Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([O:13][CH3:14])[C:5]2[O:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[C:3]=1[F:15].C([Li])CCC.[CH:21](N1CCOCC1)=[O:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:15][C:3]1[C:4]2[O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]=2[C:11]([O:13][CH3:14])=[CH:12][C:2]=1[CH:21]=[O:22]
Reactant: COc1cc(Br)c(F)c2c1OCCCO2
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(F)c2c1OCCCO2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 548 mg of 7-bromo-6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepine in 15 ml of THF there was added dropwise 0.81 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 0.3 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (239 mg) as a solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH2:9]O)=[CH:5][CH:6]=1.[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=[O:15].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:11][C:12]([CH2:16][CH2:9][CH:8]=[CH:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[CH:13][CH:14]=[O:15]
Reactant: OC/C=C/c1ccccc1
Reactant: CC(C)=CC=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=CC=O)CCC=Cc1ccccc1
Yield: 81 %

Procedure:
A mixture of 187 parts of cinnamic alcohol, 360 parts of 3,3-dimethylacrolein and 550 parts of toluene is heated with 33 parts of glacial acetic acid in a V4A steel stirred vesel having a capacity of 5 liters for six hours at 140°C at a pressure of 2 atmospheres, the water forming being continuously removed as an azeotropic mixture with toluene. The product is distilled. 149 parts of 3-methyl-7-phenyl-2,6-heptadien-1-al is obtained having a boiling point of 118° to 120°C at 10-3 mm. The yield is 81% of theory (based on cinnamic alcohol) at a conversion of 66%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22](CC)CC)C.ClC(OCC)=O.CN>ClCCl.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([NH:22][CH3:20])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
trans-1-Benzyloxycarbonyl-4-hydroxy-L-proline (3.06 g) was dissolved in dry dichloromethane (48 ml), and triethylamine (1.75 ml) was added thereto, followed by addition of ethyl chloroformate (1.88 g) at -50° C. under nitrogen stream. The resultant mixture was stirred at -30° to -50° C. for 30 minutes, and a solution of methylamine (1.44 g) in dichloromethane (5 ml) and methanol (3.7 ml) was added thereto at -50° C. Stirring was continued at -30° to -50° C. for 20 minutes. The reaction mixture was successively washed with dilute hydrochloric acid, aqueous sodium chloride solution, dilute sodium hydroxide solution and sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue was crystallized from ether to give (2S,4R)-1-benzyloxycarbonyl-2-methylaminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH3:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1>C1CCCCC1>[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH2:10][CH2:9]1
Reactant: Nn1cccc1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCCCC1
Product: CN1CCC(Nn2cccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 441.9 %

