Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: Nc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
In a flame-dried r.b. flask equipped with a mangetic stirring bar was dissolved 3-(4-nitrophenyl)pyridine (131 mg, 0.655 mmol) and 10% Pd on C (10 mg) in anhydrous CH2Cl2 (3 mL) was added. The flask was repeatedly evacuated and filled with N2 to remove any residual O2, and then H2 gas was introduced. The solution was stirred at rt for 18 h, filtered though a Celite™ plug and concentrated in vacuo to give the desired amine (105 mg, 95%) as an off-white solid. Data for 3-(4-aminophenyl)pyridine: Rf =0.17 (silica gel, methanol/CHCl3, 5/95); 1H NMR (400 MHz, acetone-d6) 8.77 (d,J=2.3, 1 H), 8.42 (dd,J=6.4, 1.6, 1 H), 7.88 (m, 1 H), 7.41 (d,J=8.5, 2 H), 7.33 (m, 1 H), 6.78 (d,J=8.5, 2 H), 4.86 (br s, 2 H).
Reaction SMILES: [C:1]([C:3]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:9])#[N:2].O.O.Cl[Sn]Cl.[OH-].[Na+]>COCCOCCOC.Cl>[NH2:26][C:25]1[C:3]([C:1]#[N:2])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:9]
Reactant: COc1ccc(CNC(=O)C(C)(C)COc2cccc([N+](=O)[O-])c2C#N)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc(CNC(=O)C(C)(C)COc2cccc(N)c2C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 3-(2-cyano-3-nitrophenoxy)-N-(4-methoxybenzyl)-2,2-dimethyl-propanamide (1.15 g, 3.0 mmol) (Example 220c) in diglyme (30 mL) was added dropwise a solution of SnCl2.2H2O (2.03 g, 9.0 mmol) in concentrated HCl (15 mL) at 0° C. The reaction mixture was then stirred at 0° C. for another 1 hr. The reaction solution was neutralized with 2 N NaOH at 0° C., and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a white solid (0.91 g) in 86% yield. MS 354 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[C:20]1([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]1=[O:28].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F>C(#N)C>[CH2:32]([O:31][CH2:30][CH2:29][C:20]1([O:1][C:2]2[CH:18]=[CH:17][C:5]([O:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)[C:21](=[O:28])[NH:22][C:23](=[O:27])[NH:24][C:25]1=[O:26])[CH3:33]
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: CNC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CC#N
Product: CCOCCC1(Oc2ccc(Oc3ccc(C(=O)NC)cc3)cc2)C(=O)NC(=O)NC1=O
Yield: 15.6 %

Procedure:
Following the procedure outlined for the preparation of Example 1 4-(4-hydroxy-phenoxy)-N-methyl-benzamide (0.14 g, 0.58 mmol) was reacted with 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.16 g, 0.58 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 0.40 g) and 2.0 mL of acetonitrile, affording 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-N-methyl-benzamide (0.040 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[S:10][CH:11]=1.[OH-].[K+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=1
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc(Br)c1-c1csc(C(=O)O)c1
Temperature: 50 °C

Procedure:
To a solution of methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.2 g, 0.63 mmol) in THF/H2O (5 mL/1 mL) was added KOH (0.15 g, 2.4 mmol). The reaction mixture was heated to 50° C. for 10 h and then concentrated and diluted with H2O (2 mL). The pH was adjusted to 6 with aqueous HCl. The mixture was extracted with DCM (3×5 mL) and the collected organic fractions were concentrated under vacuum to give crude 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid, which was used directly without further purification. LC-MS (ES) m/z=302 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:15](F)(F)[C:16]1[CH:17]=[C:18](CBr)[CH:19]=[CH:20][CH:21]=1>>[C:16]1([CH2:15][O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1

Procedure:
When the bridging group n is --OCH2 --, 1,4-dioxaspiro[4.5]decan-8-ol (the preparation of which was previously described) is treated with sodium hydride and reacted with an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 3-trifluoromethylphenylmethyl bromide, affording the corresponding 8-phenylmethoxy-1,4-dioxaspiro[4.5]decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethoxycyclohexanone, which is in turn reacted with cyanoguanidine, yielding the targeted 2,4-diamino-6-phenylmethoxy-5,6,7,8-tetrahydroquinazoline. Example 11 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]2[CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N=C2NC3(CCCC3)CS2)c(C)c1
Reactant: BrC1CCCC1
Product: COC(=O)c1ccc(N=C2SCC3(CCCC3)N2C2CCCC2)c(C)c1

