Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]12([O:18][OH:19])[CH2:16][CH:12]([C:13]1([CH3:15])[CH3:14])[CH2:11][CH2:10][CH:9]2[CH3:17].S(=O)(=O)(O)O>>[CH3:6][C:5]([O:19][O:18][C:8]12[CH2:16][CH:12]([C:13]1([CH3:14])[CH3:15])[CH2:11][CH2:10][CH:9]2[CH3:17])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(=O)C=C(C)C
Reactant: CC1CCC2CC1(OO)C2(C)C
Agent: O=S(=O)(O)O
Product: CC(=O)CC(C)(C)OOC12CC(CCC1C)C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
A mixture of 11.8 g. (0.12 mole) of mesityl oxide and 25.40 g. (0.15 mole) of pinanyl hydroperoxide was stirred at 0° C. while 2.0 g. of 77% sulfuric acid solution was slowly added. The reaction mixture was allowed to warm slowly to 25° C. and stirred for a total of 16 hours. The organic layer was taken up in 30 ml. of either and washed with water, 5% sodium hydroxide solution and again with water to pH 8. The mixture was then subjected to steam distillation in the presence of sodium bicarbonate solution at 20 torr for 2 hours to remove unreacted mesityl oxide and pinanyl hydroperoxide. The product was taken up in ether, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure leaving 18.14 g. of product (56.9% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH3:20][N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CN1CCC[C@H]1CN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1CN1CCNCC1
Yield: 94.1 %

Procedure:
To a solution of (S)-1-benzyl-4-[(1-methylpyrrolidin-2-yl) methyl] piperazine 0.71 g (2.61 mmol) in 40 ml THF was added 10% Pd/C 0.4 g and exposed to 1 atm hydrogen overnight. The reaction mixture was filtered. The filtrate was concentrated to give 0.450 g of desired product in 94% yield.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:19]Br.Cl>ClCCl>[Br:19][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3][C:2]2=[O:1])=[CH:7][C:8]=1[CH3:12]
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)C(=O)CCC2(C)C
Reaction time: 1.5 h
Yield: 56.9 %

Procedure:
A solution of 1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene (40.0 g, 212 mmol) in dichloromethane (80 mL) was added dropwise at room temperature under argon with vigourous stiring to a suspension of aluminum chloride (56 g, 424 mmol) in dichloromethane (80 mL). Bromine (13 mL, 254 mmol) was then added slowly. The reaction mixture was stirred for 1.5 hours then poured into concentrated hydrochloride acid (6N, 300 mL) and extracted with ether. The organic layer was washed with water, aq NaHCO3, water, brine and dried (Mg2SO4). The residue was purified on silica gel (eluent: 5 to 8% ethyl acetate in hexane) to give 32.2 g of 7-bromo-1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene (64%). 1H NMR (300 MHz; CDCl3): 1.32 (s, 6 H), 1.94 (t, J=6.9 Hz, 2 H), 2.38 (s, 3 H), 2.64 (t, J=6.6 HZ, 2 H), 7.23 (s, 1 H), 8.06 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.NN>C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([CH2:11][NH2:12])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Agent: NN
Solvent: CCO
Product: NCC1CC2(CCN1)OCCO2
Temperature: 80 °C
Reaction time: 6 h
Yield: 63.3 %

Procedure:
To a suspension of the above 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione (3.85 mmol) in absolute ethanol (25 ml) was added hydrazine (0.36 ml, 11.55 mmol). The reaction was stirred at 80° C. (oil bath) for 6 h., then cooled to ambient temperature and stirred for an additional 12 h. The thick precipitate was filtered off and washed with ethanol. The filtrate was concentrated in vacuo and reconstituted in dichloromethane (20 ml), forming a small amount of a second precipitate which was filtered off. The filtrate was evaporated in vacuo and the resulting oil was dissolved in water (10 ml) and basified with 1N sodium hydroxide until pH=10. The aqueous layer was extracted with 20% isopropyl alcohol/chloroform (12×40 ml). The combined organic extracts were dried (K2CO3), filtered and the solvent evaporated in vacuo affording 0.42 g (63%) of (1,4-dioxa-8-aza-spiro[4.5]dec-7-yl)methylamine as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:39])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:35]([F:36])([F:37])[C:31]1[CH:30]=[C:29]([NH:28][C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:14]4[C:15]5[CH2:16][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)=[O:39])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Reaction time: 1 h

