Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]2[N:6]=[C:7]([CH2:9][CH:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[NH:8][C:4]=2[CH:3]=1.[ClH:27]>C(O)(=O)C>[Cl:26][C:25]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([CH2:9][CH:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:11][C:12]([OH:14])=[O:13])[NH:6][C:5]=2[CH:24]=1.[ClH:27]
Reactant: CCOC(=O)CC(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)c1ccc(Cl)cc1

Procedure:
The solution of ethyl 4-(5,6-dichloro-2-benzimidazolyl)-3-(4-chlorophenyl)butanoate (0.31 g) in a mixture of acetic acid (2 ml) and conc. HCl (0.5 ml) was heated to reflux for 1 h. Then all volatiles are removed at the water aspirator. The residue is dried by distillation with toluene (50 ml) and triturated with boiling acetone (5 ml). The precipitate is collected by filtration, washed with acetone and dried in vacuo to yield 4-(5,6-dichloro-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid•HCl (0.26 g) as colourless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[CH2:16][C:17]([NH2:19])=O.O.[OH-].[Na+]>O1CCCC1>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH:8]1[CH2:16][CH2:17][NH2:19]
Reactant: NC(=O)CC1Cc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Suspended in 400 ml of tetrahydrofuran were 8.77 g (0.23 mol) of lithium aluminum hydride, and a suspension of 27.8 g (0.160 mol) of (indan-2-yl)acetamide in 100 ml of tetrahydro-furan was added under chilling with ice water. After stirring for 30 minutes at room temperature, the suspension mixture was refluxed for 5 hours. While chilling with ice water, 9 ml of water, 9 ml of 15% sodium hydroxide and 26 ml of water were added dropwise in that order to decompose excess of the reagents. Solids were separated by filtration, and the filtrate was concentrated, thereby obtaining 26.1 g of an oily substance. Yield: 100%.
Reaction SMILES: [NH:1]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4].[C:18](=O)([O:23]C1C2N=NNC=2C=CC=1)[O:19][CH2:20][CH:21]=[CH2:22]>>[NH:1]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH2:3][O:4][C:18]([O:19][CH2:20][CH:21]=[CH2:22])=[O:23]
Reactant: C=CCOC(=O)Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)OC(=O)[C@H](CO)NN1CCOCC1
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C

Procedure:
Morpholino-Ser(OAloc) was prepared from Ser(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]=O>C(OCC)(=O)C>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccc2ccccc2c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
To a solution of t-butyl carbazate (7.59 g, 57.4 mmol) in ethyl acetate (22 mL) was added with stirring 2-napthaldehyde (8.98 g, 57.5 mmol). This clear yellow solution was stirred at rt for 15 min. Hexanes (105 mL) was added dropwise and solids precipitated from solution. The slurry was cooled to 0° C., the solids were then filtered and rinsed with cold hexanes (20 mL). A second crop of solids was obtained from the filtrate, filtered and combined with the first crop. The combined solids were recrystallized (EtOAc) and filtered. A second crop was collected by concentrating the filtrate to half its original volume and filtering the resulting solids at 0° C. The two crops of solids were combined and dried in vacuo at 40° C. to afford the title compound as a solid (13.17 g, 85.0%): mp 182.1-190° C. (dec.); 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.93-7.86 (m, 4H), 7.52-7.49 (m, 2H), 1.47 (s, 9H); 13C N (DMSO-d6) δ 153.1, 143.9, 134.1, 133.6, 133.1, 129.1, 128.9, 128.5, 128.4, 127.5, 127.3, 123.1, 80.1, 28.8; IR (CHCl3) 3061, 3010, 2982, 1733, 1505, 1369 cm−1; Anal. Calcd. for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 70.95; H, 6.89; N, 10.31.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]([NH:21][C@@H:22]([CH2:28][OH:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCCC1>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:10]([C:19]1[O:29][CH2:28][C@@H:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H](CO)NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Yield: 78.4 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-({[(1S)-2-ethoxy-1-(hydroxymethyl)-2-oxoethyl]amino}carbonyl)hexanoate (Preparation 60) (4.14 g, 10 mmol) in anhydrous tetrahydrofuran (40 ml) was treated with (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt [Burgess Reagent] (2.62 g, 11 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 1 hour. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (80:20) to (50:50) to afford the title compound as a colourless oil (3.10 g)
Reaction SMILES: S(=O)(=O)(O)O.C([CH:8]([C:30]([O:32]CC)=[O:31])[C:9]1[CH:10]=[C:11]([C:18](C)([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])#N>C(O)(=O)C.O>[C:30]([CH2:8][C:9]1[CH:10]=[C:11]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])([OH:32])=[O:31]
Reactant: CCOC(=O)C(C#N)c1cc(C(C)(C(=O)OCC)C(=O)OCC)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc([N+](=O)[O-])c(CC(=O)O)c1
Yield: 75 %

