Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:28]I>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH:23]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(-c3ccncc3)sc2-c2ccc(OC)cc2)cc1
Reactant: CI
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(C3=CCN(C)CC3)sc2-c2ccc(OC)cc2)cc1
Reaction time: 48 h

Procedure:
A solution of 4,5-bis(4-methoxyphenyl)-2-(4-pyridyl)thiazole (1.78 g) and methyl iodide (2.96 ml) in a mixture of chloroform and methanol (5:2) (28 ml) was allowed to stand at ambient temperature for 2 days. The reaction mixture was evaporated in vacuo and the residue containing 4-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]-1-methylpyridinium iodide was dissolved in a mixture of methanol (20 ml). To the resulting solution was added portionwise sodium borohydride (0.54 g) with stirring at 5° to 10° C. The reaction mixture was stirred for one hour at the same temperature. Water was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in chloroform and washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was recrystallized from a aqueous methanol to give 4,5-bis(4-methoxyphenyl)-2-(1-methyl-1,2,5,6-tetrahydro-4-pyridyl)thiazole (0.16 g).
Reaction SMILES: CC(C)([O-:4])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[CH2:15]1[C:24](=O)[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1.C(O)(=O)C>O1CCCC1>[C:16]1(=[C:9](/[NH:7][CH:8]=[O:4])\[C:10]([O:12][CH2:13][CH3:14])=[O:11])\[CH2:15][CH2:24][CH2:23][C:22]2[C:17]\1=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1CCc2ccccc2C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)/C(NC=O)=C1\CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a stirred slurry of potassium t-butoxide (4.7 g, 42.0 mmol) in 30 mL tetrahydrofuran at 0° C. is added ethyl isocyanoacetate (4.53 g, 40.0 mmol). This is stirred for 30 mins whereupon a solution of β-tetralone (5.88 g, 40.0 mmol) in tetrahydrofuran (20 mL) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 3 hours. The reaction mixture is then recooled in an ice bath and to this is added acetic acid (2.5 g, 41.6 mmol), allowed to warm to room temperature and stirred for an additional 30 mins. The solvent is removed in-vacuo and the residue partitioned between water and ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, filtered, evaporated and crystallized from cyclohexane to give 4.67 g of a white solid (contains some E-isomer), MS: m/z 260.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:31][CH:30]=[CH:29]2.O.[C:52]([OH:56])(=[O:55])[CH:53]=O>>[C:47]([O:46][C:44]([N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][CH:53]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:11]([CH3:12])[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)=[O:24])=[CH:16][CH:17]=3)[C:52]([OH:56])=[O:55])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CN(CCc1ccc(B(O)O)cc1)C(=O)Nc1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: O=CC(=O)O
Solvent: O
Product: CN(CCc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 44 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 23D (164 mg, 0.50 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 23E (128 mg, 44%) as a yellow oil. MS (ESI) m/z 695.19 (M+H)+.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([SH:25])[CH:11]=[C:12]([CH2:14][CH2:15][CH:16]=[C:17]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH3:18])[CH3:13].[CH3:26][C:27]1[CH:28]=[C:29]([SH:35])[CH:30]=[C:31]([CH3:34])[C:32]=1[OH:33].CO[C:38](OC)([CH3:40])[CH3:39]>C1C=CC=CC=1>[CH3:34][C:31]1[CH:30]=[C:29]([S:35][C:38]([CH3:40])([S:25][CH2:10][CH:11]=[C:12]([CH3:13])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH3:39])[CH:28]=[C:27]([CH3:26])[C:32]=1[OH:33]
Reactant: Cc1cc(S)cc(C)c1O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCS
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCSC(C)(C)Sc1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 113.9 %

Procedure:
A catalytic amount of boron trifluoride etherate (10.54 mL) was added to a chilled solution (ice bath) of farnesyl mercaptan (8.0 g, 33.6 mmoles), prepared according to the procedure published by U.S. Pat. No. 3,665,040, 3,5-dimethyl-4-hydroxy thiophenol (4.33 g, 28.0 mmoles) and 2,2-dimethoxy propane (4.1 mL, 33.6 mmoles) in 200 mL of reagent grade benzene. The slightly cloudy solution was stirred at 0° C. for approximately 15 minutes before the ice cooling bath was removed and the mixture was allowed to warm to ambient temperature slowly. Stirring was continued for an additional 15 minutes. The reaction was neutralized by quenching with 10 mL of aqueous saturated sodium bicarbonate solution, most of the solvents were evaporated under reduced pressure and the organic residue was extracted into ethyl acetate, washed with water, dried over MgSO4 (or Na2SO4) and concentrated under reduced pressure to give 13.8 g of a pale oily material contaminated with white solid. The oily fraction was dissolved into hexanes and the white solid was separated by filtration and identified to be one of the side products, 2,2-bis[(3,5-dimethyl-4-hydroxy)thio phenyl]propane, 2.12 g. The oily fraction was reconcentrated and partitioned over a flash column packed with SiO2 --H (Merck), eluted with 2% tert-butyl alcohol in hexanes. Yield was 5.0 g of the desired product (12 mmoles, 41.1% based upon the thio phenol starting material used).