Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]#[CH:24])[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[OH:25][N:26]=[C:27](Cl)[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:23]2[O:25][N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=1
Reactant: Cc1ccc(C(Cl)=NO)cc1
Reactant: C#Cc1cc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(-c3cc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a solution of tert-butyl N-(5-bromo-3-ethynyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (423 mg, 1.065 mmol) and N-hydroxy-4-methyl-benzimidoyl chloride (212.5 mg, 1.065 mmol) [Bioorganic & Medicinal Chemistry, 17(13), 4773-4785; 2009] in THF (10 mL) at ambient temperature was added Et3N (129.3 mg, 178.1 μL, 1.278 mmol) dropwise. The mixture was stirred at ambient temperature for 16 hours then at 65° C. for 2 hours. The mixture was concentrated in vacuo and the residue redissolved in DCM and washed with saturated aqueous NaHCO3 (×2) and brine (×1). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 20% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as a white solid (472 mg, 84% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.28 (s, 18H), 2.39 (s, 3H), 7.39 (d, 2H), 7.60 (s, 1H), 7.68 (d, 2H), 8.73 (d, 1H) and 8.82 (d, 1H) ppm; MS (ES+) 532.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[N:2].C([Sn]([N:24]=[N+:25]=[N-:26])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1.C(OCC)C>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:24]=[N:25][NH:26][N:2]=1
Reactant: COc1ccccc1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1ccccc1-c1nn[nH]n1
Yield: 98.1 %

Procedure:
A mixture of 1-cyano-2-methoxybenzene (1.02 g, 7.7 mmol) and tributyltin azide (3.4 g, 10.0 mmol) in 3.0 mL of xylene was heated under reflux for 5hours. The reaction mixture then was cooled and diluted with diethyl ether.Anhydrous hydrochloric acid was bubbled into the mixture and a white precipitate formed. The precipitate was collected by suction filtration and washed repeatedly with diethyl ether. Drying gave 5-(2-methoxyphenyl)-2H-tetrazole (1.33 g, 7.55 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[CH:3]=1)[CH3:38]
Reactant: CC(=O)CN1CCC(CCN2CCN(c3cccc(N)c3)CC2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccc(N2CCN(CCC3CCN(CC(C)=O)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a cooled solution of 0.1 g (0.3 mmol) of 1-(4-{2-[4-(3-aminophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one in 5 mL of dichloromethane and 0.03 g (0.3 mmol) of triethylamine, is slowly added 0.032 g (0.3 mmol) of ethyl chloroformate. The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The product is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5) to give 0.025 g (20%) of [3-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)phenyl]carbamic acid ethyl ester as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](Cl)(=[O:9])[CH:7]=[CH2:8]>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:6](=[O:9])[CH:7]=[CH2:8]
Reactant: NCCCO
Reactant: C=CC(=O)Cl
Solvent: CC#N
Product: C=CC(=O)NCCCO

Procedure:
To a 250 mL, four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, a 100 mL dropping fuel, and a nitrogen inlet/outlet, 30.0 g of 1-amino-3-propanol (0.4 mole), and 100 mL of acetonitrile were added. The mixture was cooled below 0° C. with an ice/water bath. To this solution, 18.1 g of freshly distilled acryloyl chloride (0.2 mole) in 50 mL of acetonitrile was added through the dropping funnel. The addition rate was controlled so that the reaction temperature was kept below 0° C. After the addition was finished and the agitation was turned off, the reaction solution separated into two liquid phases. The bottom layer viscous salt solution phase was discarded. 100 mL of deionized water was added to the top layer acetonitrile solution phase. After removing all acetonitrile by vacuum distillation, the aqueous solution was passed through a mixed bed ion-exchange column packed with 20 g of Dowex MR-3C resin. A total of 76 grams of eluate was collected. The final solution has the following properties: HPLC and FT-IR analysis indicates there is no ester formation; HPAA concentration: 7.2% (wt/wt); pH=5.6 at 25° C.; Conductivity=56.6 μS/cm at 25° C.; Viscosity=1.1 cPs at 25° C. The relative low yield of HPAA is due to the fact that HPAA is soluble in the salt phase. HPAA in the salt phase can be recovered by acetone extraction since HPAA is soluble in acetone, and the salt is insoluble.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([NH:20][NH2:21])=[O:19])[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]1=2)[C:8](=[O:10])[CH3:9].Cl[C:37]([O:39][CH2:40][CH3:41])=O>CO.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[O:19][C:37]([O:39][CH2:40][CH3:41])=[N:21][N:20]=2)[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)NN)c2cc(Cl)ccc21
Reactant: CCOC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1nnc(N2CCCC(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(C)=O)c3ccc(Cl)cc32)o1