Procedure:
To a solution of 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 mL, 260 mmol) is added at 0° C. The reaction is allowed to reach room temperature and stirred for an additional 1 h. TFA/DCM are evaporated and then the product is taken up in EtOAc (100 mL) and washed with dilute NH4OH in H2O (20 mL). The organic layer is separated and the water layer is extracted further with EtOAc (2×). The combined organics are dried and evaporated. The crude residue is separated via FCC (eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1)) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl phenyl)-amide. MS (ESI) m/z 440.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.55 (s, 1 H)8.33 (d, J=8.84 Hz, 1 H)8.06 (br. S., 1 H)7.89 (d, J=8.34 Hz, 1 H)7.94 (d, J=3.54 Hz, 1 H)7.57 (t, J=7.96 Hz, 1 H)7.41-7.46 (m, 2 H)7.13 (dd, J=9.09, 2.27 Hz, 1 H)6.74 (d, J=3.03 Hz, 1 H)4.26 (d, J=12.13 Hz, 4 H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:22])[C:9]([NH2:21])=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:2].[C:27]1(=O)[C:31]2=[CH:32][S:33][CH:34]=[C:30]2[C:29](=O)[O:28]1>C(O)(=O)C.C(O)C>[CH2:19]([CH:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:12][C:11]1[C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:7][C:8]2[N:22]3[C:29](=[O:28])[C:30]4[C:31](=[CH:32][S:33][CH:34]=4)[C:27]3=[N:21][C:9]=2[CH:10]=1)[CH3:20]
Reactant: CCCCC(CC)COc1cc(N)c(N)cc1OCC(CC)CCCC
Reactant: O=C1OC(=O)c2cscc21
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC(CC)COc1cc2nc3n(c2cc1OCC(CC)CCCC)C(=O)c1cscc1-3

Procedure:
A mixture of 4,5-bis((2-ethylhexyl)oxy)benzene-1,2-diamine (5.8 g, 0.016 mol) and thieno[3,4-c]furan-1,3-dione (2.5 g, 0.016 mol) is refluxed in a 100 mL acetic acid:ethanol (1:1) solvent blend for 24 hours. The solvent is distilled off and the crude product is purified by column chromatography (CHCl3) to yield the final product.
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1>CS(C)=O.O.[Cl-].[Na+].O>[CH:7]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1)=[O:5]
Reactant: C[N+](C)(C)[O-]
Reactant: N#Cc1cc2cc(CBr)ccc2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc2cc(C=O)ccc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
Trimethlamine-N-oxide (6.75 g, 90 mmol) was added to a solution of 5-(bromomethyl)benzofuran-2-carbonitrile (4.46 g, 18.89 mmol) in 57 mL of DMSO and 6 mL of H2O. The mixture was stirred at 70° C. for 3 hr. After the reaction was cooled to room temperature, the mixture was diluted with 72 mL of brine, and extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (2×20 mL), brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography, 100% Heptane-30% Ethyl Acetate/70% Heptane, to give 5-formylbenzofuran-2-carbonitrile (1.5 g). 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=8.7 Hz, 1H), 8.12 (dd, J=8.7, 1.7 Hz, 1H), 8.30 (d, J=0.9 Hz, 1H), 8.46 (dd, J=1.6, 0.6 Hz, 1H), 10.11 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][CH:27]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(=O)NCc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(C)=O)cc3)ccn2c1=O
Yield: 99.6 %

Procedure:
Methyl 8-(4-(acetamidomethyl)phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (4-(acetamidomethyl)phenyl)-boronic acid (79.3 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (137 mg, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28]Br>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(F)c(F)c1
Yield: 96.5 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.24 g) was benzylated with 3,4-difluorobenzyl bromide (1.60 g), thereby yielding 1.67 g of the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)CCCCCCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCCCCC(=O)OC
Yield: 71 %

Procedure:
Using the procedure of example 122, (E)-3-[2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester (example 176) was alkylated with methyl 9-bromononanoate giving the title compound, in 71% yield, as a colorless oil.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>>[OH:14][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Benzaldehyde (0.40 mmol) then was added thereto. After reacting for 51 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times). The combined extracts were washed with brine and dried over Na2 SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy-phenylmethylphosphonate as final product in a yield of 90%. The chemical reaction in this Example is shown in chemical formula 27.
Reaction SMILES: C(O[CH:5](OC(C)C)[N:6]([CH3:8])[CH3:7])(C)C.[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([CH3:23])=[CH:16][C:15]=1[F:24]>CN(C=O)C>[Br:13][C:14]1[C:15]([F:24])=[CH:16][C:17]([CH:23]=[CH:5][N:6]([CH3:7])[CH3:8])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A mixture of N,N-dimethylformamide diisopropyl acetal (1.32 mL, 6.31 mmol) and 1-bromo-2-fluoro-4-methyl-5-nitro-benzene (1.23 g, 5.26 mmol) in dry DMF (15.0 mL) was stirred at 125° C. for 3 h. The resulting mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was washed with hexane to give [2-(4-bromo-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine as dark red solid (1.89 mg, 83%). 1H NMR (CDCl3, 400 MHz): 2.92 (s, 6H), 5.88 (d, J=12.3 Hz, 1H), 6.98 (d, J=13.2 Hz, 1H), 7.11 (d, J=10.8 Hz, 1H), 8.10 (d, J=6.9 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH:15]([CH3:18])[CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH:15]([CH3:18])[CH:16]=[O:17])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: CNC(C)C=O
Solvent: c1ccccc1
Product: CC(C=O)N(C)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams), the dimethyl acetal of 2-methylaminopropionaldehyde (5.5 grams) and benzene (20 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and thermometer. The reaction mixture was heated on a steam bath with stirring until all reactants had dissolved. After this time the reaction mixture was stripped of benzene to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]-propionaldehyde as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Cl)[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:27]3[CH2:28][CH2:29][N:24]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CCN(c4ccncc4)CC3)cc21
Temperature: 200 °C
Yield: 24.8 %