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[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.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)N(C)CCC1.CCOCC>[CH:1]([N:14]1[CH2:17][CH:16]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[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
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCOCC
Solvent: CN1CCCN(C)C1=O
Product: c1ccc(CNC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of methanesulfonic acid 1-benzhydrylazetidin-3-yl ester (0.32 g, 1 mmol) in N,N′-dimethylpropyleneurea (0.5 ml) was added benzylamine (0.5 ml, 5 mmol), and the mixture was stirred at 70° C. for 18 h. It was then cooled to room temperature and diluted with ether (30 ml). The resulting suspension was filtered and the ether solution was evaporated. The residue was partitioned between hexanes and water, and hexanes solution was washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. It was then filtered through a pad of silica gel, and the filter pad was eluted with a 1:1 mixture of ether-hexanes. Evaporation of solvents followed by trituration with isooctane gave 0.22 g of a white solid; m.p. 73-75° C.; MS (ES) m/z 329.0 (MH+); HRMS (El) Calcd. for C23H24N2 (M+): 328.1940, Found: 328.1936.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][C:9](=O)N(C)C.C[O-].[Na+].C(=O)([O-])N.C[O-].[Na+].CO.[Br:31][CH2:32][CH2:33]CBr>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:33][CH2:32][Br:31]
Reactant: BrCCCBr
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Agent: C[O-]
Agent: NC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(SCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-chloro-4-dimethylcarbamoylthiophenylacetate (8.5 g, 0.0295 mol) in methanol (30 mL) was added 25% NaOMe in methanol (7.0 mL, 0.034 mol). The reaction was heated to reflux for 2 h. TLC analysis shows residual starting carbamate. Additional NaOMe/MeOH (1.0 mL) was added and the mixture stirred an additional 30 min at reflux. After cooling to ambient temperature, the thiolate solution was added dropwise to a solution of 1,3-dibromopropane (12 mL, 0.12 mol) in methanol (30 mL). The resulting solution was refluxed for 3 h then cooled to ambient temperature, After standing overnight, the reaction was quenched by pouring into ice water. After adjusting to pH1 with conc. HCl, the aqueous solution was extracted with EtOAc (0.2 L then 2×0.1 L). The combined organics were washed with water, brine, dried over anhyd. MgSO4, filtered, and concentrated. The residue was chromatographed over silica gel with 10% of ethyl acetate in hexane to afford the title compound.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19].O>CN(C)C=O.C(O)(=O)C>[CH2:19]([CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:18]=[CH2:17]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C(=O)OCC)C(=O)c1ccccc1
Yield: 84.1 %

Procedure:
Ethyl benzoylacetate (6 grams) is dissolved in 40 ml of dimethyl formamide and 1.5 grams of sodium hydride is added thereto with ice cooling and stirring. Ten minutes thereafter, 4 grams of allyl bromide is added thereto, the mixture is stirred at room temperature for one hour, and poured into water. The mixture is neutralized with acetic acid, and extracted with ether. The ether extract is washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom to give 6.1 grams of colorless oily product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: ClCCCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCCCCCl
Yield: 95 %

Procedure:
A mixture of 16.6 g (0.1 mole) of acetovanillone, 34.3 g (0.2 mole) of 1-bromo-4-chlorobutane and 41.4 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil which readily crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 24.4 g (95%) of title compound as an off-white solid. An analytical sample, mp 68.5°-70.5° C., was prepared from isopropyl ether.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:12]=[C:11]([I:13])[C:10]([CH3:14])=[CH:9][N:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:13][C:11]1[C:10]([CH3:14])=[CH:9][N:8]=[C:7]([NH2:6])[CH:12]=1
