (30 ml) containing 2% acetic anhydride and N-bromo-succinimide (0.013 mol) added. The reaction mixture was kept at 55° C. for 40 min. Ice-cold water (150 ml) containing a little sodium bisulphite was added to the cold reaction mixture. The precipitate formed was recrystallised from water; yield 35%, m.p. 244° C. (Found: C, 30.34; H, 2.81. Calc. for C6H7BrN2OS: C, 30.65; H, 3.00).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C1C=CC=CC=1.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.CCOCC.O.C(O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][CH:27]=[C:18]([O:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]=3)[CH:24]=2)[N:3]=1
Reactant: Fc1cccc(Br)n1
Reactant: CCCCCCCCOc1ccc2cc(B(O)O)ccc2c1
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: [Cl-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc2cc(-c3cccc(F)n3)ccc2c1
Yield: 68.7 %

Procedure:
8.51 g (50 mmol) of 2-bromo-6-fluoropyridine, 14.5 g (50 mmol) of 6-octyloxynaphthalene-2-boronic acid, 1.73 g (1.5 mmol) of tetrakis(triphenylphosphine)palladium(0) and 10.6 g (100 mmol) of sodium carbonate are refluxed in 375 ml of benzene, 250 ml of ethanol and 125 ml of water for 3 hours. The mixture is then distributed between sodium chloride solution and ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, concentrated, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate), giving 12.08 g of 2-fluoro-6-(6-octyloxynaphth-2-yl)pyridine. ##STR67##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:17]([NH:25][C:14]([C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: CCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
(R)-(+)-1-(tert-Butoxycarbonyl)-2-piperidinecarboxylic acid (Aldrich Chemical Company, Milwaukee, Wis.) (1.00 g; 4.36 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. n-Octylamine (0.620 g; 4.80 mmol), N,N-diisopropylethylamine (1.24 g; 9.60 mmol) and PyBOP (2.50 g; 4.80 mmol) are added sequentially. The reaction is stirred for 25 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography using a gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product (22) as an oil. ISMS: MH+341.2
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:16][C@H:17]([CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (147 mg, 0.61 mmol), 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (216 mg, 0.61 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (341.4 mg, 0.73 mmol) in chloroform (6 mL). DIEA (530 μL, 3.03 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (233 mg, 0.43 mmol, 71%): LC-MS (ES) m/z=541 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][OH:23].BrBr.N12CCCN=C1CCCCC2.O>C(Cl)(Cl)Cl>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2](=[O:1])[C:3]3([CH2:19][CH2:20][CH2:21][CH2:22][O:23]3)[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(CCCCO)c(O)c2cccnc2n1-c1ccccc1
Agent: BrBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1c2cccnc2N(c2ccccc2)C(=O)C12CCCCO2