Procedure:
A solution of 1-aminopyrrole (4.2 g, 0.05 mol) and 1-methyl-4-piperidine (6.9 g, 0.06 mol) in cyclohexane was refluxed overnight (about 16 hours) over 4 Å molecular sieves. After 3 hours, an additional 1 g of 1-methyl-4-piperidone was added. The molecular sieves were filtered off and the cyclohexane removed by evaporation under reduced pressure. The resulting oil was dissolved in isopropanol and 5 g of sodium borohydride added. The mixture was stirred at reflux for three hours, then methanol was added, the heat was removed, and stirring continued until the mixture had cooled to room temperature. The solvent was removed by evaporation under reduced pressure to give a residue to which water was added. This mixture was extracted with dichloromethane, the dichloromethane solution was dried with saturated sodium chloride solution and magnesium sulfate, and the dichloromethane evaporated in vacuo to give 7 g (78%) of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine. To a cooled solution of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine (5.4 g, 0.03 mol) and triethylamine (3.35 g, 0.033 mol) in CHCl3 (100 ml) was added dropwise a solution of propionyl chloride (3.07 g, 0.033 mol) in CHCl3 (100 ml). The reaction mixture was stirred at ice bath temperature for one hour, then at room temperature overnight (about 16 hours). The chloroform solution was washed with water, dried with saturated sodium chloride and magnesium sulfate, and the chloroform removed to give 4.8 g of an oil. The oxalate was formed by adding ethereal oxalic acid but did not crystallize. The resultant oil was basified, extracted with dichloromethane and dried to give 3.2 g of an oil. This oil was chromatographed on a high pressure liquid chromatograph (HPLC) using 11/2% diethylamine in acetonitrile. The resultant 1.5 g of free base was converted to the maleate (1.9 g) by adding ethereal maleic acid and recrystallized from absolute ethanol/ether to give 1.8 g, m.p. 146°-147° C. of N-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate. The recovered starting material was reacted again with propionyl chloride (0.7 g) in CH2Cl2 (20 ml) with sodium bicarbonate (1 g) at room temperature overnight. Work-up gave an oil which was dissolved in ether, and an ether solution of maleic acid added to give the maleate salt. Recrystallization from absolute ethanol/ether gave an additional 1.5 g of product of N-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate, mp 146°-147° C., combined yield 3.3 g (9.39 mmol), 31.3% yield from 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine.
Reaction SMILES: [N:1]([C:4]1[C:9]([C:10](=[O:44])[CH2:11][N:12]([CH2:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=2)[C:13]([C:15]2[CH:16]=[N:17][N:18]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:14])=[C:8]([Cl:45])[CH:7]=[CH:6][N:5]=1)=[N+]=[N-].P(C)(C)C.O>C1COCC1>[NH2:1][C:4]1[C:9]([C:10](=[O:44])[CH2:11][N:12]([CH2:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=2)[C:13]([C:15]2[CH:16]=[N:17][N:18]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:14])=[C:8]([Cl:45])[CH:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)ccnc3N=[N+]=[N-])Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)ccnc3N)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound 21-1 (60 mg, 0.09 mmol) in THF (5 mL) was added Me3P (1.0 M in THF, 0.18 mL, 0.18 mmol) at 0° C. and mixture was stirred at room temperature for 2 h. H2O (0.06 mL) was added to the reaction mixture at 0° C. and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 21-2 (40 mg, 69%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]=[C:10]([CH3:16])[C:11](OCC)=[O:12]>C(O)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:11](=[O:12])[C:10]([CH3:16])=[CH:9]2
Reactant: CCOC(=O)C(C)=Cc1cc(Cl)ccc1N
Solvent: CCO
Product: Cc1cc2cc(Cl)ccc2[nH]c1=O

Procedure:
In a 50-ml Erlenmeyer flask made of quartz, 0.5 g of (E) ethyl 3-(2-amino-5-chlorophenyl)-2-methyl-2-propenate was dissolved in 10 ml of ethanol; and, while being stirred, the mixture was irradiated with ultraviolet rays at 256 nm for 72 hours. The reaction liquid was concentrated under a reduced pressure, and the resulting crude crystal was recrystallized from ethanol, whereby the aimed compound was obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])/[C:3](/[CH3:8])=[CH:4]\[C:5]([OH:7])=[O:6]>CO>[F:1][C:2]([F:10])([F:9])[CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: C/C(=C/C(=O)O)C(F)(F)F
Solvent: CO
Product: CC(CC(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 63 h
Yield: 85.4 %

Procedure:
In an atmosphere of argon, 12 mg (14.1×10-3 mmol) of Ru(OAc)2 [(S)-(-)-OcH-binap] complex and 434.7 mg (2.82 mmol) of 3-trifluoromethylcrotonic acid were dissolved in 14 ml of methanol, and the resulting solution was put into a 100 ml capacity autoclave and stirred at 25° C. for 63 hours under a hydrogen pressure of 100 atm. The reaction solution was concentrated and then subjected to distillation to obtain 376 mg of (-)-3-trifluoromethylbutanoic acid with a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC2CCCCC2)CC1