Reactant: COc1ccc(CNc2cc(I)c(C)cn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(N)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine (118 g, 310 mmol) in DCM (1900 mL) was added TFA (360 mL, 4830 mmol). The reaction mixture was allowed to stir at rt for 2 h and was then concentrated. The residue was dissolved in EtOAc and diluted with saturated aqueous NaHCO3. The mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 4-iodo-5-methylpyridin-2-amine (53 g, 75%) which was used in the next step without purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCBr
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 8-bromooctanoic acid (2.5 g, 11.2 mmol, commercially available e.g. from Aldrich) in toluene (50 ml) was added thionyl chloride (2 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was co-evaporated with dichloromethane (2×25 ml) to give a brown oil which solidified on standing (found to be starting acid by NMR). This material was redissolved in toluene (25 ml), thionyl chloride (2 ml) was added, and the mixture was stirred at room temperature for 8 hours and then left standing overnight. The reaction mixture was evaporated to dryness and the residue was co-evaporated with dichloromethane (2×30 ml) to give the title compound as a brown oil (2.4 g), as a 3:2 mixture of product: starting acid (by NMR). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.37 (4H, m), 1.45 (2H, m), 1.67 (2H, m), 1.86 (2H, m), 2.90 (2H, t, J=7 Hz), 3.42 (2H, t, J=7 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([OH:21])=O)[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N(O)N=[N:28]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:28])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 30 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
To a solution of 2-(4-nitrophenyl)benzo[d]oxazole-4-carboxylic acid (1.42 g, 5 mmol) in DMF (70 mL) was added HOBt (0.75 g, 5.5 mmol), NH4Cl (0.27 g, 5.0 mmol), DIPEA (1.94 g, 15.0 mmol) and EDCI (1.15 g, 6.0 mmol). The mixture was stirred at 30° C. for 18 hr. The resulting mixture was purged in water (10 mL) and aqueous hydrochloric acid (1 N) to pH=3, then filtered, and the filtrate was washed with saturated sodium bicarbonate solution (100 mL×2) and brine (100 mL×2), and dried in vacuum to obtain the crude product. Re-crystallization in THF obtained 2-(4-nitrophenyl)benzo[d]oxazole-4-carboxamide as a yellow solid (800 mg, yield 56%). LC-MS (ESI) m/e 284 [M+1]+.
Reaction SMILES: O1CCOC[CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:17]([OH:19])=[O:18].[C:26]([NH:33][CH2:34][CH2:35][NH2:36])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[CH3:2][O:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:14]([NH:36][CH2:35][CH2:34][NH:33][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
A 2 L flask equipped with a stir bar was charged with 1,4-dioxane (300 mL), DMF (40 mL), K2CO3 (10 g) and 3-fluoro-4-nitrobenzoic acid (9.7 g). Mono-N-Boc-1,2-diaminoethane (8.6 g) was added to the reaction mixture and stirred for 12 h at 60° C. The reaction mixture was concentrated and the residue was dissolved in CH2Cl2 (400 mL) and H2O (500 mL). The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with CH2Cl2 (2×100 mL). The organic phases were combined and washed with H2O (5×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound as an orange solid (14 g, 84%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:11](Cl)=[O:12].[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]3[CH2:27][NH:28][CH2:29][CH2:30][N:25]3[C:24](=[O:31])[O:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCCl>[C:1]([NH:9][C:11]([N:28]1[CH2:29][CH2:30][N:25]2[C:24](=[O:31])[O:23][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:26]2[CH2:27]1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccccc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: ClCCCl
Product: O=C(NC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Temperature: 90 °C
Reaction time: 30 h
Yield: 23.3 %

Procedure:
Benzamide (1.0 g, 8.3 mmol) was dissolved in 1,2-dichloroethane (5 mL), oxalyl dichloride (1.2 g, 9.1 mmol) was added thereto, and the mixture was stirred at 90° C. for 30 hours. The reaction solution was concentrated under reduced pressure. Toluene (4 mL) was added thereto and dissolved. Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.68 mmol) was added thereto, and the mixture was stirred at 60° C. for 6 hours. The reaction solution was concentrated under reduced pressure to a half its original volume, and the precipitated crystals were filtered off. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1), and toluene (4 mL) was added thereto. The precipitated crystals were filtered off, and the filtrate was concentrated. The residue was further purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (70 mg, yield 23%).
