Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:32])([CH3:31])[CH2:3][C@@:4]1([CH:28]([CH3:30])[CH3:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:25]([C:22]2[N:21]=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:32])[CH3:31])([CH:28]([CH3:29])[CH3:30])[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[CH:24][N:23]=2)=[O:26])[CH2:35][CH2:34]1
Reactant: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(-c3cnc(C(=O)O)nc3)cc2)C(=O)O1
Reactant: NC1CC1
Product: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(-c3cnc(C(=O)NC4CC4)nc3)cc2)C(=O)O1

Procedure:
The title compound was prepared from 5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxylic acid and cyclopropylamine following a procedure analogous to that described in Example 25 Step 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a solution of methyl 2-(5-fluoro-1-benzofuran-2-yl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.38 mmol) in methanol (50 mL) was added sodium hydroxide (150 mg, 3.75 mmol) and water (2 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with HCl (3N) and filtered to give 2-(5-fluoro-1-benzofuran-2-yl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (36.5 mg, 25%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][O:11][CH2:12]3)[CH:5]=[C:4]([Cl:16])[N:3]=1.[I-:17].[Na+].I>C(Cl)(Cl)Cl.O>[Cl:16][C:4]1[N:3]=[C:2]([I:17])[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][O:11][CH2:12]3)[CH:5]=1
Reactant: Clc1cc(N2C3CCC2COC3)nc(Cl)n1
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1cc(N2C3CCC2COC3)nc(I)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
In a 250 mL round-bottomed flask was placed 8-(2,6-dichloropyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (34, 980 mg, 3.77 mmol) in chloroform (4 ml) to give a very light yellow solution. Sodium iodide (941 mg, 6.28 mmol) was added to give a suspension. The mixture was cooled to 0° C. and an aqueous solution (57% w/w) of hydrogen iodide (4.97 ml, 37.7 mmol) was added, resulting in a yellow precipitate. The mixture was slowly warmed to room temperature and stirred at room temperature for 4 h. The mixture was diluted with water and quenched with NaOH (5M) to pH˜8. Aqueous sodium thiosulfate was added to decolorize. The mixture was extracted with dichloromethane, dried over MgSO4 and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-40%). Collected fractions were concentrated to give the title compound (516 mg) as a white solid. LCMS analysis revealed that the product contained ˜20% starting material. The mixture was used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])([O-])=O.[OH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: COc1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
40 g of 2-nitro-4-methoxyphenol were stirred into a mixture of 200 ml of water and 200 ml of 35% strength sodium hydroxide solution in the dark. 100 g of sodium thiosulfate were added to the reaction mixture and the mixture was stirred at room temperature for a further 2 hours. For work-up, the reaction mixture was neutralized by the addition of 12N hydrochloric acid solution and extracted four times with 500 ml of ethyl acetate. The organic extracts were washed twice with 500 ml of water, dried, filtered and evaporated. 30 g of 2-amino-4-methoxyphenol were obtained as a residue and further processed without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[NH2:5].[N:22](OCCC(C)C)=O.C(O)(=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4](=[N+:5]=[N-:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 2.5 g (8.77 mmol) O-benzyl tyrosine methyl ester, 1.03 g (8.77 mmol) isoamyl nitrite, and 1.57 g (26.2 mmol) glacial acetic acid in chloroform (65 mL) was stirred and refluxed 15 min and then cooled to RT. The solution was concentrated to an oily residue, dissolved in EtOAc (100 mL), and washed with 5% NaHCO3. The organics were then dried (MgSO4), filtered, and concentrated to an oily residue which was chromatographed on silica gel using Hexane/EtOAc (1:1) to yield the title compound. 1H NMR (CDCl3) δ 7.43-7.31 (m, 5H) 7.14 (d, 2H, J=8.7) 6.90 (m, 2H) 5.03 (s, 2H) 3.76 (s, 3H) 3.56 (s, 2H).
