Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH2:51]([O:58][P:59]([CH2:68][C@H:69]([OH:72])[CH2:70][NH2:71])([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][P:59]([CH2:68][C@H:69]([OH:72])[CH2:70][NH:71][C:16](=[O:18])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:13]([CH3:14])[CH3:15])([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:60])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Yield: 48.8 %

Procedure:
A flask was charged with N-Cbz-L-valine (1.02 g, 4.04 mmol) and DMF (60 mL) and stirred under nitrogen. To this was added diisopropylethylamine (2.11 mL, 12.1 mmol) followed by TBTU (1.30 g, 4.04 mmol). After stirring for 5 minutes, a solution of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (8.08 mmol) dissolved in DMF (10 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (300 mL) and the organic layer washed with 1N HCl (2×100 mL), water (100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as an amber oil. The crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 120 g RediSep disposable column to give (1.10 g, 1.97 mmol) of [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.25 (m, 10H), 6.70-6.51 (m, 1H), 5.48-5.35 (m, 1H), 5.18-5.01 (m, 4H), 4.20-3.98 (m, 2H), 3.62-3.42 (m, 1H), 3.38-3.18 (m, 1H), 2.30-2.05 (m, 1H), 2.03-1.60 (m, 10H, 1.38-1.02 (m, 5H), 0.98 (dd, 6H). LCMS m/z: [M+H]+=559.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([CH:14]=[O:15])[S:12][CH:13]=1.[C:16]([Mg]Br)#[CH:17]>CCCCCC.C(OCC)(=O)C>[C:16]([CH:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:10]=1)[OH:15])#[CH:17]
Reactant: O=Cc1nc(COC2CCCCO2)cs1
Reactant: C#C[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#CC(O)c1nc(COC2CCCCO2)cs1

Procedure:
The product was prepared starting with the product of Stage B and ethynyl magnesium bromide using the procedure of Example 1 to obtain the desired product with a Rf=0.11 (hexane-ethyl acetate (7-3)).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][O:15][C:12]2=[CH:13][N:14]=1)[CH2:3]C(OCC)=O.S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:2]([C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][O:15][C:12]2=[CH:13][N:14]=1)(=[O:1])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cc2ccoc2cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2ccoc2cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Ethyl β-oxo-5-furo[2,3-c]pyridinepropionate(1.17 g, 15 5.0 mmol) was dissolved in 20 mL of toluene, and 1.5 mL (7.5 mmol) of 10 N sulfuric acid was added at room temperature with stirring. After addition, the reaction mixture was heated to 80° C., and a reaction was carried out for 6 hours with stirring. The solution was then cooled to room temperature and neutralized with 12 mL of 5% sodium hydroxide aqueous solution. The organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 580 mg of 5-acetylfuro[2,3-c]pyridine in a purity of 99% by HPLC (72% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.C(O)C.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(F)cc2)CC1

Procedure:
A mixture of 160 parts of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane, 72 parts of hydrochloric acid, 800 parts of ethanol and 800 parts of water is stirred and refluxed for 2 h. 30. Then there are added dropwise 72 parts of sulfuric acid. Upon completion, stirring is continued at reflux temperature for one hour. The reaction mixture is cooled, poured onto water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is fractionated, yielding 68.5 parts of 4-(4-fluorophenyl)cyclohexanone; b.p. 110° C. at 1 mm. pressure.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.Cl.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:38]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[O:45])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccncc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.5 %

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.06 ml TEA (0.44 mmol) were dissolved in 1.5 ml dichloromethane and treated with 36 mg isonicotinic acid chloride hydrochloride (0.2 mmol). After 22 h of stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 86 mg yellow solid which was purified by column chromatography (9.5 g silicagel, dichloromethane/methanol 24:1). 46 mg product as a light yellow solid (48%) was obtained. MS (ISP) 606.3 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[ClH:33].C(OCC)(=O)C>C(OCC)C>[ClH:33].[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), (trimethyl)silyl isocyanate (78 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and THF, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (39.5 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([CH:16]=[O:17])=[C:4]([N:18](CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)[N:3]=1.C1(CO)CCCCC1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([CH:16]=[O:17])=[C:4]([NH2:18])[N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(OCC3CCCCC3)c2C=O)cc1
Agent: OCC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c(C=O)c(OCC2CCCCC2)n1

Procedure:
The mixture of 2-Amino-4-cyclohexylmethoxy-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde and cyclohexylmethanol obtained previously was stirred in trifluoracetic acid (2 ml) at 65° C. for 24 h. The same workup procedure was used as previously, with purification of the product by column chromatography eluting with 40% EtOAc/petrol (40:60) yielding a pale yellow solid. M.p. 159-160° C.
Reaction SMILES: [CH3:1]N.[NH4+].[C:4]([CH:6]([CH2:11][CH3:12])[CH2:7][C:8]([O-])=[O:9])#[N:5]>[Pd].O>[CH2:11]([CH:6]1[CH2:4][N:5]([CH3:1])[C:8](=[O:9])[CH2:7]1)[CH3:12]
Reactant: CCC(C#N)CC(=O)[O-]
Reactant: CN
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Product: CCC1CC(=O)N(C)C1
Temperature: 140 °C
Yield: 69.8 %