Procedure:
Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to Method C2a to give 2-(4-methoxycarbonyl-2-methylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2-(4-methoxycarbonyl-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH2:9]([OH:11])[CH3:10]>C(Cl)(Cl)Cl>[C:1](=[NH:2])([O:11][CH2:9][CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: N#Cc1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccncc1
Reaction time: 8 h

Procedure:
A solution of 4-cyanopyridine (135 g) and ethanol (83.3 ml) in chloroform (1000 ml) is cooled in an ice bath for 30 min. Anhydrous HCl (143 g) is bubbled into the cold mixture over a period of 7 hours with stirring continued overnight with cooling. The reaction mixture is filtered and the filtered solid added portionwise to an ice cold 10% K2CO3 solution (500 g in 5 l H2O) with stirring. A liter of ether is added to the mixture after 20 min with stirring. The aqueous layer is extracted with ether and the organic extracts combined and dried overnight. The dried solution is filtered, evaporated in vacuo and vacuum distilled giving as a main fraction 75.5 g of a colorless liquid, b.p. 63°-65° C. (0.14 mm).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1)=O.[NH3:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH2:13][CH2:1][C:3]1[CH:4]=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: N
Reactant: Cc1cc(C=O)cc(B(O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(CN)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-Formyl-5-methylphenylboronic acid (1 eq, 3.05 mmol, 0.5 g) in dry DCM (5 ml) under an inert atmosphere of argon is treated with ammonia solution 35% (1.1 eq, 3.35 mmol, 0.185 ml) followed by acetic acid (1.1 eq, 3.35 mmol, 0.192 ml) and NaBH(OAc)3 (1.2 eq, 3.66 mmol, 0.776 mg) and the resulting mixture is stirred at room temperature overnight. The reaction is quenched by addition of acetonitrile and filtered under vacuum. The filtrate is concentrated in vacuo to afford the title compound which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][NH2:12])[CH:6]=1)[CH3:2].O=[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][C:17]#[N:18].Cl>C(O)C>[NH2:18][C:17]1[N:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:13])[N:12]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: CCOC(=O)c1cccc(NN)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc(-n2nc(-c3ccccc3)cc2N)c1
Yield: 91.1 %