Procedure:
In acetic acid (1 mL) was dissolved diethyl 2-[3-[cyano(ethoxycarbonyl)methyl]-4-nitrophenyl]-2-methylmalonate (obtained in the same manner as in Example 5, 406 mg, 1 mmol.). The solution was heated for 36 hours under reflux, after addition of water (0.9 mL) and concentrated sulfuric acid (0.1 mL). The reaction mixture was diluted with water, and then extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to give 189 mg (yield: 75%) of the desired compound as a brown crystalline product.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH2:14].C1C=CC=CC=1.Cl[S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][S:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:32][CH:33]=1)(=[O:24])=[O:23]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc2c3c(c1)CCCC3CCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
5,6,6a,7,8,9-Hexahydro-4H-2-phenalenylamine (0.130 g) was dissolved in pyridine (5 ml) and anhydrous benzene (2 ml), the solution was added with 4-chlorosulfonylbenzoic acid (0.161 g) and 4-dimethylaminopyridine (one pellet), and the mixture was stirred overnight at room temperature. The reaction mixture was made to be at 60° C., stirred for 3 hours, left to cool, then added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.194 g, yield: 75%) as brown needles (melting point: 266-268° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.[OH-].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: OB(O)c1c(F)cccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(O)c1ccnc(-c2c(F)cccc2F)n1
Temperature: 120 °C

Procedure:
To a solution of 2-chloropyrimidine-4-carboxylic acid (1.0 equiv.) in DME and 2M Na2CO3 (3:1, 0.25 M) was added 2,6-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120° C. for 30 minutes. The mixture was diluted with ethyl acetate and 1N NaOH was added. The organic phase was separated and extracted three more times with 1N NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH 1 by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 2-(2,6-difluorophenyl)pyrimidine-4-carboxylic acid in 81%. LCMS (m/z): 237.0 (MH+), Rt=0.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.O.O[N:28]1[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1>CN(C)C=O>[ClH:1].[NH2:28][C@@H:32]1[CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N[C@@H]1CCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 23 h
Yield: 188.6 %

Procedure:
The compound obtained in Referential Example 61 (1.40 g) was dissolved in N,N-dimethylformamide (15 mL), and to the solution were added 5-chloroindole-2-carboxylic acid (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g), and 1-hydroxybenzotriazole monohydrate (473 mg), followed by stirring at room temperature for 23 hours. The solvent was distilled away under reduced pressure, and to the residue were added methylene chloride and saturated aqueous sodium hydrogencarbonate. The resultant precipitate was collected by filtration, and the precipitate was washed with ethyl acetate, methylene chloride, and methanol. Aside from this, the filtrate was partitioned, and the organic layer was separated, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride:methanol=19:1), to thereby give a pale-yellow solid. This pale-yellow solid was combined with the precipitate collected by the above-described filtration, and this mixture was dissolved in methylene chloride (10 mL). Trifluoroacetic acid (10 mL) was added thereto, and the thus-obtained mixture was stirred at room temperature for 3 hours. The solvent was distilled away under reduced pressure, and to the residue were added methylene chloride and 1N aqueous sodium hydroxide. The resultant precipitate was collected by filtration. The organic layer of the filtrate was separated, and was dried over sodium sulfate anhydrate. To the solution was added the precipitate collected by the above-described filtration, and a 4N HCl-dioxane solution (20 mL) was added thereto. The solvent was distilled away under reduced pressure, and after methylene chloride (10 mL) and a 4N HCl-dioxane solution (10 mL) were added to the residue, the solvent was distilled away again under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration, to thereby give the title compound (1.83 g).
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][C@@H:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[O:6])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:2]2([C:5](=[O:6])[NH:7][C@@H:8]3[CH2:14][CH2:13][C:12]4[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=4[N:10]4[CH:19]=[CH:20][N:21]=[C:9]34)[CH2:3][CH2:4]2)=[O:28])=[CH:25][CH:24]=1
Reactant: NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Yield: 79.2 %

