Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][C@:10]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29]>>[CH3:29][O:28][N:27]([CH3:26])[C:13]([C@H:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][C@@:10]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:11]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1C[C@@]2(C[C@H]1C(=O)O)C(=O)Nc1ccccc12
Agent: Cl
Product: CON(C)C(=O)[C@@H]1C[C@]2(CN1C(=O)OC(C)(C)C)C(=O)Nc1ccccc12

Procedure:
(3S,5′S)-tert-butyl 5′-(methoxy(methyl)carbamoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 10, Step 5, substituting (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid with (3S,5′S)-1′-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxylic acid, and substituting NH4Cl with N,O-dimethylhydroxylamine hydrochloride. LCMS (APCI+) m/z 376 [M+H]+; Rt=2.88 min.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(O)cc2)n1
Reaction time: 1 h
Yield: 17.5 %

Procedure:
A mixture of Intermediate 70a (124 mg, 169 μmol) and TBAF (1M in THF, 0.34 mL, 0.34 mmol) in THF (5 mL) was stirred for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, then further purified by HPLC (30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as an off-white solid (18.4 mg, 18%). LCMS (Method 5) Rt 4.22 min, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.25 (9H, s), 1.61 (2H, m), 1.72 (4H, m), 1.79-1.98 (2H, m), 1.99-2.15 (2H, m), 3.13 (4H, m), 4.81 (1H, m), 5.54 (1H, t, J 4.5), 6.29 (1H, s), 6.85 (2H, m), 7.09 (1H, d, J 8.7), 7.14 (1H, dd, J 9.7, 2.0), 7.20-7.39 (6H, m), 7.59-7.64 (2H, m), 7.95 (1H, s), 9.77 (1H, br s).
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[O:8]C(=O)C1C=CC=CC=1)(=[O:4])C.[C:39](Cl)(=O)[CH3:40]>ClCCl.C(OCC)(=O)C>[C:2]([O:5][C@@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[OH:8])(=[O:4])[C:40]1[CH:39]=[CH:27][CH:17]=[CH:7][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 63.7 %

Procedure:
HCl (gas) was bubbled for 1.5 hours into a solution of 50 g (99.16 mole) of the compound (12) dissolved in 460 ml of anhydrous dichloromethane and 7.5 ml of acetyl chloride at 0° C. The resulting solution was kept in a refrigerator for 12 hours and then evaporated in vacuo. The residue was coevaporated with toluene (3×150 ml) at 45° C. and redissolved in 105 ml of acetonitrile. To this solution, 13 ml of water was added dropwise at 0° C. A white solid began to precipitate from the mixture after 30 minutes, after which the mixture was kept in a refrigerator for 2 hours to induce additional precipitation. After filtration of the resulting solid, the filter cake was carefully washed with cold diethylether to remove the reaction by-product 1-hydroxy-isomer, which is indistinguishable by TLC from the compound (13). The white solid thereby obtained was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate to remove the remaining HCl, dried over MgSO4 and filtered. The solvent was removed from the filtrate to obtain 29.2 g (Yield: 63.7%) of the compound (13) in the form of a white solid. m.p.: 137-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][C:6]([CH2:27][C:28]([OH:30])=[O:29])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:36]>ClCl>[C:21]1([S:20]([CH2:19][C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:16])[F:17])[CH:13]=[CH:14][C:9]=2[C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([CH2:27][C:28]([OH:30])=[O:29])[CH:7]=2)=[O:36])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CSc1ccccc1
Agent: ClCl
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (6-methoxy-2′-phenylsulfanylmethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.030 g, 0.07 mmol) in CH2 Cl2 was added 3-chloroperoxybenzoic acid (0.015 g, 0.07 mmol), and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=1)[C:19]([O:21][CH3:22])=[O:20]>C(O)C>[C:37]([O:36][C:34]([NH:33][C:30]1[CH:29]=[CH:28][C:27]([S:26][C:25]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[NH:15][C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)c1ccc2c(Cl)ncnc2c1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Solvent: CCO
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3cc(C(C)C)ccc23)c1
Yield: 33 %