Procedure:
A suspension of 4-Hydroxy-3-(4-hydroxybutyl)-1-phenyl-(1,8)-naphthyridin-2(1H)-one (2 g.) in chloroform was stirred in an ice-bath. A solution of bromine (1 g.) in chloroform was added dropwise and the mixture was stirred overnight at room temperature. To this mixture was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (2 g) in chloroform at room temperature. After about 3/4 hr. water was added and the pH was adjusted to be slightly acidic. The chloroform layer was separated and washed with saturated NaCl solution. The solution was dried and evaporated to a solid which was washed with ethanol/water and dried to yield 1-phenyl-3', 4', 5', 6'-tetrahydro-spiro[1,8-naphthyridine-3,2'-(2H) pyran]-2,4-dione, m.p. 213°-215° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([C:12]([O:14]C)=O)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[CH3:16][NH:17]C>CO>[CH3:16][NH:17][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[N:6]([C:2]([NH2:1])=[N:3][N:4]=2)[N:7]=1)=[O:14]
Reactant: CNC
Reactant: COC(=O)c1cc(C)c2nnc(N)n2n1
Solvent: CO
Product: CNC(=O)c1cc(C)c2nnc(N)n2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 3-amino-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylate (W1.146; 210 mg) was dissolved in methanol (4 ml), cooled to 0° C., slowly admixed dropwise with dimethylamine (2.02 ml; 2 M in THF) and stirred at 0° C. After 3 h, a further 5 equivalents of dimethylamine solution were added and the mixture was stirred at 40° C. for 4 h. After standing overnight, another 5 equivalents of dimethylamine solution were added and the mixture was stirred at 40° C. for a further 8 h. After standing overnight again, a further 5 equivalents of dimethylamine solution were added and then the mixture was stirred at 100° C. in a microwave for 30 min. Subsequently, the mixture was concentrated and purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 92 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:15]2[S:42][CH:41]=[CH:40][C:16]=2[C:17]2[CH:18]=[C:19]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]3[S:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.[Li+].CCC[CH2-].[CH3:53][Sn:54](Cl)([CH3:56])[CH3:55]>CCCCCC>[CH2:28]([O:27][C:19]1[C:20]2[S:26][C:25]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:24][C:21]=2[C:22]2[CH:23]=[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:15]3[S:42][C:41]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:40][C:16]=3[C:17]=2[CH:18]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCOc1cc2c3ccsc3c(OCCCCCCCCCCCC)cc2c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCOc1cc2c3cc([Sn](C)(C)C)sc3c(OCCCCCCCCCCCC)cc2c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
5,10-Bis-dodecyloxy-1,6-dithia-dicyclopenta[a,f]naphthalene (BB-3, 0.366 g, 0.6 mmol) was added into a 50 mL flask. The system was vacuumed and backfilled with argon 3 times before 17 mL of anhydrous THF was injected. N-Butyllithium (0.6 mL, 2.5 M in hexane, 1.5 mmol) was added after the mixture was cooled to −78° C. A white precipitate was observed after the mixture was stirred at −78° C. for 30 minutes. Stirring was continued at room temperature for one more hour before the mixture was cooled down to −78° C. again. Trimethyltin chloride (0.5 g, 2.5 mmol) was added in portions and stirring was continued overnight at room temperature. Hexane (100 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 50 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum yielded a white solid. The colorless crystalline product (0.48 g, ˜85.7% yield) was obtained after recrystallization from a hexane/iso-propanol mixture. 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 2H), δ 7.51 (s, 2H), δ 4.37 (t, 4H, J=6.5 Hz), δ 2.00 (m, 4H), δ 1.63 (m, 4H), δ 1.46 (m, 4H), δ 1.30 (m, 28H), δ 0.90 (t, 6H, J=7.0 Hz), δ 0.51 (m, 18H).
Reaction SMILES: C(OC([N:8]([C:16]1[N:17]=[CH:18][CH:19]=[C:20]2[CH:24]=[C:23]([Sn](C)(C)C)[O:22][C:21]=12)C(OC(C)(C)C)=O)=O)(C)(C)C.Br[C:30]1[N:34]2[CH:35]=[CH:36][N:37]=[CH:38][C:33]2=[N:32][CH:31]=1.[F-].[Cs+]>O1CCOCC1>[N:32]1[CH:31]=[C:30]([C:23]2[O:22][C:21]3=[C:16]([NH2:8])[N:17]=[CH:18][CH:19]=[C:20]3[CH:24]=2)[N:34]2[CH:35]=[CH:36][N:37]=[CH:38][C:33]=12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc([Sn](C)(C)C)oc12
Reactant: Brc1cnc2cnccn12
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Nc1nccc2cc(-c3cnc4cnccn34)oc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
A mixture of di-tert-butyl[2-(trimethylstannanyl)furo[2,3-c]pyridin-7-yl]imidodicarbonate (0.0994 g, 0.200 mmol) in 1,4-dioxane (1.5 mL) was degassed with nitrogen for 10 min. To this mixture was added 3-bromoimidazo[1,2-a]pyrazine (0.033 g, 0.17 mmol), Pd(FPh3)4 (0.0192 g, 0.0167 mmol) and cesium fluoride (0.0850 g, 0.560 mmol). The temperature was raised to 100° C. and the mixture was heated for 16 h. Following removal of solvent, the residue was purified by ISCO chromatography (0 to 10% methanol:DCM). The resultant material was dissolved in dichloromethane (2 mL) and cooled to 0° C. To this mixture was slowly added TFA (2 mL). The ice bath was removed and the mixture was stirred for 2 h and then concentrated to a light brown residue. The residue was dissolved in DCM (30 mL) and saturated aqueous sodium bicarbonate (5 mL) was added and then the mixture was concentrated. Purification by ISCO chromatography (0 to 20% methanol:DCM) afforded 0.021 g (49%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ=9.19 (dd, J=1.4, 4.7 Hz, 1 H), 9.17 (d, J=1.5 Hz, 1 H), 8.46 (s, 1 H), 7.76 (dd, J=4.3, 5.6 Hz, 2 H), 7.43 (s, 1 H), 7.37 (s, 1 H); MS (ESI): 252.17 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2.Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([O:41][CH3:42])=[O:40])[CH:34]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F-].[Cs+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]([O:41][CH3:42])=[O:40])[CH:34]=2)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: COc1ccc(B(O)O)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCCC
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2)ccn1
Temperature: 90 °C
Reaction time: 7 h
Yield: 19.9 %

Procedure:
A suspension of the [4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]boronic acid produced in Example 1-1 (511 mg, 1.20 mmol), methyl 4-chloropyridine-2-carboxylate (207 mg, 1.20 mmol), tri(o-tolyl)phosphine (73.3 mg, 0.24 mmol), cesium fluoride (548 mg, 3.61 mmol), and palladium(II) acetate (13.5 mg, 0.06 mol) in 1,2-dimethoxyethane (10.2 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 90° C. for 7 hours. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=34:66 to 25:75, v/v) to obtain the title compound (123 mg, yield: 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22].B(Br)(Br)Br.Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22]
Reactant: COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Reaction time: 2 h
Yield: 62 %