Procedure:
Combine 1-amino-N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]cyclopropanecarboxamide (160 mg, 0.57 mmol), 4-chlorobenzoic acid (106 mg, 0.68 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (259.0 mg, 0.68 mmol;) in N,N-dimethylformamide (4 mL). Add diisopropylethylamine (DIEA) (0.25 mL, 1.42 mmol) and stir the reaction at ambient temperature for approximately 5 hours under nitrogen. Dilute the reaction with ethyl acetate, wash with sodium bicarbonate, water (2×), and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (40% EtOAc/hexanes to 100% EtOAc) to give the title compound (190.0 mg, 80%): MS (m/z): 421 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68]>CN(C=O)C>[C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:33]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:65][CH2:66][C:67]([OH:69])=[O:68])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)no2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)O)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Prepared using General Procedures 7 and 8: To a solution of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid, Compound 2 (10.0 mg, 0.017 mmol) in anhydrous DMF (1 mL) was added HOBt (3.52 mg, 0.027 mmol) and EDCI (4.88 mg, 0.027 mmol) at RT. After 2 h, tert-butyl 2-aminoacetate (3.49 mg, 0.027 mmol) was added and the reaction mixture stirred at RT for 2 h. LCMS analysis showed complete conversion to the intermediate. The reaction mixture was partitioned between NaHCO3 aqueous (5 ml) and DCM (1 mL), the organic layer was collected and concentrated by vacuum and then was re-dissolved in 1 mL of DCM and 0.1 mL of TFA. The mixture was heated to 30° C. for 3 h. The final compound was purified by HPLC to afford 9.6 mg (88%) of (S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamido)acetic acid. LCMS-ESI (m/z) calculated for C37H44N4O6: 640.3; no m/z observed, tR=11.51 min (Method 2). 1H NMR (400 MHz, DMSO) δ: 8.60 (d, J=8.4 Hz, 1H), 8.47 (t, J=5.7 Hz, 1H), 8.10 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 4.83 (d, J=8.1 Hz, 1H), 4.09 (t, J=6.4 Hz, 2H), 3.94-3.69 (m, 2H), 3.34 (s, 2H), 3.26 (d, J=13.5 Hz, 1H), 3.15-3.01 (m, 1H), 1.83-1.65 (m, 2H), 1.50-1.15 (m, 16H), 0.87 (t, J=6.7 Hz, 3H). 13C NMR (101 MHz, DMSO) δ: 175.12, 171.58, 171.13, 167.99, 166.02, 162.54, 154.10, 142.44, 131.16, 130.02, 129.89, 127.23, 126.81, 124.91, 124.25, 115.50, 115.36, 67.97, 54.23, 40.10, 37.12, 34.57, 31.19, 30.88, 28.46, 28.37, 25.36, 22.02, 13.93.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:9])[CH:7]=[CH2:8].[O:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>O>[C:6]([CH:7]1[CH2:8][CH:16]2[O:15][CH:19]1[CH:18]=[CH:17]2)([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9]
Reactant: C=CC(=O)OCCCC
Reactant: c1ccoc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: CCCCOC(=O)C1CC2C=CC1O2
Reaction time: 1 h

Procedure:
3.3 g (0.013 Mol) SnCl4 is added to 64 g (0.5 Mol) butyl acrylate and dissolved with stirring. Then during cooling to 20° to 25° C., 34 g (0.5 Mol) furane is added drop-wise. The exothermic reaction finishes after one hour, after which stirring is continued for one hour at 25° C. and 30 g of water added. The organic phase is separated. First, the unconverted furane is distilled off under a pressure of 10 Torr, and then the residue is distilled under a pressure of 0.02 Torr. The 2-carbobutoxy-7-oxabicyclo(2.2.1)hept-5-ene boils at 65° C. and is obtained in a yield of 34.3 g (35% of the theoretical).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[OH:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[CH2:22][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=2)[C:9]=1[OH:15]
Reactant: COc1ccc(CBr)cc1OC
Reactant: COc1cc(COc2cccc(O)c2O)cc(OC)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(COc2cccc(OCc3ccc(OC)c(OC)c3)c2O)cc(OC)c1
Yield: 31.9 %