Procedure:
The products of Example 431F (0.572 g, 2.768 mmol) and methyl 3-amino-4-(4-(tert-butoxycarbonylamino)phenylthio)benzoate the product of Example 385C or Example 432C (0.902 g, 2.409 mmol) were reacted in anhydrous ethanol (25 mL) under a nitrogen atmosphere at reflux for 30 minutes. The reaction was cooled and concentrated by rotary evaporation. The residue was dissolved in methylene chloride (50 mL) and washed with saturated aqueous sodium hydrogencarbonate (25 mL) and water (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with 3:97 methanol/methylene chloride afforded the title compound as a white solid (0.505 g, 0.927 mmol, 33%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.32 (d, J=6.99 Hz, 6 H) 1.48 (s, 9 H) 2.99-3.21 (m, 1 H) 3.83 (s, 3 H) 6.93 (d, J=8.46 Hz, 1 H) 7.37 (d, J=8.82 Hz, 2 H) 7.55 (d, J=8.82 Hz, 2 H) 7.55-7.64 (m, 2 H) 7.75 (dd, J=8.46, 1.84 Hz, 1 H) 7.91 (d, J=1.84 Hz, 1 H) 8.41 (d, J=8.46 Hz, 1 H) 8.45 (s, 1 H) 9.62 (s, 1 H) 9.92 (s, 1 H). MS (ESI+) m/z 545 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][O:34][CH2:35][CH2:36][N:37]([CH2:47][CH2:48][O:49][CH3:50])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][C:38]([N:37]([CH2:47][CH2:48][O:49][CH3:50])[CH2:36][CH2:35][O:34][CH3:33])=[O:46])[CH2:41][CH2:42]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride to give 2-(4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxy-ethyl)-acetamide in an analogous manner as described in example 1. LR-MS: 702.3 [(M+H)+]
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:37][O:38][C:39](=[O:42])[CH2:40][NH2:41]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:41][CH2:40][C:39]([O:38][CH3:37])=[O:42])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)CN
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Yield: 34.7 %

