Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]3[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.CCOC(C)=O.O>C(O)(C(F)(F)F)=O>[NH:27]1[CH2:26][CH:25]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])=[N:9]2)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C1CNC1
Yield: 94.9 %

Procedure:
tert-Butyl 3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate (800 mg) in TFA (8 mL) was stirred for 1 hour. To the residue was added EtOAc and 1 water and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was evaporated to around 50 ml and washed with 2M HCl. The combined aqueous layer was adjusted with NaOH to pH 8-9, extracted with EtOAc and the combined organic layer washed with brine, and dried over Na2SO4. The solvent was removed to obtain 600 mg of 1-(azetidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6]O)([O-:3])=[O:2].C(Cl)(Cl)Cl.P(Br)(Br)[Br:18]>O>[N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][Br:18])([O-:3])=[O:2]
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)ccc1CBr
Yield: 80 %

Procedure:
To a solution of 16.5 g. of 2-nitro-4-chlorobenzyl alcohol in 200 ml. of chloroform was added dropwise 13 g. of phosphorus tribromide, and the mixture was heated to reflux for 1 hour on a water bath. The reaction mixture was then poured into water, and the chloroform layer was separated and washed with water. After the solvent was removed, the residue was extracted with ligroin while warming and allowed to stand to form colorless acicular crystals of 2-nitro-4-chlorobenzyl bromide (80% yield) melting at 42° to 43° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]1=[O:14])[CH3:2].[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[C:4]1=[O:14])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCn1c(=O)c(=O)[nH]c2cccnc21
Product: CCOC(=O)c1ncn2c1c(=O)n(CC)c1ncccc12

Procedure:
Ethyl 5-et hyl-4,5-dihydro-4-oxo-imidazo(1,5-a)pyrido(2,3-e)-pyrazine-3-carboxylate was prepared from 4-ethyl-1,2,3,4-tetrahydro-2,3-dioxo-pyrido(2,3-e)pyrazine and ethyl isocyanoacetate. M.p. 215.5°-216.8° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1)(=O)=O.[I-:24].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[I:24][CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1
Reactant: CS(=O)(=O)OCC1COc2ccc(Oc3ccccc3)cc2O1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: ICC1COc2ccc(Oc3ccccc3)cc2O1

Procedure:
2-Methanesulfonyloxymethyl-7-phenoxy-1,4-benzodioxane (1.85 g, 5.5 mmol) and sodium iodide (1.54 g, 11.0 mmol) are taken up in methyl ethyl ketone (60 mL) and heated at reflux for 3 hours. The mixture is cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to give 2-iodomethyl-7-phenoxy-1,4-benzodioxane as a tan solid. This is used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.I[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:27]1([CH2:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([S:14][CH3:13])=[CH:20][CH:19]=2)[C:22]([OH:24])=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to −78° C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at −78° C. for 1h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93° C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5]2.C(O)C.C([O-])=O.[NH4+]>[Pd].O1CCCC1>[NH2:12][C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2NC1=O
Temperature: 65 °C
Yield: 92.7 %

Procedure:
tert-Butyl 6-bromo-8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (628 g) was added to ethanol (3.1 L), and the mixture was heated at 65° C. To the mixture, 10% Pd—C (water content: 53%) (67.1 g) and ammonium formate (1.03 kg) were sequentially added, and the resultant mixture was stirred for 10 minutes under heating and reflux. Tetrahydrofuran (2.5 L) was added to the reaction mixture so as to dissolve the precipitates, and undissolved matter was removed through filtration with Celite. The filtrate was concentrated under reduced pressure, and water was added to the residue. The formed precipitates were recovered through filtration. The thus-obtained solid was dried, whereby the title compound (418 g) was yielded as a powdery compound.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[NH4+:5].[NH:6]1[C:14]2[C:9](=[CH:10]C=C[CH:13]=2)[C:8]([CH2:15][C:16](=O)C(O)=O)=[CH:7]1>>[CH:2]1[C:1]([OH:4])=[CH:10][C:9]2[C:8]([CH2:15][CH2:16][NH2:5])=[CH:7][NH:6][C:14]=2[CH:13]=1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Product: NCCc1c[nH]c2ccc(O)cc12
Reaction time: 0.08 h