Procedure:
First, 5.4 g of N-[2-fluoro-5-(2-methoxyphenoxy)-4-nitrophenyl]acetamide was dissolved in 50 ml of methylene chloride, to which 4.7 g of boron tribromide was added under ice cooling. After stirring at the same temperature for 2 hours, concentrated hydrochloric acid was added, and the mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The resulting crystals were washed with t-butyl methyl ether to give 3.2 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide.
Reaction SMILES: [CH2:1]1[C@@H:8]2[C@@H:4]([CH2:5][C:6](=[O:9])[CH2:7]2)[CH2:3][C:2]1=[O:10].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]1[C@H:8]2[C@H:4]([CH2:5][C:6](=[O:9])[CH2:7]2)[CH2:3][C:2]21[O:13][CH2:12][CH2:11][O:10]2
Reactant: OCCO
Reactant: O=C1C[C@H]2CC(=O)C[C@H]2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Yield: 30.6 %

Procedure:
cis-Tetrahydropentalene-2,5(1H,3H)-dione (5 g, 36 mmol) and ethylene glycol (2.3 g, 36 mmol) were dissolved in toluene. To the resulting solution was added PTSA (684 mg, 3.6 mmol). The reaction mixture was refluxed for 12 h meanwhile the resulting water was removed away. Direct chromatography on silica gel gave 2.0 g (11 mmol, yield: 31%) of the desired product, (3a′R,6a′S)-tetrahydro-1′H-spiro[1,3-dioxolane-2,2′-pentalen]-5′(3H)-one: MS (m/e): 183 (M+1)+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH2:10]2)[CH:5]=[N:4]1.Cl.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][Cl:31]>>[ClH:31].[ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH:10]2[CH2:30][CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])[CH:5]=[N:4]1
Reactant: CC1(C)N=CC2=C3N=C(c4ccccc4)N=C3C(=O)CC2C1=O
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCC1C(=O)C2=NC(c3ccccc3)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
Prepared analogous to Example 23 from 3.4 gm of 7,7-dimethyl-2-phenyl-5H,7H-imidazo(4,5-h]isoquinoline-4,6-dione hydrochloride and 1.7gm of 3-dimethylamino-propyl chloride hydrochloride (reaction temperature: 50°-60° C.; reaction time: 18 hous).
Reaction SMILES: [CH3:1][C:2]1[N:11]([N:12]2[C:24](=[O:25])[C:22]3[C:23]4[N:15]([C:16]([O:26][CH3:27])=[CH:17][C:18]=4[CH2:19][CH2:20][CH:21]=3)[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:13]2)[C:10](=[O:34])[C:9]2[C:4](=[CH:5][C:6]([C:35]([O:37]C)=[O:36])=[CH:7][CH:8]=2)[N:3]=1.O.[OH-].[K+]>C1COCC1>[CH3:1][C:2]1[N:11]([N:12]2[C:24](=[O:25])[C:22]3[C:23]4[N:15]([C:16]([O:26][CH3:27])=[CH:17][C:18]=4[CH2:19][CH2:20][CH:21]=3)[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:13]2)[C:10](=[O:34])[C:9]2[C:4](=[CH:5][C:6]([C:35]([OH:37])=[O:36])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(=O)n(N3C=C(c4ccccc4)n4c(OC)cc5c4C(=CCC5)C3=O)c(C)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c3n1C(c1ccccc1)=CN(n1c(C)nc4cc(C(=O)O)ccc4c1=O)C(=O)C3=CCC2
Temperature: 22.5 °C
Reaction time: 5 h

Procedure:
1.3 g of product of Example 2B (2.55 mmol) are dissolved in 55 ml of THF, 18 ml of water containing 0.33 g of potassium hydroxide are added and the mixture is stirred at 20-25° C. for 5 h. Ice is added and the mixture is acidified to pH=5. It is extracted with CH2Cl2. The extracts are purified by chromatography. 0.55 g obtained. Yld: 44%. Decomposition starting at 225° C.—TLC (DM5): Rf=0.1.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:29]=[O:30].[Cl-].[NH4+]>C(#N)C.O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:29]=[O:30])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Yield: 15.1 %

Procedure:
To a solution of 1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ol (297 mg, 1.24 mmol) from step 2 in anhydrous acetonitrile (6 mL) was added magnesium chloride (177 mg, 1.86 mmol), triethylamine (650 μl, 4.65 mmol) and paraformaldehyde (251 mg, 8.38 mmol). The reaction mixture was reflux for a half hour. Added some water and saturated aqueous ammonium chloride until pH=7. Extracted it with ether several times. The organic layer was combined, dried over magnesium sulfate, and filtrated. The solution was evaporated under vacuum. The crude residue was purified by prep TLC eluting with 25% ethyl acetate-hexane and providing 50 mg (15%) of the title compound. 1H-NMR (CDCl3) δ 11.4 (s, 1H), 9.38 (s, 1H), 7.30-7.20 (m, 3H), 7.14-7.10 (m, 2H), 6.94 (s, 1H), 5.93 (s, 1H), 4.48 (s, 2H), 3.36 (t, J=5.5 Hz, 2H), 2.68 (t, J=6.2 Hz, 2H); MS LC-MS (MH+=268.5), LC MS RT: 3.24 min.