Reaction SMILES: Cl.[CH:2]1([NH:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:15][C:16]1[O:17][C:18]([CH3:25])=[C:19]([CH3:24])[C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH:2]1([N:7]([C:21]([C:20]2[C:19]([CH3:24])=[C:18]([CH3:25])[O:17][C:16]=2[CH3:15])=[O:22])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCC1
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1oc(C)c(C(=O)N(O)C2CCCC2)c1C
Temperature: 25 °C

Procedure:
27.5 Parts of N-cyclopentylhydroxylamine hydrochloride is dissolved in 200 parts of dichloromethane; a solution of 33.6 parts of sodium hydrogen carbonate in 300 parts of water is then added. At room temperature and while stirring thoroughly, 34.5 parts of 2,4,5-trimethylfuran-3-carboxylic chloride is dripped into this mixture. After the mixture has been stirred for 2 hours the dichloromethane phase is separated, dried over anhydrous sodium sulfate and evaporated. There is obtained 36 parts of N-cyclopentyl-2,4,5-trimethylfuran-3-hydroxamic acid in the form of an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(N(C(C)C)CC)(C)C.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.O>CN(C)C=O>[CH3:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]([NH:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1-Fluoro-5-methyl-2-nitro-4-(trifluoromethyl)benzene (D56) (4.9 mmol, 1.1 g) was dissolved in dry dimethylformamide (3 ml) and diisopropylethylamine (1 eq., 4.9 mmol, 0.460 ml), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 4.9 mmol, 981 mg) were added at room temperature and the mixture was stirred at 80° C. for 3 hours. The crude mixture was then cooled to room temperature and water was added; the aqueous solution was extracted with ethyl acetate; organics were alternatively washed with brine and water. The organics were combined dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate-n-hexane) to yield the title compound, 1.29 g, 65%, M+−H=402.
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:10]2[C:5]([NH:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]2[CH3:22])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].C(OCC)(=O)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH3:22])[C:8](=[O:23])[C:7]([CH3:25])([CH3:24])[NH:6]2
Reactant: COc1cc(OC(F)(F)F)ccc1B(O)O
Reactant: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC(F)(F)F)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of 7-bromo-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-1, 49.7 mg, mmol), 2-methoxy-4-trifluoromethoxyphenylboronic acid (58.1 mg, 0.246 mmol), cessium carbonate (119 mg, 0.36 mmol) and bis(triphenylphosphin)palladium (II) dichloride (12.0 mg, 0.0171 mmol) was suspended in anhydrous N,N-dimethylformamide (0.5 ml) and stirred at 80° C. for 2 hours under argon atomosphere. After cooling down, ethyl acetate (100 mL) and water (100 mL) was added and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (52.7 mg) as a colorless amorphous product. (Yield 58%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.C1COCC1.[O:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][O:32]2)=[O:38])=[C:4]([F:26])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)[C@H]1CCCO1
Yield: 13.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phen yl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-70, 0.090 g, 0.233 mmol), THF:DMF (5 mL:1 mL), (R)-(−)-tetrahydrofuran-2-carboxylic acid (0.040 g, 0.349 mmol), TBTU (0.224 g, 0.699 mmol), and TEA (0.5 mL). The obtained crude was purified with column chromatography using basic alumina as stationary phase and 2% ammonia in 10.0% MeOH:DCM solution as mobile phase to afford 0.015 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.78-1.91 (m, 2H), 2.09-2.15 (m, 1H), 3.74 (m, 1H), 3.88-3.94 (m, 1H), 4.28 (m, 1H), 4.43 (m, 2H), 7.65 (m, 2H), 7.86 (d, J=8.72 Hz, 2H), 8.18 (d, J=8.52 Hz, 2H), 8.45 (d, J=16.0 Hz, 1H), 12.71 (s, 1H).