Procedure:
To a mixture of 3-hydrazinobenzoic acid ethyl ester (4.5 g, 25.0 mmol) and commercially available 3-oxo-3-phenylpropionitrile (5.5 g, 37.5 mmol) in ethanol (50 mL) was added conc. HCl (5 mL). The resulting mixture was heated to reflux for 3 h. After removal of the solvent, the residue was washed with Et2O to afford ethyl 3-(5-amino-3-phenyl-1H-pyrazol-1-yl)benzoate (7 g, 2% yield, 2 steps) which was used in the next reaction without further purification.
Reaction SMILES: C1N(CCCS(O)(=O)=O)CCOC1.C([O-])(=O)C.[Na+].C1N(CCS(O)(=O)=O)CCN(CCS(O)(=O)=O)C1.C1N(CCCS(O)(=O)=O)CCN(CCO)C1.C([O-])(=O)C.[O:57]=[CH:58][C@@H:59]([C@H:61]([C@@H:63]([C@@H:65]([CH2:67][OH:68])[OH:66])[OH:64])[OH:62])[OH:60]>C1(C=CC=C(O)C=1)O.[NH4+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[Fe+3].Cl>[OH:57][CH2:58][C:59]([C@H:61]([C@@H:63]([C@@H:65]([CH2:67][OH:68])[OH:66])[OH:64])[OH:62])=[O:60]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Fe+3]
Agent: CC(=O)[O-]
Agent: Cl
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
Glucose isomerase assays: TNXI 1F1 and Gensweet™ were assayed routinely with glucose as the substrate. The enzyme (1–1.5 mg/mL) was incubated in 100 mM MOPS buffer (pH 7.0) [or 100 mM sodium acetate buffer (pH 5.5)] containing 1 mM CoCl2 and 0.4 mM glucose at 80° C. for 10 min. The reaction was stopped by transferring the tube to an ice bath. The amount of fructose produced was determined by the modified resorcinol-ferric ammonium sulfate-hydrochloric acid method (Schenk and Bisswanger, 1998). To determine the effect of temperature on the activity of TNXI 1F1 and Gensweet™, the holo-enzyme was incubated in the reaction mixture at the temperatures of interest in a heated water bath (45–95° C.) or a heated oil bath (95–110° C.) for 10 min. The effect of pH on activity was determined using the routine assay described above except that the MOPS buffer was substituted with 100 mM sodium acetate buffer (pH 4.3–5.8), 100 mM PIPES buffer (pH 6.1–7.0), or 100 mM EPPS buffer (pH 7.2–8.1). All pHs were adjusted at room temperature, and the ΔpKa/Δt's for acetate, PIPES, and EPPS (0, −0.0085, −0.011, respectively) (USB, Cleveland, Ohio) were taken into account for the results. To determine the kinetic parameters, assays were performed in the presence of 10–1,500 mM glucose, 50 mM MOPS (pH 7.0) and 1 mM CoCl2. One unit of glucose isomerase activity is defined as the amount of enzyme that produces 1 μmol of fructose per minute under the assay conditions.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH:28]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:39][C:36]2[CH:35]=[CH:34][C:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(-c2cccnc2)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(-c2cccnc2)cc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-pyridin-3-ylphenol (J. Med. Chem. 1986, 29, 1461): 1H-NMR (CDCl3) δ 8.88 (1H, m), 8.64–8.53 (2H, m), 8.17 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=7.5 Hz), 7.96 (2H, d, J=8.4 Hz), 7.69 (2H, d, J=8.6 Hz), 7.47 (1H, d, J=8.6 Hz), 7.42 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.6 Hz), 6.97 (1H, d, J=8.6 Hz), 5.38 (1H, m), 1.60 (3H, d, J=7.5 Hz), 1.57 (9H, s).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CCN(CC)CC.[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(Cl)Cl>[CH2:14]([O:21][CH2:22][C:23]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCNC1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)N1CCC(O)C1
Reaction time: 3.5 h
Yield: 98.1 %

Procedure:
A solution of 4.4 mL (52.93 mmol) 3-pyrrolidinol in 250 mL CH2Cl2 at 0° C. was added 8.4 mL (60.26 mmol) NEt3 and 8.2 mL (51.97 mmol) benzyloxyacetyl chloride. The reaction was stirred for 3.5 h and then poured into 400 mL H2O. The reaction was extracted with CH2Cl2, dried over MgSO4, filtered and rotary evaporated to yield 12.0 g (98%) of N-(benzyloxyacetyl)-3-pyrrolidinol as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)nc1
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.06 mmol, Step-1, single enantiomer) and propionyl chloride (8 mg, 0.09 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][O:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)OC(=O)COCCc1cccc(Br)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)COCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl 2-(3-bromophenethoxy)acetate (580 mg, 1.84 mmol) in THF/CH3OH/H2O (8/4/4 mL) was added LiOH.H2O (232 mg, 5.5 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred for 2 h at room temperature. After concentration under vacuum, the pH of the residual solution was adjusted to 2 with 1M hydrochloric acid. The carboxylic acid was extracted into EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 2-(3-bromophenethoxy)acetic acid (470 mg, 99%) as a colorless oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[OH:25])([O-:15])=[O:14].Cl>O>[OH:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[N:21]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:20]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl chloroformate (5 ml) was added to a pyridine (30 ml) solution containing 5-nitro-1H-indazol-3-ol (5.42 g) obtained in the 1st step, followed by stirring at room temperature for 1.5 hours. Water and concentrated hydrochloric acid (32 ml) were added dropwise to the reaction solution and a solid precipitate was collected by filtration. The obtained residue was washed with water. A brown solid of ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (7.5 g) was thus obtained.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:5])C.O.[Li].CO.Cl>O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CC1c1ccc(F)cc1
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC1c1ccc(F)cc1
Temperature: 80 °C
Yield: 109.5 %