Procedure:
A mixture of 1-ethyl-7-chloro-4-quinolon-3-ylcarboxylic acid (182 mg) and 1-(4-pyridyl) piperazine (125 mg ) was heated to 200° C. for 20 minutes. The mixture was cooled and methanol (5 ml) was added. The resulting solid was filtered and washed with methanol (10 ml) to give the title compound (68 mg), as a solid: NMR (d6DMSO) δ1.4(t,3H), 3.75-3.85(m,4H), 3.9-4.0(m,4H), 4.55(q,2H), 6.9(d,1H), 7.2(d,2H), 7.3(dd,1H), 8.2(d,1H), 8.3(d,2H), 8.9(s,1H); m/e 379(M+H)+
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:33]=[CH:32][C:10]([CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:9][CH:8]=1)=[O:5])C.S(=O)(=O)(O)O.O>CS(C)=O>[C:4]([CH2:6][C:7]1[CH:33]=[CH:32][C:10]([CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 93.6 %

Procedure:
3-(4-Ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (110 mg, 0.25 mmol, prepared in Example 32) was dissolved in DMSO (3 ml) at 50° C., admixed with 50% sulfuric acid (2 ml) at 100° C., and then heated under reflux for 1 hour. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (96 mg, 93%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2=[CH:18][CH:19]=[CH:20][C:21]3=[CH:22][CH:23]=[CH:24][C:5](=[C:6]23)[NH:4][C:3]1=[O:25].C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl>C(OCC)(=O)C>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][N:4]1[C:3](=[O:25])[C@H:2]([OH:1])[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2=[CH:18][CH:19]=[CH:20][C:21]3=[CH:22][CH:23]=[CH:24][C:5]1=[C:6]23
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cccc4cccc(c34)NC(=O)[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 1.1 g of (±)-cis-2,3-dihydro-3-hydroxy2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one, 0.48 g of powdered potassium carbonate and 0.425 g of 2-dimethylaminoethyl chloride in 25 mL of ethyl acetate was stirred and heated at reflux for 3 hours, then twice an additional 0.10 g of 2-dimethylaminoethyl chloride was added at 3 hour intervals. The mixture was heated at reflux for a total of 17 hours then was cooled to room temperature and filtered. The filtrate was diluted with 40 mL of ethyl acetate and washed with brine (40 mL) and dried (magnesium sulfate). Removal of the solvent gave 1.2 g (92%) of (±)-cis-2,3-dihydro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)- one. A sample of this compound was crystallized from ethyl acetate, mp. 121°-122°.
Reaction SMILES: Cl.[CH2:2]([C:9]1[S:13][C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:27]([C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][N:31]([C@H:40]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:42])[CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([C:9]1[S:13][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:27][C@@H:29]3[C@@H:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:32][N:31]([C@H:40]([CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)[C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=[O:42])[CH2:30]3)[CH2:16][CH2:15]2)=[N:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(Cc2cnc(C3CCNCC3)s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4ncc(Cc5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
To a solution of 24 mg of 4-(5-benzyl-thiazol-2-yl) -piperidine hydrochloride (from Step C) in 3 ml DCE was added 8 mg of triethylamine. After 20 minutes, 35 mg of α-(R)-(3-(R)-Formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) was added, followed by 31 mg of sodium triacetoxyborohydride. The reaction was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane followed by 50% EtOAc in hexane to give 44 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)cc1C(F)(F)F
Reaction time: 12 h
Yield: 98.8 %

Procedure:
A solution of 4-nitro-3-(trifluoromethyl)phenol (Aldrich, 414 mg, 2.0 mmol) in 10 mL of MeOH was added 10% Pd/C (100 mg). The suspension was stirred under H2 atmosphere for 12 h and it was then filtered and concentrated in vacuo to give 4-amino-3-(trifluoromethyl)phenol (350 mg, 95% yield), which was sufficiently pure to use in the next step. MS(ESI+): m/z 178.02 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)=[CH:4][C:3]=1[Cl:27]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(N)ccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
A mixture of 1,1-dimethylethyl 4-{3-[6-amino-2-(methyloxy)-3-pyridinyl]-3-oxopropyl}-1-piperidinecarboxylate (step 3, 300 mg, 0.825 mmol) and N-chlorosuccinimide (115.7 mg, 0.866mmol) in N,N-dimethylformamide (5 ml) was stirred at 80° C. for 4 h. After cooling to room temperature, the mixture was diluted with diethylether (150 ml), washed with water (50 ml×2) and brine (150 ml), and dried over magnesium sulfate. Removal of solvent gave a brown oil, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 182 mg (56%) of the title compound as a colorless oil.