Procedure:
Into a 100 mL graduated cylinder was placed 79.4 mL of an aqueous reaction mixture containing 1.26M 3-cyanopentanoic acid ammonium salt (0.1 mole 3-cyanopentanoic acid ammonium salt, produced by the enzymatic hydrolysis of 2-ethylsuccinonitrile; Example 13 filtered product mixture), then 17.2 mL of 40 wt. % methylamine (6.21 g methylamine, 0.2 mole) was added and the final volume adjusted to 100 mL with distilled water. The final concentrations of 3-cyanopentanoic acid ammonium salt and methylamine were 1.0M and 2.0M, respectively. To the resulting solution was added 0.636 g (5 wt. %/wt. of 3-cyanopentanoic acid) of 5% Pd on carbon powder, and the resulting mixture charged to a 300-mL 314 SS Autoclave Engineers EZE-Seal stirred autoclave equipped with a Dispersimax® turbine-type impeller. After flushing the reactor with nitrogen, the contents of the reactor were stirred at 1000 rpm and heated at 140° C. under 500 psig of hydrogen gas for 4 h. Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis. After cooling to room temperature, analysis of the final reaction mixture by gas chromatography indicated a 69.8% yield of 4-ethyl-1-methylpyrrolidin-2-one and a 20.4% yield of 4-ethylpyrrolidin-2-one, with no 3-cyanopentanoic acid ammonium salt remaining.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4][C:3]([CH2:2][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:6]=2[CH:8]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc2sc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2sc(CN3CCNCC3)nc2c1

Procedure:
A mixture of 2-(bromomethyl)-5-fluoro-1,3-benzothiazole (150 mg, 0.61 mmol), potassium carbonate (253 mg, 1.83 mmol) and piperazine (263 mg, 3.05 mmol) in acetonitrile (30 ml) was heated at reflux for 4.5 hours with stirring and was then concentrated under vacuum. The residue was dissolved in dichloromethane (100 ml), washed with brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 5-fluoro-2-(piperazin-1-ylmethyl)-1,3-benzothiazole as a yellow crude solid (130 mg). (ES, m/z): [M+H]+ 252.1; 1H NMR (400 MHz, CDCl3): δ 7.81 (dd, J=8.8, 5.2 Hz, 1H), 7.70 (dd, J=9.6, 2.4 Hz, 1H), 7.16-7.11 (m, 1H), 3.93 (s, 2H), 2.97-2.93 (m, 4H), 2.64-2.63 (m, 4H), 1.98 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([OH:17])[CH2:4][CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[N:20]([CH2:5][CH2:4][CH:3]([OH:17])[C:2]([F:19])([F:18])[F:1])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCC(O)C(F)(F)F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCC(O)C(F)(F)F
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 4-toluenesulfonic acid 4,4,4-trifluoro-3-hydroxybutyl ester (1.30 g, 4.36 mmol) in DMSO (7 mL) was treated with sodium azide (0.306 g, 4.71 mmol) at is ambient temperature and then heated at 50° C. for 23 h. The mixture was diluted with cold water and extracted with diethyl ether. The combined organic extracts were washed (brine), dried, and evaporated without heat to give the product as a yellow oil (0.737 g, 100%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.COCCOC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1)=[CH2:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2cn[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: C=Cc1ccc2cn[nH]c2c1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a suspension of 6-bromo-1H-indazole (600 mg, 3.05 mmol) in toluene (18 ml) and 1,2-dimethoxyethane (6 ml) were added tributyl(vinyl)tin (1.33 ml, 4.57 mmol) and PdCl2(PPh3)2 (214 mg, 0.31 mmol). The reaction was purged with argon then heated at reflux for 3 h. Additional tributyl(vinyl)tin (0.66 ml, 2.28 mmol) and PdCl2(PPh3)2 (107 mg, 0.15 mmol) were added and heating was continued for 1 h. The same reaction was performed on an additional batch of 6-bromo-1H-indazole (200 mg, 1.02 mmol) and the two crude batches were combined. The reactions were diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 5% to 50% EtOAc/heptane to isolate 350 mg (60%) of 6-vinyl-1H-indazole as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.07 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.85 (dd, J=17.4, 11.0 Hz, 1H), 5.86 (d, J=17.4 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]3[N:18]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:16][C:13]3=[N:14][CH:15]=2)[CH:7]=[N:6]1.[Li+].[OH-].Cl>CO.O>[N:26]1[C:27]2[C:22](=[CH:21][C:20]([CH2:19][N:18]3[C:12]4[C:13](=[N:14][CH:15]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH:9]=5)[N:11]=4)[N:16]=[N:17]3)=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)Cn1cc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1cc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
To a solution of [4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-acetic acid methyl ester (242 mgs, 0.60 mmol) in MeOH (4 mL) was added a freshly prepared solution of LiOH (72 mgs, 3.02 mmol) in water (1 mL). The reaction was stirred for 16 hours at ambient temperature. The white suspension was then neutralized to pH 7 with 1 N HCl, and a white solid precipitated out. The solid was filtered, washed with water, and dried under a high vacuum for 16 hours to afford [4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-acetic acid (131 mgs, 56% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]=1[C:15]([O:17]C)=[O:16].O.[OH-].[Na+]>O1CCOCC1>[I:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(I)ccn(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(I)ccn(-c2ccccc2)c1=O
Temperature: 50 °C
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (2.34 g, 6.59 mmol) in dioxane (39 mL) was added water (12 mL) followed by sodium hydroxide 6M solution (4.39 ml, 26.4 mmol). The reaction mixture was heated at 50° C. for 4 h. LCMS analysis of an aliquot showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated in vacuo. Water was added, and the pH was adjusted to ˜3 with 6M aqueous hydrochloric acid solution. The solid formed was isolated by filtration and was dried under high vacuum overnight to give 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (1.79 g, 5.25 mmol, 80% yield), which was used without further purification. MS (ESI pos. ion) m/z: 364 (M+Na). Calc'd exact mass for C12H81NO3: 341.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.O[CH:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1C=CC=CC=1>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:29]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)C(O)Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Yield: 55.2 %