Procedure:
A preliminary experiment was conducted on groups of 2 male Sprague-Dawley rats each, weighing 220-250 g. Hyperammoniemia was induced by administration of 5 moles/kg i.p. of ammonium acetate one hour before sacrifice. 3-Indolpyruvic acid was administered in 10 mg/kg p.o. doses one hour before the ammonium acetate, that is 2 hours before sacrifice. After decapitation, the cerebral hemispheres were rapidly removed, weighed and homogenized with a double volume of physiological solution +0,1 ml of 20% vitamin C. 1 ml of homogenate was treated with 0,43 ml of 12% TCA and 0,025 ml of 20% vitamin C. After standing for 5 minutes at 5° C., the mixture was centrifuged at 11,000 revolutions per minute in a Sorvall centrifuge, SS 34 rotor, for 10 minutes at 5° C. The supernatant was removed and injected into a high pressure liquid chromatograph, equipped with a RP-8 column (Merck). Administration of 3-indolpyruvic acid led in one case to a 20% increase, and in the other a 50% increase in brain serotonin.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:26][CH2:27][CH2:28][CH3:29])[C:3](=[O:25])/[CH:4]=[CH:5]/[C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[CH2:12][CH2:13][S:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.[BH4-].[Na+].C(O)(=O)C.O>CO>[OH:25][C@@H:3]([C:2]([CH3:1])([CH3:30])[CH2:26][CH2:27][CH2:28][CH3:29])/[CH:4]=[CH:5]/[C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[CH2:12][CH2:13][S:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1
Reactant: CCCCC(C)(C)C(=O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Yield: 70 %

Procedure:
To a solution of the compound 6 (124 mg) in anhydrous methanol (1.40 mL) were added sodium borohydride (10.4 mg) and a catalytic amount of acetic acid at −78° C. and the solution was stirred at the same temperature for 1 hour. After return to room temperature, to the reaction solution was added water and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1), to give the title compound (87.2 mg) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[CH3:2].[BrH:21]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([Br:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)C(C)(C)CCCC=Cc1ccccc1Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)CCCCC(Br)c1ccccc1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
7-(2-Chlorophenyl)-2,2-dimethylhept-6-enoic acid ethyl ester (11.75 g, 0.040 mole) was dissolved in acetic acid (80 mL) under an argon atmosphere. The flask was cooled in an ice-water bath. Hydrogen bromide gas was passed slowly through the solution for 3 hours while the solution slowly warmed to room temperature. Ice (250 g) was added and after mixing, the product was extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were combined and washed with saturated sodium bicarbonate solution (3×75 mL) and water (100 mL). The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining oil (14.06 g) was purified by column chromatography on silica gel (250 g), eluting with 3:1 (followed by 2:1) heptane/ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure to provide 7-bromo-7-(2-chlorophenyl)-2,2-dimethylheptanoic acid ethyl ester (12.9 g, 86% yield) as a clear oil. 1H NMR (300 MHz, CDCl3/TMS): δ=7.57 (d, 1H, J=7.50 Hz), 7.33-7.15 (m, 3H), 5.43 (t, 1H, J=6.9 Hz), 4.08 (q, 2H, J=7.2 Hz), 2.30-2.21 (m, 2H), 1.55-1.42 (m, 3H), 1.34-1.19 (m, 5H), 1.13 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=177.72, 139.41, 132.69, 129.67, 129.28, 128.92, 127.48, 60.36, 50.17, 42.26, 40.57, 39.19, 28.59, 25.38, 25.34, 24.45, 14.50. MS (HR, DIP-CI): Calculated for (MH+): 375.0726, found 375.0726.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.Cl.[NH2:31][NH:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:33]([NH:32][N:31]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1)(=[O:34])[NH2:35]
Reactant: NNC(N)=O
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 47.4 %

Procedure:
A mixture of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (231 mg), semicarbazide hydrochloride (101 mg), potassium carbonate (125 mg), water (2 ml), and ethanol (10 ml) was heated under reflux for 4 hours. Ethanol was evaporated in vacuo and the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml). After an additional extraction with dichloromethane, the combined extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to give colorless crystals of 3-[2-(2-carbamoylhydrazonocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (125.8 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:21]=[CH:20]2)(=[O:15])[CH3:14].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:10])[CH3:11])[NH:8][S:27]([C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([O:16][C:13](=[O:15])[CH3:14])[CH:18]=2)[CH:23]=1)(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Oc1ccc2cc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Yield: 67.4 %

Procedure:
D-valine tert-butyl ester (6.24 g, 35.9 mmol), 6-acetoxy naphthalene-2-sulfonyl chloride (10.2 g, 35.9 mmol) and triethylamine (12.5 mL, 89.7 mmol) are stirred in dioxane-water (1:1, 243 mL) at ambient temperature for 2 hours. The reaction mixture is acidified with a solution of aqueous citric acid (10% w/w, 800 mL). The precipitate is collected by filtration affording product as pale yellow crystals (10.2 g, 68% yield). LCMS (m/z): (439.28; M+18, 420.24; M−1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[OH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:2]1
Reactant: O[C@@H]1CCNC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CC[C@@H](O)C2)cc1
Yield: 99.9 %

Procedure:
Dissolve (R)-pyrrolidin-3-ol (0.08 mL, 1.00 mmol) and 4-fluorobenzonitrile (121 mg, 1.00 mmol) into 1 mL of DMSO. Add K2CO3 (276 mg, 2.00 mmol) and heat the mixture at 120° C. for 16 h. LC-MS analysis indicates the desired intermediate. Add 10 mL of H2O. Filter the precipitate and dry in a Buchner funnel for 1 h to give 188 mg of 4-((R)-3-hydroxy-pyrrolidin-1-yl)-benzonitrile.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.C([N:35]1[CH:39]=[C:38]([CH2:40][C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[N:37]=[CH:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:37]2[C:38]([CH2:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=3)=[CH:39][N:35]=[CH:36]2)=[CH:10][CH:9]=1
Reactant: O=c1ccccn1-c1ccc(CBr)cc1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: CC#N
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-n3ccccc3=O)cc2)cc1