Procedure:
A solution of ethyl 5-{(1R)-1 -[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.18 g, 3.00 mmol) and triethylamine (1.51 g, 15.00 mmol) in ethanol (30 ml) was treated with glycine methyl ester hydrochloride (1.88 g, 15.00 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane:ethyl acetate (50:50) to afford the title compound (456 mg).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[OH-].[Na+].Cl>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CCOC(=O)CCc1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(CCC(=O)O)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a THF (5 ml) and methanol (5 ml) mixed solution of 1.01 g of ethyl 3-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl }phenyl)propanoate was added 5 ml of a 1M aqueous sodium hydroxide solution, followed by 1 hour of stirring at room temperature. To the reaction solution was added 5 ml of a 1M aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated, thus obtained crude crystals were recrystallized from ethanol to obtain 673 mg of 3-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl) propanoic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.CCOC(C)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(N)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
The ester from above (29.37 g, 150 mmol) was added to a 2L Parr hydrogenation flask and dissolved in anhydrous MeOH (200 mL) plus EtOAc (25 mL). The solution was then treated with 10% Pd/C (2.25 g, 50% wet) and fitted to a hydrogenator apparatus. After purging the flask 3 times with hydrogen gas, the mixture was shaken for 1 hour at 30 psi. The flask was then removed, and filtered through a celite pad washing with MeOH. The solvent was then removed under reduced pressure to afford 3-amino-4-methyl-benzoic acid methyl ester as a white solid (25.0 g, 100%). 1H NMR (CDCl3) δ 2.21 (s, 3H), 3.70 (br s, 2H, NH2), 3.88 (s, 3H), 7.10 (d, 1H, J=7.5 Hz), 7.35 (s, 1H), 7.37 (d, 1H, J=8.4 Hz).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[CH2:26]([O:25][C:23]([C:22]([CH3:29])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1)[CH3:28])=[O:24])[CH3:27]
Reactant: O=C(O)CCCc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A 12-L 3-neck round-bottom flask was equipped with an overhead air-driven stirrer apparatus, condenser, nitrogen inlet, thermometer/thermocouple, and heating mantle. The flask was charged with ethyl acetate (450 mL) and 21% (wt.) sodium ethoxide in ethanol solution (3318 mL, 8.87 moles, 2 eq). The resulting mixture was heated to reflux under a nitrogen atmosphere and maintained at reflux for 30 min. The mixture was then allowed to cool slightly below reflux, and 4-(4-hydroxyphenyl)butyric acid (800 g, 4.43 moles) was added. The flask contents were re-heated to reflux for 30 min, at which point ethyl 2-bromoisobutyrate (EBIB, 1954 mL, 13.32 moles, 3.0 eqs.) was added. After 1 h at reflux, the flask was equipped with a 2-L addition funnel, which was charged sodium ethoxide in ethanol solution (1660 mL, 4.43 moles, 1 eq.). The sodium ethoxide solution was added dropwise to the refluxing reaction over 1 h. After an additional 30 min at reflux, HPLC analysis showed the reaction was complete. The heat source was removed and the flask contents were cooled to 5-10° C. and then transferred to a 22-L bottom-outlet flask. While stirring, the mixture was quenched with dilute phosphoric acid (6000 mL), transferred to a 20-L Buchi flask, and concentrated in vacuo to remove ethanol. The resulting aqueous mixture of crystals and excess EBIB was refrigerated overnight. The crystals were then filtered and washed with water (2000 mL). The solids were removed from the funnel and placed in a 20-L Buchi flask equipped with an overhead stirring apparatus. After the addition of water (2000 mL), the solids were stirred at ambient temperature for 30 min, then filtered and washed with heptane (2×2500 mL)). The solids were then placed in the vacuum oven and dried at 45° C. to afford the title compound as an off-white solid (1247 g, 95.5%). 1H NMR (500 MHz, CDCl3) δ 1.25 (t, 3 H), 1.57 (s, 6 H), 1.92 (m, 2 H), 2.35 (t, 2 H), 2.60 (t, 2 H), 4.23 (q, 2 H), 6.76 (d, 2 H), 7.03 (d, 2 H). 13C NMR (CDCl3) δ 14.1, 25.4, 26.3, 33.3, 34.2, 61.4, 119.4, 129.1, 134.9, 153.7, 174.4, 179.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][C:8]=1[CH3:9].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:28]([O:35][C:36]1[CH:69]=[CH:68][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:51](=[O:59])[C:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=3)=[CH:45][CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH2:28]([O:35][C:36]1[CH:69]=[CH:68][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:51](=[O:59])[C:52]3[CH:53]=[CH:54][C:55]([NH:58][C:11](=[O:13])[CH2:10][C:5]4[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:56][CH:57]=3)=[CH:45][CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1
Reactant: COc1cc(CC(=O)O)ccc1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(C)c(OC)c4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Prepared using General Procedures 6 and 8: To 2-(3-methoxy-4-methylphenyl)acetic acid (14.1 mg, 0.08 mmol) were added HOBT (12.0 mg, 0.08 mmol) in DMF (0.1 mL) and EDC (15.0 mg, 0.08 mmol) in DMF (0.1 mL). After stirring at room temperature for 30 min, 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (30 mg, 0.05 mmol) and TEA (0.019 mL, 0.10 mmol) in DMF (0.3 mL) were added. The reaction was stirred for 18 h then purified by preparative HPLC to provide 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate. To 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate in DCM (1.0 mL) was added TFA (0.2 mL). The reaction was stirred at 30° C. for 6 h. The reaction was concentrated to afford 22.3 mg (65%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)acetic acid 4. LCMS-ESI (m/z) calculated for C40H44N2O8: 680; no m/z observed, tR=11.45 min (Method 2). 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.06 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.24 (d, J=8.5 Hz, 2H), 7.17-7.02 (m, 3H), 6.91 (s, 1H), 6.79 (d, J=7.5 Hz, 1H), 4.62 (d, J=36.2 Hz, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.95 (d, J=28.6 Hz, 2H), 3.77 (s, 3H), 3.60 (s, 2H), 2.10 (s, 3H), 1.74 (dd, J=9.8, 4.8 Hz, 2H), 1.48-1.24 (m, 8H), 0.86 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(4-nitrophenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [ClH:1].Cl.C([O:5][C:6]([C:8]1([CH2:20][O:21][C:22]2[C:31]([Cl:32])=[C:30]3[C:25]([CH:26]=[CH:27][C:28]([C:33](=[NH:35])[NH2:34])=[CH:29]3)=[CH:24][CH:23]=2)[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C>Cl>[ClH:32].[ClH:1].[C:33]([C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[C:31]([Cl:32])[C:22]([O:21][CH2:20][C:8]3([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][N:11]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[CH2:12][CH2:13]3)=[CH:23][CH:24]=2)[CH:29]=1)(=[NH:34])[NH2:35]
Reactant: CCOC(=O)C1(COc2ccc3ccc(C(=N)N)cc3c2Cl)CCN(c2ccncc2)CC1
Agent: Cl
Product: N=C(N)c1ccc2ccc(OCC3(C(=O)O)CCN(c4ccncc4)CC3)c(Cl)c2c1
Yield: 132.5 %