Reaction SMILES: [CH:1]1([C@H:4]([OH:9])[CH2:5]/[CH:6]=[CH:7]/[CH3:8])[CH2:3][CH2:2]1.[CH2:10]([O:12][CH:13]([O:29][CH2:30][CH3:31])[CH2:14]O[C@H](CC=C)COCC1C=CC=CC=1)[CH3:11]>>[CH2:10]([O:12][CH:13]([O:29][CH2:30][CH3:31])[CH2:14][O:9][C@@H:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5]/[CH:6]=[CH:7]/[CH3:8])[CH3:11]
Reactant: C/C=C/C[C@@H](O)C1CC1
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Product: C/C=C/C[C@@H](OCC(OCC)OCC)C1CC1

Procedure:
(1R,3E)-1-Cyclopropylpent-3-en-1-ol (C24) was converted to the product according to the method used for the synthesis of ({[(2R)-2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2) in Preparation P1, except that all reagents were combined at 0° C. The product was obtained as a colorless oil. Yield: 550 mg, 2.27 mmol, 48%. 1H NMR (400 MHz, CDCl3) δ 5.44-5.59 (m, 2H), 4.62 (dd, J=5.3, 5.3 Hz, 1H), 3.66-3.76 (m, 3H), 3.54-3.63 (m, 2H), 3.47 (dd, J=10.3, 5.5 Hz, 1H), 2.65 (dt, J=8.5, 5.9 Hz, 1H), 2.28-2.33 (m, 2H), 1.65-1.68 (m, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 0.79-0.88 (m, 1H), 0.53-0.60 (m, 1H), 0.42-0.50 (m, 1H), 0.34-0.41 (m, 1H), 0.06-0.13 (m, 1H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[Br:23]>>[Br:23][C:13]1[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][O:16][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: Nc1onc(-c2ccccc2)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1onc(-c2ccccc2)c1Br)c1ccccc1
Yield: 36 %

Procedure:
This compound was prepared from benzenesulfonyl chloride and 5-amino-4-bromo-3-phenylisoxazole according to the method in Example 25b in 36% yield. Recrystallization from methanol gave a yellow solid, m.p. 113-115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](OC(F)(F)F)=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[C:10]([O:30][CH3:31])[CH:9]=2)[CH:7]=1.[F:34]C1C=CC(S(Cl)(=O)=O)=CC=1.FC1C=CC(OC)=C(C2C=CC(CN)=C(OC)C=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([F:34])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[C:10]([O:30][CH3:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cc(-c2cc(F)ccc2OC)ccc1CNS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: COc1cc(-c2cc(F)ccc2OC)ccc1CN
Product: COc1cc(-c2cc(F)ccc2OC)ccc1CNS(=O)(=O)c1ccc(F)cc1

Procedure:
Prepared in a similar manner to N-(5′-Fluoro-3,2′-dimethoxy-biphenyl-4ylmethyl)-4-trifluoromethoxy-benzenesulfonamide (Example 16) starting with 4-fluorobenzene sulfonyl chloride and C-(5′-fluoro-3,2′-dimethoxy-biphenyl-4-yl)-methylamine. Title compound: 1H NMR (400 MHz, CDCl3): 7.7-7.8 (m, 2H), 7.0-7.1 (m, 2H), 6.85-7.15 (m, 6H), 5.06-5.15 (m, 1H), 4.21 (d, 2H), 3.76 (s, 3H), 3.77 (s, 3H) ppm; MS (ESI) m/z: 442.0 [M+Na]+.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[CH3:6][C:2]1([CH3:7])[O:1][C:17](=[O:18])[CH2:16][O:4][C:3]1=[O:5]
Reactant: CC(C)(O)C(=O)O
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)COC1=O
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a flask containing two liters of chloroform, 1 mole of 2-hydroxy-isobutyric acid (104.1 gms.) and 2.2 moles of triethylamine (224 gms.), cooled in an ice bath, was slowly added 1 mole of chloroacetyl chloride (127 gms.). Addition took one hour. The chloroform was evaporated to yield a reddish semi-solid which was triturated several times with acetone followed by decantation of the reddish acetone extract. The white solid residue was triethylamine hydrochloride. The acetone extracts were combined and concentrated under vacuum to a red oil which was distilled under vacuum. The fraction