Procedure:
In a round flask was charged with 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (1700 mg, 8.16 mmol), lithium monohydrate (1370 mg, 32.7 mmol), methanol (25 mL) and water (10 mL). The mixture was heated at 80° C. for 2 hours. The reaction mixture was rotavaped. The residue was neutralized with 4N hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over sodium sulfate and evaporated to give 1.61 grams of white solid as desired product. LC-MS m/e 179 (MH−).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]([C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)=[CH:10][N:9]=[CH:8]1.F.O>O1CCCC1>[O:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:20][CH:21]=2)=[CH:10][N:9]=[CH:8]1
Reactant: COC(=O)c1ccc(-c2cnco2)cc1
Agent: F
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2cnco2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A solution (2.08 mL) of lithium aluminum hydride (2.4 mole) in tetrahydrofuran was added dropwise under ice cooling to a solution of methyl 4-(1,3-oxazol-5-yl)benzoate (1.02 g) in tetrahydrofuran (20 mL), followed by stirring at 0° C. for 30 minutes. Hydrogen fluoride (840 mg) and water (270 mL) were added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through flash column chromatography (n-hexane:ethyl acetate=3:2), followed by concentration under reduced pressure, to thereby yield the title compound (321 mg).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:16])=[O:17]
Reactant: CC(O)CCO
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 1,3-butane diol (2.18 g, 24 mmol) and TEA (1.64 g, 16 mmol) in CH2Cl2 (15 mL) at 0° C. was added o-(trifluoromethyl)benzenesulfonyl chloride (2 g, 8 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 45 min. The organics were extracted with CH2Cl2 (150 mL) and washed with 0.5 M HCl (2×80 mL) and saturated aqueous NaCl (1×50 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography (50% ethyl acetate in hexanes) yielded the desired product (2 g, 84%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.92 (m, 1H), 7.74 (m, 2H), 4.34 (m, 1H), 4.24 (m, 1H), 3.95 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.20 (d, 3H, J=6.3 Hz). Anal. Calcd. For C11H13F3O4S: C, 44.29; H, 4.39. Found: C, 44.29; H, 4.28.
Reaction SMILES: Br[C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][OH:9])[CH:3]=1.[CH3:10][N:11](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:7][C:5]1[S:6][C:2]([C:10]#[N:11])=[CH:3][C:4]=1[CH2:8][OH:9]
Reactant: OCc1cc(Br)sc1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(CO)c(Cl)s1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 25.0 g (5-bromo-2-chlorothiophen-3-yl)methanol in 330 mL of dimethylformamide, 25.8 g of zinc cyanide (I) and 12.7 g tetrakis(triphenylphosphine)palladium(0) were added at room temperature, and stirred at 100° C. for 4 hours. Diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:5), to afford 16.0 g of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)(=O)C(Cl)=O.O[C:24]1[CH:59]=[CH:58][C:27]([CH2:28][N:29]([CH2:50][C:51]([O:53]C(C)(C)C)=[O:52])[C:30](=[O:49])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:48])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:33][CH:32]=2)=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][C:24]2[CH:59]=[CH:58][C:27]([CH2:28][N:29]([CH2:50][C:51]([OH:53])=[O:52])[C:30](=[O:49])[C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:48])[CH2:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=4)=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:13])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(hexyloxy)benzoic acid (26 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 30 min. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 2 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to yield 18.2 mg (35%) of 2-(N-(4-((4-(hexyloxy)benzoyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido) acetic acid 18. LCMS-ESI (m/z) calculated for C38H40N2O8: 652; found 651 [M−H]−, tR=9.01 min (Method 4). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.25 (s, 1H), 8.10-7.99 (m, 2H), 7.68-7.62 (m, 2H), 7.50-7.19 (m, 8H), 7.17-7.07 (m, 2H), 6.91-6.84 (m, 2H), 4.70-4.54 (d, J=35.9 Hz, 2H), 4.12-4.04 (t, J=6.5 Hz, 2H), 4.00-3.86 (d, J=34.1 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H), 1.79-1.69 (m, 2H), 1.47-1.38 (m, 2H), 1.37-1.28 (ddd, J=7.6, 3.9, 2.1 Hz, 4H), 0.91-0.84 (m, 3H).