Procedure:
4-(-2-Oxo-2-H-pyridin-1-yl)benzyl bromide from Step 3 (1.7 mmol, 450 mg) and 4-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile (1.7 mmol) were suspended in CH3CN and heated to reflux for 3 hours. The reaction mixture was concentrated and the residue taken up in MeOH and refluxed for 2 hours. The MeOH was removed in-vacuo. The resulting oil was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield an oil which was purified by flash chromatography using 5% IPA/CHCl3 saturated with NH3 as an eluent. Pure fractions were collected and concentrated to give a white solid. The solids were washed with warm 50% EtOAc/Hexane and collected on a frit. The white solid was collected and dried under high vacuum at 50° for 12 hours to give the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[Cl-].[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-])=[O:24].C(Cl)(=O)C(Cl)=O.C(OC)(=O)CCCCC([O-])=O>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:27][CH3:28])=[O:26])[CH:11]=[CH:10]2
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: COc1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 8 h

Procedure:
Into a solution of 6.32 g (47.4 mmol) of anhydrous aluminum chloride in 60 ml of dry nitrobenzene was added 5.03 g (31.7 mmol) of 2-methoxynaphthalene chilled with an ice bath, followed by stirring. Subsequently, under an ice bath, monomethyl adipate chloride (synthesized by adding 5.0 ml (57.3 mmol) of oxalyl chloride under an ice bath to a solution of 5.85 ml (39.5 mmol) monomethyl adipate in 50 ml of dry methylene chloride) to carry out the reaction for 6 hours, and evaporating methylene chloride and excessive oxalyl chloride under a reduced pressure) was gradually added, and the reaction was carried out at 0° C. to room temperature overnight (for 15 hours). The reaction mixture was poured into ice-water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the organic solvent and nitrobenzene under a reduced pressure, the desired product was obtained by silica gel chromatography. Yield: 3.82 g (40%).
Reaction SMILES: I[C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:31][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>CC(O)C.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:2]2[C:6]3=[N:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:10]=[C:5]3[N:4]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:3]=2)[CH:30]=[N:31][CH:32]=1
Reactant: COC(=O)c1ccc2c(n1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(n1)c(-c1cncc(OC)c1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 59.1 %

Procedure:
A glass microwave reaction vessel was charged with methyl 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.300 g, 0.658 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (0.216 g, 0.921 mmol, Sigma-Aldrich), and K3PO4 (0.419 g, 1.973 mmol) in 70% i-PrOH in H2O (3.30 mL). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 10 min. 2 M HCl (aq.) was added and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (eluting with 0-10% MeOH in DCM) to provide methyl 3-(5-methoxy-3-pyridinyl)-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.170 g, 0.389 mmol, 59.1%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 438.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 2.37 (3H, s), 3.96 (3H, s), 4.00 (3H, s), 7.29 (2H, d, J=8.22 Hz), 7.79-7.85 (2H, m), 8.16-8.21 (2H, m), 8.27-8.34 (2H, m), 8.42 (1H, d, J=8.61 Hz), 8.81 (1H, d, J=1.56 Hz).
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[CH:10][C:11]=3[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1CCc1ccccc1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.03 (d, J=8.3 Hz, 2H), 7.67-7.62 (m, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.26-7.21 (m, 3H), 7.15 (t, J=7.3 Hz, 1H), 7.08 (d, J=6.8 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.64 (s, 1H), 4.24 (t, J=6.4 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H), 2.87-2.79 (m, 4H), 2.35 (s, 3H), 1.43 (s, 6H), MS (ES) m/e 562 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28](=[NH:30])[NH2:29])[CH:25]=[CH:24][C:23]=1[OH:31])(=[O:21])=[O:20])C>Cl.C(#N)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([OH:31])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:14])[CH3:15])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:32])=[O:3])(=[O:20])=[O:21])[CH:27]=1)(=[NH:29])[NH2:30]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C(=N)N)ccc1O
Agent: Cl
Solvent: CC#N
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C(=N)N)ccc2O)c(OCC(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Ethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate (50 mg) was dissolved in a mixture of 3 mL of 1 mol/L hydrochloric acid and 1 mL of acetonitrile at 60° C. The solution was stirred at 60° C. for 4 hours, and the colorless solid obtained by concentration under reduced pressure of the reaction mixture was dissolved in a mixture of 3 mL of 1 mol/L hydrochloric acid and 1 mL of acetnitrile at 60° C. After the solution was stirred at 60° C. for 4 hours, then at room temperature for 10 hours, the reaction mixture was concentrated under reduced pressure to give a colorless solid. The solid was triturated with water and diethyl ether, and collected by filtration to give 31 mg of [2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetic acid.