distilling at 103°-110°C./0.7-0.9 torr. was collected. This fraction solidified to a green semi-solid which was recrystallized from isopropyl alcohol and then sublimed at 75°C./0.1 torr. to yield 15 grams of white solid, m.p. 82°-83°C. This was dissolved in 3000 ml. of benzene at 10°C. and extracted successively with three 300 ml. portions of 0.01 N HCl solution saturated with sodium chloride in a separatory funnel, and the benzene layer quickly dried by filtration through a bed of anhydrous sodium sulfate into a flask containing anhydrous magnesium sulfate. After the removal of the magnesium sulfate by filtration and the benzene under vacuum, the solid 3,3-dimethyl-1,4-dioxane-2,5-dione was recrystallized from isopropyl alcohol and sublimed at 75°C/0.1 torr. to yield 13 grams of solid, m.p. 85°-86°C., % C found = 50.00 vs. 50.00 calculated, % H found = 5.52 vs. 5.60 calculated.
Reaction SMILES: [Li+].[OH-].[CH3:3][CH:4]([CH3:34])[CH2:5][CH2:6][CH:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].Cl>O.C1COCC1>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][CH:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=1)[CH2:6][CH2:5][CH:4]([CH3:3])[CH3:34]
Reactant: COC(=O)C[C@@H]1CCN(C(CCC(C)C)CCC(C)C)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCC(CCC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 97.8 %

Procedure:
A solution of LiOH (1.6 g, 67 mmol) in H2O (15 ml) was added to a stirred solution of methyl {(2S,4R)-1-[4-methyl-1-(3-methylbutyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Step 1, 6.0 g, 13.2 mmol) in THF (15 ml) at RT. The mixture was stirred and heated at 60° C. for 18 hrs. After cooling to RT 2N HCl (35 ml) was added and the THF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The pH of the aqueous layer was adjusted to pH7 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (×3). The combined extracts were dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography (silica, 4-8% MeOH/CH2Cl2) to give the acid (5.7 g) as a colourless solid. 1H NMR (500 MHz, CD3OD): δ 0.68-0.75 (1H, m), 0.83-0.87 (12H, m), 0.97-1.09 (2H, m), 1.10-1.17 (1H, m), 1.32-1.50 (7H, m), 1.69-1.75 (1H, m), 1.86-2.00 (3H, m), 2.16-2.24 (2H, m), 2.25-2.31 (1H, m), 2.54 (1H, t, J 11.6), 3.17 (1H, d, J 11.8), 3.93 (1H, d, J 10.3), 7.54 (2H, brd, J 7), 7.65 (2H, d, J 8.2); M/Z (ES+) 442 (MH+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=[O:21])[O:19][C:17](=O)[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].Cl.[CH2:25]([O:27][C:28](=[O:38])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH2:30])[CH3:26]>C1(C)C=CC=CC=1.C(OCC)C>[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=[O:21])[N:30]([C@@H:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:27][CH2:25][CH3:26])=[O:38])[C:17](=[O:19])[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Diisopropylethylamine (24 ml, 0.138 mole) (Aldrich) was added to a suspension of 4-nitrophthalic anhydride (25 g, 0.13 mole) (Tokyo Kasei) and L-glutamic acid diethyl ester hydrochloride (35 g, 0.146 mole) (Aldrich) in toluene (130 ml). The reaction mixture was stirred at reflux utilizing a Dean-Stark trap for 2.5 hours. After cooling, the solution was diluted with diethyl ether (300 ml), washed with water (75 ml), saturated NaHCO3 solution (50 ml), dried (MgSO4), and concentrated in vacuo at 70° C. to give diethyl (S)-2-(4-nitrophthalimido)glutarate as an oil that solidified to a white solid on standing (35.8 g). M.P.