Procedure:
To a stirring solution of N-(3,5-Bistrifluoromethyl-benzyl)-N-(8-chloro-1-hydrazinocarbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.13 mmol, 73 mg) in MeOH (1 mL) was added ethyl chloroformate (0.41 mmol, 45.0 μL) and the reaction mixture was refluxed for 12 h. After completion (by TLC), the mixture was cooled, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product as viscous oil. Purification by flash silica gel column chromatography gave the title compound as colorless foam; Rf 0.40 (EtOAc/Hexane, 1:1, v/v); MS (ES+): 599 (M+Na+).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:28](Cl)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[C:28]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)Cl
Reactant: CCCCCCCCC=CCCCCCCCC(O)CC(=O)OC(C)(C)C
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
Starting from tert-butyl 3-hydroxy-11-eicosenoate (11 g) and 9-octadecenoyl chloride (15 g), tert-butyl 3-(9-octadecenoyloxy)-11-eicosenoate (14 g) was obtained as an oil according to a similar manner to that of Preparation A-2(4).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[C:10]=1[CH3:11])=[O:5])[CH3:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[C:16]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn(-c2cc(F)ccc2[N+](=O)[O-])c1C
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2cc(-n3ccnc3)ccc2[N+](=O)[O-])c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
A mixture of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole (20.0 g, 68 mmol), imidazole (4.7 g, 69 mmol), potassium carbonate (9.5 g, 69 mmol) and acetonitrile (150 ml) was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and washed twice with water. The organic phase was dried (MgSO4), filtered and evaporated in vacuo to give 14.1 g (61%) of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-(1-imidazolyl) phenyl)-1H-imidazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH:15]([C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](Cl)=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(OCC)(=O)C>[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54].[CH:15]([C:18]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:23]/[C:24]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:27][CH:28]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(C=CC(=O)Cl)cc1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 4-isopropylcinnamoyl chloride (Perkin, W. H. J. Chem. Soc., 1877, 31, 388) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([CH3:16])([CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:7][OH:8])=[O:4].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([NH:5][C:6]([CH3:16])([CH2:9][CH2:10][C:11]1[S:12][C:13]([Br:17])=[CH:14][CH:15]=1)[CH2:7][OH:8])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)NC(C)(CO)CCc1cccs1
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(CO)CCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butan-1-ol (11.7 g, 48.0 mmol) obtained in Example 1(d) was dissolved in dimethylformamide (120 ml), and N-bromosuccinimide (10.8 g, 60.8 mmol) was added thereto in an ice bath followed by stirring for 4 hours at room temperature under a nitrogen atmosphere. The reaction mixture was poured into ice-cold 10% hydrochloric acid (300 ml), and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4:1-1:3); to afford the title compound (12.4 g, 80% yield) as a pale yellow oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]1=[O:43]>CN(C)C=O>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]2=[O:43])[C:16](=[O:20])[CH2:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1N(CCBr)CCC1(c1ccccc1)c1ccccc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)CCN1CCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of product from Example 64C (0.11 g, 0.4 mmol)) in N,N-dimethylformamide was added a 60% dispersion of sodium hydride in mineral oil (0.03 g, 0.75 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Then 1-(2-bromoethyl)-3,3-diphenylpyrrolidin-2-one (Example 64B, 0.142 g, 0.4 mmol) was added, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated and partitioned in water/methylene chloride. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed, eluting first with 5% ethyl acetate/hexane and then eluting the title compound with 15% methanol/methylene chloride. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (m, 20H), 3.48 (t, J=6.44 Hz, 2H), 3.42 (m, 2H), 3.28 (m, 2H), 3.12 (s, 2H), 2.70 (m, 2H), 2.66 (m, 2H), 2.42 (m, 2H); MS (ESI+) m/z 530 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6](=[O:9])[CH2:7][CH3:8])[CH2:2]1.[CH3:10][O-:11].[Na+]>C(OCC)=O>[CH3:8][CH:7]([C:6](=[O:9])[CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[CH:10]=[O:11]
Reactant: CCC(=O)C1CCOC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC=O
Product: CC(C=O)C(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Into a 100-mL round-bottom flask, was placed 1-(tetrahydrofuran-3-yl)propan-1-one (compound 263.2, 2.5 g, 19.5 mmol), sodium methoxide (1.4 g, 25.9 mmol) and ethyl formate (20 mL). The mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (1:20 to 1:5) as eluent to obtain the title compound as a yellow solid (2.0 g, 66%).
Reaction SMILES: [C:1]12([CH2:12][C:11](=[O:13])[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>>[CH2:20]([O:27][C:11]([CH2:12][C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(O)CC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of 1,1-cyclohexanediacetic anhydride (5.0 g, 27 mmol), pyridine (2.2 mL, 27 mmol), and benzyl alcohol (2.8 mL, 27 mmol) and toluene (5.0 mL, 47 mmol) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed three times with 1 N HCl and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated to dryness to yield the title compound (7.06 g, 89% yield) as a clear oil. 1H NMR (DMSO-d6, 400 mHz) δ (ppm): 11.96 (s, 1H), 7.32 (m, 5H), 5.03 (s, 2H), 2.52 (s, 2H), 2.34 (s, 2H), 1.40 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[S:5][CH:6]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:6]1[S:5][C:4]([NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[N:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1csc(NC(=O)C2CC2)n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NC(=O)C2CC2)sc1Br
Reaction time: 0.5 h