Procedure:
3-(3,5-Dimethoxybenzyloxy)-benzene-1,2-diol (0.28 g, 1.03 mmol), 4-bromomethyl-1,2-dimethoxy-benzene (0.24 g, 1.03 mmol), potassium carbonate (0.14 g, 1.03 mmol) and 18-crown-6-ether (0.03 g, 0.11 mmol) were stirred together at room temperature in acetone (30 cm3, 99%) under nitrogen for 21 hours. The solution was evaporated under reduced pressure, and the residue was taken up in dichloromethane (10 cm3) and water (10 cm3). The aqueous layer was extracted with dichloromethane (2×10 cm3), and the combined extracts were washed with water (2×40 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was taken up in diethyl ether (30 cm3) and washed with sodium hydroxide (2×15 cm3, 3% aqueous solution). The sodium hydroxide portion was saturated with solid carbon dioxide pellets and extracted with diethyl ether (3×30 cm3). The extracts were evaporated under reduced pressure to give a crude oil. The oil was chromatographed (SiO2, heptane:ethyl acetate, 1:1) to give the phenol, (0.14 g, 31%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O1CCCC1.C([O-])=O.[NH4+]>[Fe].O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 75 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
tert-Butyl 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylate (1.25 g, 3.90 mmoles), 1 equivalent), tetrahydrofuran (10 ml), water (10 ml), iron dust (1.09 g, 19.5 mmoles, 5 equivalents), and ammonium formate (1.23 g, 19.5 mmoles, 5 equivalents) were combined and heated, with stirring to 75° C. for 12 hours (overnight). The hot mixture was filtered through a plug of Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with water and saturated sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.11 g of tert-butyl 4-(4-amino-3-methylphenyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3), δ 6.47 (d, 1H), 6.16 (d, 1H), 6.14 (d, 1H), 5.85 (bs, 2H), 3.35 (m, 4H), 3.19 (m, 4H), 2.35 (s, 3H), 1.42 (s, 9H). MS (EI) for C16H25N3O2, 292 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=O)[CH2:4]1.[CH3:10][O:11][NH:12][CH3:13].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.ClCCl>[CH3:10][O:11][N:12]([CH3:13])[C:7]([CH:5]1[CH2:4][CH:3]([O:2][CH3:1])[CH2:6]1)=[O:9]
Reactant: CNOC
Reactant: COC1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1CC(C(=O)N(C)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dichloromethane (20 mL) was added to the vial containing 3-methoxycyclobutanecarboxylic acid (1:1 isomers, 1500 mg, 11.53 mmol), N-methoxymethanamine.HCl (1514 mg, 15.53 mmol) and HATU (6570 mg, 17.3 mmol). Hunig's base (8.03 mL, 46.1 mmol) was then added. The mixture was stirred at room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc three times. Insoluble solids were observed in the aqueous layer. The combined organic layers were washed with brined, dried over Na2SO4 and concentrated. The crude was dissolved in EtOAc and loaded to the column and purified by CombiFlash (40 g silica gel, EtOAc/heptane: 0->50%), leading to less polar diastereomer A and slightly more polar diastereomer B. Diastereomer A: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.09-2.25 (m, 2H) 2.43-2.57 (m, 2H) 3.17 (s, 3H) 3.23 (s, 3H) 3.43 (m, 1H) 3.63 (s, 3H) 3.98-4.09 (m, 1H). GCMS: observed 173 for C8H15NO3.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:12]=2)[CH:15]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)CC(=O)CCCl
Solvent: CCO
Product: CCOC(=O)CCc1cn2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 13903.8 %

Procedure:
4.28 mg of ethyl 5-chloro-3-oxopentanoate was dissolved in 40 ml of ethanol, 2.94 g of 2-amino-5-bromopyridine was added and the mixture was stirred all night by heating under reflux. The mixture was cooled down to room temperature, and the solvents were distilled outunder reduced pressure. Ethyl acetate followed by saturated sodium bicarbonate aqueous solution were added. Organic layer was dried with anhydrous sodium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by preparative thin-layer silicagel chromatography (hexane:ethyl acetate=50:50) to obtain 990 mg of the above compound as crude product.