=65.5°-66.5° C. 1H NMR (DMSO-d6, 300 MHz) δ: 1.12 (t, J=7 Hz, 3H, ester CH3), 1.14 (t, J=7 Hz, 3H, ester CH3), 2.2-2.5 (m, 4H, glu CH2CH2), 3.96 (q, J=7 Hz, 2H, ester CH2), 4.08-4.19 (m, 2H, ester CH2), 4.97-5.04 (m, 1H, glu CH), 8.19 (dd, J=8,0.5 Hz, 1H, Ar), 8.56 (dd, J=2,0.5 Hz, 1H, Ar), 8.68 (dd, J=8,2 Hz, 1H, Ar). Mass spectrum (CI-CH4); 379 (M+1, 28.8%), 333 (71.6%), 305 (100%). Anal. Calculated for C17H18N2O8 : C, 53.97; H, 4.80; N, 7.40. Found: C, 53.89; H, 4.82; N, 7.42.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10](C)[C:11](=O)OC(C)(C)C)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1cc(Br)cn(C)c1=O
Temperature: 30 °C
Yield: 66.6 %

Procedure:
To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-methylcarbamate (94.8 mg, crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise with stirring at 30° C. The reaction mixture was stirred at 30° C. for 30 min. The mixture was filtered and the filter cake collected. The filtrate was adjusted to pH=9 with saturated aqueous NaHCO3, extracted with ethyl acetate (20 mL), dried over Na2SO4, filtered and concentrated to give a green solid which was combined with the filter cake to give the title compound (43.2 mg). 1H NMR (CDCl3 400 MHz): δ 6.74 (d, J=2.4 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 5.15 (s, 1H), 3.53 (s, 3H), 2.83 (s, 3H). LCMS (M+H)+ 217
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)(O)[O-].[Na+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH2:14][CH2:15]2)=[N:2]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C

Procedure:
A suspension of 4-(1H-indazol-3-yl)piperazine (1.6 g, 7.9 mmol), N-(2-bromoethyl)phthalimide (2.1 g, 7.9 mmol), and sodium bicarbonate (0.7 g, 8.3 mmol) in acetonitrile (160 ml) was warmed to reflux for 24 hours. Upon cooling to room temperature, the reaction mixture was filtered through a pad of celite and the solids were washed with DCM. The combined filtrates were concentrated to give the N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide which was used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[N:23][OH:24])[NH2:22])=[CH:17][CH:16]=1)[CH2:3][N:4]1[CH2:7][CH:6]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:5]1.CCN(C(C)C)C(C)C.[C:34]1([C:40]2[C:44]([C:45]([F:48])([F:47])[F:46])=[C:43]([C:49](F)=O)[O:42][N:41]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C.C(OCC)(=O)C>[OH:1][CH:2]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:49]([C:43]3[O:42][N:41]=[C:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:44]=3[C:45]([F:48])([F:46])[F:47])[O:24][N:23]=2)=[CH:19][CH:20]=1)[CH2:3][N:4]1[CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)C1CN(CC(O)c2ccc(C(N)=NO)cc2)C1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)C1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 1-(2-hydroxy-2-(4-(N′-hydroxycarbamimidoyl)phenyl)ethyl)azetidine-3-carboxylate (111 mg, 0.33 mmol) and DIEA (0.115 mL, 0.660 mmol) in acetonitrile (10 mL) was added 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, Int-I-G (86 mg, 0.33 mmol). After 1 hour, TBAF (0.330 mL, 0.330 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. Crude residue was treated with TFA/DCM to remove t-butyl ester. The resulting material was concentrated in vacuo and purified by HPLC to yield 36 mg of 1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidine-3-carboxylic acid as the tetrabutylammonium salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.22 (2H, d, J=8.35 Hz), 7.68 (4H, d, J=8.35 Hz), 7.53-7.65 (3H, m), 5.04 (1H, dd, J=10.11, 3.08 Hz), 4.45 (4H, t, J=9.89 Hz), 3.73 (1H, br. s.), 3.36-3.62 (2H, m). MS (m+1)=501. HPLC Peak RT=3.23 minutes (Analytical Method A). Purity=98%.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.CCCCCC.C([Li])CCC.C([N:24]([CH2:33][CH3:34])[C:25]([C:27]1[CH:31]=[CH:30][O:29][C:28]=1[CH3:32])=[O:26])C.[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]CC#N)=[CH:40][CH:39]=1)[CH3:36].Cl>C1COCC1>[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:34][C:33]2[NH:24][C:25](=[O:26])[C:27]3[CH:31]=[CH:30][O:29][C:28]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCOc1ccc(CCC#N)cc1