Procedure:
Following the procedure described in Step 2 of Example 4, 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (2.38 g, 5.62 mmol) was coupled to ethyl 2-hydroxy-3-phenylpropanoate (1.65 g, 8.50 mmol) in presence of triphenylphosphine (2.23 g, 8.50 mmol) and diisopropylazodicarboxylate (1.7 mL, 8.5 mmol) in benzene (62 mL). Purification by HPLC, using 95% acetonitrile in water as the mobile phase, yielded ethyl 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a yellow gum (1.86 g). 1HNMR (300 MHz, DMSO-d6): δ8.45 (s, 1H), 8.25 (d, 1H, J=7.7 Hz), 8.1 (d, 1H, J=7.7 Hz), 7.95-8.1 (m, 2H), 7.85 (d, 1H, J=7.7 Hz), 7.4-7.5 (m, 5H), 7.2-7.4 (m, 3H), 5.5 (t, 1H, J=6.0 Hz), 4.1 (q, 2H, J=7.0 Hz), 2.75 (t, 2H, J=7.0 Hz), 1.45-1.6 (m, 2H), 1.05-1.25 (m, 6H), and 0.7 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:12]2[CH:13]=[C:14]([OH:16])[CH:15]=[C:10]3[C:11]=2[C:6]([CH2:7][CH2:8][CH2:9]3)=[N:5]1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([O:16][C:14]1[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][C:6]3=[N:5][N:4]([CH2:3][CH:2]([OH:1])[CH3:17])[C:12]([CH:13]=1)=[C:11]23)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(O)Cn1nc2c3c(cc(O)cc31)CCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(O)Cn1nc2c3c(cc(OCc4ccccc4)cc31)CCC2
Yield: 47.1 %

Procedure:
To a stirred solution of the product from Step E (1.2 g, 5.2 mmol) in ethanol (20 mL) was added K2CO3 (0.86 g, 6.3 mmol) followed by benzyl bromide (0.74 mL, 6.3 mmol) at room temperature. The resultant dark solution was heated at reflux for 4 h. Solvent was evaporated, the residue was diluted with 2 N HCl (60 mL), and this solution was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (30 mL), dried, and evaporated to a residue which was purified by column chromatography (silica, 40% ethyl acetate in hexane) to give an oil (0.79 g, 47%): MS (ES) m/z 232 (M+); 1H NMR (CDCl3) δ 7.32 (5H, m), 6.60 (1H, s), 6.59 (1H, s), 5.29 (2H, s), 4.31 (2H, m), 4.19 (1H, m), 2.90 (2H, m), 2.11 (2H, m), 1.21 (3H, d, J=6.0 Hz).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=2)[C:6]([O:17][CH3:18])=[CH:5]1)(=O)C.O.[OH-].[Li+]>C1COCC1.O>[CH3:18][O:17][C:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)[NH:4][CH:5]=1
Reactant: COC(=O)c1ccc2c(OC)cn(C(C)=O)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c[nH]c2cc(C(=O)O)ccc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of methyl 1-acetyl-3-methoxyindole-6-carboxylate (74 mg, 0.3 mmol) in THF (10 ml) and water (2 ml) was added lithium hydroxide hydrate (63 mg, 1.5 mmol). The reaction mixture was warmed to 50° C. and stirred for 3 h. The THF was removed under reduced pressure and the pH of the aqueous phase adjusted to 3. Extraction of the aqueous layer with ethyl acetate, drying and concentration gave the acid (50 mg, 87%);
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([OH:25])=[O:15])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: O=C(O)c1ccccc1COc1ccc(-c2ccccc2)cc1

Procedure:
2-(Biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 50 mg. Mass spectrum (ES) MH+=305.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30]C)=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([OH:30])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.22 mmol) in methanol (10 ml) was added NaOH (36 mg, 0.9 mmol) and water (1 ml). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (25.0 mg, 25%).