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound, cyclohexanone (0.73 ml) and sodium cyanoborohydride (0.86 g) were reacted and treated in the same manner as in Example 136 to give 1.42 g of 4-amino-5-chloro-N-((1-(5-(cyclohexylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C@H:4]([NH:8][C:9](=O)OC(C)(C)C)[CH2:3]1.[Cl:16][C:17]1[CH:24]=C(F)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[Cl:16][C:17]1[CH:24]=[C:9]([NH:8][C@H:4]2[CH2:5][C:6](=[O:7])[N:2]([CH3:1])[CH2:3]2)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CN1C[C@@H](NC(=O)OC(C)(C)C)CC1=O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
1,1-Dimethylethyl [(3S)-1-methyl-5-oxo-3-pyrrolidinyl]carbamate (0.96 g, 4.5 mmol) was suspended in 4N HCl in dioxane (3 mL) and the mixture was stirred at room temperature for 12 h. Solvent was removed and the residue was dissolved in DMSO (27 mL) and H2O (3 mL). To this solution, 2-chloro-4-fluorobenzonitrile (0.77 g, 4.90 mmol) and NaHCO3 (1.89 g, 22.5 mmol) were added and the reaction mixture was stirred at 75° C. for 18 h. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to give the titled product (0.598 g, 53%) as a white solid. 1H-NMR (CDCl3) δ: 2.350 (1H, m), 2.914 (4H, m), 3.305 (1H, m), 3.825 (1H, m), 4.200 (1H, m), 4.835 (1H, d, J=6.8 Hz), 6.492 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.626 (1H, d, J=2.4 Hz), 7.454 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 250.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:48]1([S:54][CH2:55]Cl)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:55][S:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCSc1ccccc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(CSc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 17 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with chloromethyl phenyl sulfide was carried out as described in Example 3, Step A, except that only 5 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (25 mL for 0.162 mole, gradient elution using 0.25-1.0% MeOH/CH2Cl2) to give the desired material as a colorless oil in 17% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 740 (M+1)+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Yield: 93.6 %