Reactant: CCN(CC)C(=O)c1ccoc1C
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(CCc2cc3occc3c(=O)[nH]2)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (11.6 mL, 68.8 mmol) in THF (100 mL) was added 1.6 M n-butyllithium hexane solution (39.0 mL, 62.4 mmol) at −78° C., and the mixture was warmed to −20° C. and stirred at the same temperature for 10 min. To this solution was added a solution of N,N-diethyl-2-methylfuran-3-carboxamide (11.3 g, 62.5 mmol) in THF (10 mL), and the mixture was further stirred for 1 hr. To the solution was added 3-(4-ethoxyphenyl)propanenitrile (11.5 g, 65.6 mmol), and the mixture was stirred at room temperature for hr. 6N Hydrochloric acid was added thereto and the mixture was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (2.74 g, yield 15%) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11].O>C1COCC1>[F:7][C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1ccc(OC)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CO)c(F)c1
Reaction time: 0.5 h
Yield: 104 %

Procedure:
To a suspension of LiAlH4 (71.6 mg, 1.89 mmol) in THF (3 ml) was added dropwise a solution of methyl 2-fluoro-4-methoxybenzoate (273.3 mg, 1.48 mmol) in THF (3 ml). The mixture was stirred for 0.5 hours. To the mixture was added dropwise aqueous THF followed by water. The mixture was extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated to give the crude title compound (240.4 mg; >99%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C:10]([OH:12])=[O:11])[O:5][N:4]=1.CCN(CC)CC.[CH3:29][C:30]([O:33][C:34](ON=C(C1C=CC=CC=1)C#N)=[O:35])([CH3:32])[CH3:31]>O1CCOCC1.O>[C:30]([O:33][C:34]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:9][C:10]([OH:12])=[O:11])[O:5][N:4]=1)=[O:35])([CH3:32])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A solution of (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid (preparation 163) (177 mg, 0.53 mmol) and Et3N (186 μl, 1.33 mmol) in dioxan (500 μl) and H2O (500 μl) was treated with Boc-ON (145 mg, 0.58 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (×2). The organic extracts were combined and the solvent removed under reduced pressure. The crude material was purified on a silica column eluting with DCM:MeOH (100:0) gradually changing to (90:10) to afford the title compound as a colourless gum (115 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH:21][C:22](=[O:30])[CH2:23][C:24]([C:26]([F:29])([F:28])[F:27])=O)=[C:4]([F:31])[CH:3]=1.C(O)(=O)C.[O-:36][C:37]#[N:38].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:21]2[C:22](=[O:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[NH:38][C:37]2=[O:36])=[CH:6][C:7]=1[O:8][C:9]1[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a mixture of 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide and 2 ml of acetic acid, 0.33 g of potassium cyanate was added, and the mixture was stirred at 50° C. for 1 hour, then, at 110° C. for 1.5 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.30 g of 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.