Procedure:
To N-(4-methylthiazol-2-yl)cyclopropanecarboxamide (10.05 g) in acetic acid (100 ml) under an ice-water bath was added bromine (3.2 ml). After 30 min, water (100 ml) was added. Filtration, washing with water (3×) and drying under vacuum afforded N-(5-bromo-4-methylthiazol-2-yl)cyclopropanecarboxamide as a white solid (12.47 g). H NMR (500 MHz, CDCl3) 2.39 (s, 3 H), 1.64-1.60 (m, 1 H), 1.27-1.24 (m, 2 H), 1.00-0.96 (m, 2 H) ppm; LC/MS: 261 (M+1)/2.91 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.ClCC1N=C(C2C=CC(C(F)(F)F)=CC=2)SC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:36])([F:19])[F:35])=[CH:26][CH:25]=3)[S:28][CH:29]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: OCCc1csc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(F)(F)F)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (example 18 a] and 4 a]) in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as a colorless gum.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].Cl.[C:17]([O:21][C:22](=[O:37])[CH:23]([NH2:36])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>CN(C)C(=O)C>[C:17]([O:21][C:22](=[O:37])[CH:23]([NH:36][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=1)([CH3:18])([CH3:20])[CH3:19]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(C)(C)C)cc1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NCc1cnc2nc(N)nc(N)c2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (53.7 mg, 0.1598 mmol) in anhydrous N,N dimethylacetamide was added 2-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester hydrochloride (51.58 mg, 0.1758 m mol). Under positive pressure of Argon, iPr2EtN (33.69 ul) was added. The reaction mixture was stirred at 50° C. for 4 hrs and then at room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 27.6 mg product was obtained. Yield: 41%; 1H NMR (500 MHz, DMSO-d6): δ 1.22491(s, 9H), 1.26835 (s, 9H), 2.921–2.971 (m, 2H), 4.130 (b, 1H), 4.427(s, 2H), 6.91485–6.93165(d, J=8.4 Hz, 2H), 7.16037–7.17723(d, J=8.43 Hz, 2H), 8.89353 (s, 1H); 9.13119 (s, 2H), 9.30829 (s, 2H); ESI-MS: m/z 468 (M++1)
Reaction SMILES: O1CCC[CH2:2]1.[Cl:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]([F:15])=[C:9]([Cl:16])[N:8]=1.[H-].[Na+].COCCl>C(OCC)(=O)C.O>[Cl:16][C:9]1[C:10]([F:15])=[CH:11][C:12]([CH2:13][O:14][CH3:2])=[C:7]([Cl:6])[N:8]=1
Reactant: OCc1cc(F)c(Cl)nc1Cl
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 100 mL of a tetrahydrofuran solution containing 5.8 g of (2,6-dichloro-5-fluoropyridin-3-yl)methanol, 1.8 g of 60% sodium hydride and 2 mL of a tetrahydrofuran solution containing 2.4 mL of chloromethyl methyl ether were added under cooling with ice, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added thereto, the organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 5.6 g of a colorless oily substance, 2,6-dichloro-3-fluoro-5-((methoxy)methyl)pyridine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[OH:35][C:36]1[C:41]([NH:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:54]=2[N:53]=[C:52]([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:51]=[CH:50]3)=O)=[C:40]([OH:62])[CH:39]=[CH:38][N:37]=1>C(Cl)Cl>[O:55]([C:52]1[CH:51]=[CH:50][C:49]2[C:54](=[C:45]([C:43]3[O:62][C:40]4[CH:39]=[CH:38][NH:37][C:36](=[O:35])[C:41]=4[N:42]=3)[CH:46]=[CH:47][CH:48]=2)[N:53]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Oc3ccccc3)nc12
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]ccc2oc(-c3cccc4ccc(Oc5ccccc5)nc34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of triphenylphosphine (421 mg, 1.607 mmol), Et3N (597 μl, 4.29 mmol), and perchloroethane (317 mg, 1.339 mmol) in DCM (5357 μl) was stirred at RT for 5 min before a slurry of N-(2,4-dihydroxypyridin-3-yl)-2-phenoxyquinoline-8-carboxamide (200 mg, 0.536 mmol) in DCM (3 ml) was added to make a light yellow solution; this was stirred for 1 h at RT. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 100% DCM to 4% MeOH/DCM) to provide 2-(2-phenoxyquinolin-8-yl)oxazolo[4,5-c]pyridin-4(5H)-one (179, 38% yield over two steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 6.46 (d, J=7.04 Hz, 1H) 7.22-7.30 (m, 2H) 7.36-7.47 (m, 5H) 7.55 (t, J=7.73 Hz, 1H) 7.95 (d, J=7.24 Hz, 1H) 8.22 (d, J=8.80 Hz, 1H) 8.64 (d, J=6.26 Hz, 1H) 12.51 (br. s., 1H). MS (ESI, pos. ion) m/z: 356.1 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=O)[CH2:2][CH3:3].[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[CH2:2][CH3:3]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: CCCc1ccccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1ccccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 26.8 %

Procedure:
A solution of (2-propyl-phenoxy)-acetic acid (180 mg, 0.93 mmol), and benzoic acid N′-isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine (0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product as a white solid (80 mg, 25%). MS m/e 355.35 (M+H+)