Procedure:
A solution of 4-(2-amidino-8-chloronaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (78 mg) in conc. hydrochloric acid was stirred at 50° C.-100° C. for 3 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was separated by HPLC (0.05% aqueous trifluoroacetic acid:methanol=1:1). The obtained residue was treated with hydrogen chloride-ethanol and dried under reduced pressure to give the title compound (49 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].Cl>C1COCC1>[C:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.4 %

Procedure:
To a mixture of 16.5 g (0.101 mol) of 4-hydroxycinnamic acid and 200 ml of a THF solution of 24 ml (0.297 mol) of pyridine was dropwise added 20 ml (0.281 mol) of acetyl chloride over 1 hour at room temperature. After the resulting mixture was stirred at room temperature for 7 hours, the reaction system was poured into 300 ml of a 2N aqueous solution of hydrochloric acid. After extracting with ether and concentrating the organic phase, there was obtained 13.14 g (0.064 mol) of 4-acetoxycinnamic acid as a white solid. The yield was 63%.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5]
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Product: O=C(Nc1ccc(-n2ccncc2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1

Procedure:
In analogy to example 1E 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5carboxylic acid ethyl ester (example 1D) was reacted with 1-(4-amino-3-fluoro-phenyl)-pyrazine-2-one (CAS 863015-77-4) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyrazine-1-yl)-phenyl]-amide. Yellow solid. MS 475.0 ([M+H]−)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=1.Cl[C:16]1[C:21]([CH:22]([CH3:24])[CH3:23])=[C:20]([O:25][CH3:26])[N:19]=[C:18]([O:27][CH3:28])[N:17]=1>CN(C=O)C.CCOC(C)=O>[CH:22]([C:21]1[C:16]([N:10]2[C:11]3[CH:12]=[C:4]([CH3:3])[CH:5]=[C:6]([C:13]#[N:14])[C:7]=3[CH:8]=[CH:9]2)=[N:17][C:18]([O:27][CH3:28])=[N:19][C:20]=1[O:25][CH3:26])([CH3:24])[CH3:23]
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: Cc1cc(C#N)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(OC)c(C(C)C)c(-n2ccc3c(C#N)cc(C)cc32)n1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
NaH (148 mg, 1.1 eq.) was added to 6-methyl-1H-indole-4-carbonitrile (526 mg, 3.37 mmol) in 20 mL of DMF. After 5 minutes, 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine was added to the reaction mixture. The reaction mixture was heated at 50° C. for 5 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated and purified (silica gel, 0-80% EtOAC/hexane) to give a white solid (470 mg, 42%). LC-MS shows 337.2 (M+1).