Procedure:
To a stirred and cooled suspension of N-tert-butyl-3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonamide (example 287) (0.239 g, 0.455 mmol) in dichloromethane (1.5 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.200 g, 94%). MS (ISP) 470.3 [(M+H)+]; mp>250° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:6]([C:5]1[C:4]([CH3:11])=[CH:3][C:2]([O:1][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:9][C:8]=1[CH3:10])=[O:7]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC(=O)N(C)C)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-2,6-dimethylbenzaldehyde (100 mg) and 2-chloro-N,N-dimethylacetamide (89 mg) in DMF (2 mL) was added K2CO3 (185 mg) and the mixture was stirred at room temperature for 48 h. The mixture was poured into water and extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using 30% EtOAc/CH2Cl2 as eluent to give 2-(4-formyl-3,5-dimethylphenoxy)-N,N-dimethylacetamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11](=[C:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:4][CH:3]=1.[CH3:20]OC(OC)N(C)C.[NH4+].[Cl-]>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:20]=[CH:19][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)Nc1ccc(F)cc1)=C(C)C
Reactant: COC(OC)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)ccn(-c2ccc(F)cc2)c1=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
A mixture of ethyl 2-(4-fluorophenylcarbamoyl)-3-methylbut-2-enoate (1.85 g, 6.97 mmol) and N,N-dimethylformamide dimethyl acetal (5 mL, 37.45 mmol) is stirred at 90° C. for 90 min. After the reaction is cooled, EtOAc (30 mL) and saturated NH4Cl solution (20 mL) are added. The organic phase is separated, dried and concentrated. The residue is purified by silica gel column chromatography eluting with DCM:MeOH (10:1). The fractions containing product are concentrated, and the residue is mixed with ether to give 1.2 g of yellow solid which is filtered and discarded. The filtrate is concentrated and purified again by silica gel column chromatography eluting with DCM:MeOH (20:1) to give the product (500 mg, 26% yield). MS (m/z): 276.1 (M+H).
Reaction SMILES: [C:1]1([C:7]2[O:16][C:10]3[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:14]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)cc12
Product: Clc1ncnc2oc(-c3ccccc3)cc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 6-phenylfuro[2,3-d]pyrimidin-4(3H)-one (1.0 g) and POCl3 (10 mL) was stirred at 55-65° C. for 3 h. The reaction mixture was poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with aq. NaHCO3 solution, water, brine and dried over sodium sulfate. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a white color solid (800 mg, 74%), mp 136-138° C. 1H NMR (400 MHz, CDCl3): δ 8.74 (1H, s), 7.90-7.93 (2H, m), 7.45-7.54 (3H, m), 7.08 (1H, s).
Reaction SMILES: Br[C:2]1([F:10])[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6].NCCN>[C].[Pd].C(O)C>[F:10][CH:2]1[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1CC1(F)Br
Agent: [Pd]
Solvent: NCCN
Solvent: CCO
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
An internal glass tube was introduced into an autoclave and 211 mg of ethyl 2-bromo-2-fluoro-1-cyclopropanecarboxylate [obtained in accordance with the method of Bulletin of Faculty of Education, Wakayama University, 33, 33 (1984); cis:trans=0.8:1], 40 mg of 5% palladium-carbon (moisture content: 55% wet) and 8 ml of ethanol were fed thereinto. Then 90 mg of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under an elevated hydrogen gas atmosphere (50 kgf/cm2) for 48 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture containing the title compound was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 95%, the yield was 81% and the cis:trans ratio was 0.8:1.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)(C)(C)C.CN1CCOCC1.ClC(OCC(C)C)=O.[OH:59][N:60]=[C:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>O1CCOCC1.CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([N:8]([CH2:7][C:6]([OH:43])=[O:5])[CH2:33][C:34]3[CH:42]=[CH:41][C:37]([C:38]4[O:59][N:60]=[C:61]([C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)[N:68]=4)=[CH:36][CH:35]=3)=[O:32])=[CH:15][CH:14]=2)=[O:31])=[C:20]([C:27]([F:28])([F:30])[F:29])[CH:21]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Reactant: NC(=NO)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nc(-c5ccccc5)no4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (129 mg, 0.22 mmol) and 4-methylmorpholine (52.0 μL, 0.47 mmol) in dioxane (2 mL) was added isobutyl chloroformate (28.0 μL, 0.22 mmol). After 1 h, the reaction mixture was added to a stirring solution of N′-hydroxybenzimidamide (32.0 mg, 0.24 mmol) in DMF (2 mL). After a further 1 h, the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to room temperature then poured onto citric acid (50 mL, 0.1 M aqueous solution) and extracted with EA(2×20 mL). The combined organic extracts were washed with NaHCO3 (20 mL), dried over MgSO4 and the solvents evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and treated with TFA (2 mL). After 2 h, the solvents were concentrated and the residue purified by preparative HPLC to afford 19 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acid 368 as a white solid. LCMS-ESI (m/z) calculated for C34H27F3N4O6: 644; found 645 [M+H]+, tR=7.56 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.34 (s, 1H), 8.22-8.16 (m, 2H), 8.15-8.08 (m, 2H), 7.81-7.49 (m, 7H), 7.49-7.29 (m, 3H), 7.29-7.05 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.98 (s, 1H), 3.91-3.77 (s, 5H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:9][CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH:5]1[CH:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:9][CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(CN=[N+]=[N-])C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(CN)C1
Yield: 90 %

Procedure:
The solution of tert-butyl 3-(azidomethyl)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate in ethyl acetate from step C was hydrogenated under hydrogen atmosphere with 10% Pd/C (500 mg) overnight. The catalyst was filtered and the filtrate was concentrated under reduced pressure to give the title compound (6.2 g, 90% yield). MS (m/z): 345 (M+H)+.