Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ncn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)pyrimidin-4-yl)propanoate (201 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (2.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered with silica gel and the solvent was evaporated under reduced pressure to give the title compound (184 mg) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>CC(O)C>[CH3:9][S:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:11][NH2:12])[CH:7]=1
Reactant: NN
Reactant: CSc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: O
Product: CSc1cc(NN)ncn1
Temperature: 90 °C

Procedure:
A mixture of 4-Chloro-6-methylsulfanyl-pyrimidine (1.1 g, 6.85 mmol), hydrazine monohydrate (1.2 g, 23.5 mmol), and 2-propanol (10 mL) is heated to 90° C. for 4 hours. The reaction mixture is then cooled to room temperature, concentrated, triturated with water, and filtered. The undissolved solid is washed with water, air-dried to give (6-Methylsulfanyl-pyrimidin-4-yl)-hydrazine as light yellow solid: 1H NMR 400 MHz (d6-DMSO) δ 8.29 (s, 1H), 8.16 (s, 1H), 6.55 (s, 1H), 4.34 (s, 2H), 2.43 (s, 3H); MS m/z 157.05 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][OH:40])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:41]([C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=1)[CH2:46]Br)#[N:42].O>O1CCCC1>[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][O:40][CH2:46][C:45]1[CH:48]=[CH:49][CH:50]=[C:43]([C:41]#[N:42])[CH:44]=1)[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C#N)c1)OCCCCCCCCCCCCCCCC
Reaction time: 0.33 h

Procedure:
Sodium hydride (50% mineral oil dispersion; 1.056 g, 0.022 mole) was added to a solution of 1,2-di-O-n-hexadecyl glycerol in tetrahydrofuran (150 ml) and stirred for 20 minutes under nitrogen. m-Cyanobenzylbromide (4.0 g, 0.020 mole) was added to the mixture and allowed to react to room temperature overnight. Water (200 ml) and then cautiously added and the aqueous mixture extracted with ethyl acetate (3×150 ml). The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil (12 g), which was chromatographed on silica gel (eluted with benzene/hexane, 8/2) resulting in pure 1,2-Di-O-(n-hexadecyl)-3-O-(3-cyanobenzyl)-glycerol (8.0 g): oil; ir(CHCl3) 2230 cm-1.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCCN(C)C(=O)CCl
Product: CCCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 37.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-methyl-N-propylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.5 mg) was obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:26]3[S:27][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccc(F)c21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3c(F)cccc23)s1
Yield: 77.3 %

Procedure:
A solution of 1-benzenesulfonyl-3-bromo-7-fluoroindole (0.5 g, 1.41 mmol), 5-formyl-2-thiophene boronic acid (0.24 g, 1.55 mmol), bis(triphenylphosphine) palladium (II) dichloride (0.06 g, 0.08 mmol) and triethylamine (0.39 ml, 2.82 mmol) in ethanol (4 ml) was subjected to microwave irradiation at 150° C. for 420 s. The resulting suspension was concentrated under reduced pressure and the residue passed through a silica pad eluting with dichloromethane to afford crude 5-(1-benzenesulfonyl-7-fluoroindol-3-yl)-thiophene-2-carboxaldehyde as a brown solid (0.42 g) which was used in the next step with no further purification.
Reaction SMILES: [C:1]([NH:18][C:19]([NH2:21])=[S:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].Br[CH2:23][C:24](=O)[C:25]([OH:27])=[O:26]>O1CCOCC1>[C:1]([N:18]1[C:24]([C:25]([OH:27])=[O:26])=[CH:23][S:20][CH:19]1[NH2:21])([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: NC(=S)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)C(=O)CBr
Solvent: C1COCCO1
Product: NC1SC=C(C(=O)O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 96.4 %

Procedure:
A solution of N-Fmoc-thiourea (5.96 g, 20 mmol) in dioxane (40 mL) was treated with bromopyruvic acid (3.34 g, 20 mmol). The reaction mixture was refluxed for 1 h, then the precipitated solids were recovered by filtration and washed with diethyl ether (3×20 mL) to afford N-Fmoc-2-aminothiazole-4-carboxylic acid (7.1 g, 97%) as a white solid: EI-HRMS m/e calcd for C19H14N2O4S (M+) 366.0674, found 366.0679.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[C:31](=[O:35])[N:30]([C:27]2[CH:28]=[CH:29][C:24]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)[CH:34]=[N:33]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ncn1-c1ccc(-n2ccnc2)cc1
Product: C[C@@H](n1ncn(-c2ccc(-n3ccnc3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1-imidazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1H-1-imidazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 22).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[C:15]=2[CH:14]=[CH:13][N:12]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH:11]1[C:20]2[C:15](=[C:16]([S:21]([O:5][C:4]3[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 5-isoquinolinesulfonyl chloride (2.64 g, 10.0 mmol), as prepared in the preceding step, were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was triturated from ether/hexane to give the title compound as a pale yellow solid (1.15 g, 37%). 1H-NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 9.60 (s, 1H), 8.86 (d, J=6.1 Hz, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.37 (t, J=6.1 Hz, 2H), 7.86 (t, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 5.97 (s, 1H), 2.08 (s, 3H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]=1[OH:36])[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1.CO.[ClH:40]>[C].[Pd].CCCCCC>[ClH:40].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:25]=1[OH:36])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)Nc1cc(OC)cc(C(C)(C)C)c1O
Agent: [Pd]
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)[C@H](CCCCN)NC(=O)Nc1cc(OC)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 85 %

Procedure:
To a mixed solution comprising 1 g of 2-[3-((1S)-5-benzyloxycarbonylamino-1-methoxycarbonylpentyl)ureido]-4-methoxy-6-tert-butylphenol and 30 ml of methanol were added 0.5 ml of conc. hydrochloric acid and 200 mg of 10% palladium-carbon (Pd-C). The mixture was subjected to catalytic reduction at normal temperature under normal pressure for one hour. After removing the catalyst, the filtrate was condensed. Hexane was added to the residue to give 685 mg of 2-[3-((1S)-5-amino-1-methoxycarbonylpentyl)ureido]-4-methoxy-6-tert-butylphenol hydrochloride (yield: 85%, state: yellow powder, IR: 3300 (br), 1725, 1650, 1560 cm-1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Br:23][CH2:24][C:25](Br)=[O:26].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Br:23][CH2:24][C:25]([NH:21][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:22])=[O:26]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CBr)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (2.0 g, 5.54 mmol) in ethyl acetate (50 ml) were added bromoacetyl bromide (723 ml, 8.30 mmol) and saturated aqueous sodium hydrogen carbonate (50 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (2.0 g, 83%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH2:34])[CH3:31])([CH3:27])([CH3:26])[CH3:25].O>CN1CCCC1=O>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:34][CH2:33][CH2:32][N:30]([CH3:31])[C:29](=[O:35])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])[S:3][C:4]=3[CH:10]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: COc1ccc(NC(=O)c2ccc3nc(Br)sc3c2)cc1OC
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)c2ccc3nc(NCCN(C)C(=O)OC(C)(C)C)sc3c2)cc1OC
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 2-bromo-N-(3,4-dimethoxyphenyl)benzo[d]thiazole-6-carboxamide (392.4 mg, 0.998 mmol), N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (193.4 mg, 1.11 mmol) and N—N-diisopropylethylamine (148.6 mg, 1.15 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred in a preheated oil bath at 120° C. for 4 h, then allowed to cool to room temperature, poured into water and extracted into ethyl acetate. The organic layer was washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by gradient flash column chromatography, eluting with 70% to 80% ethyl acetate in heptane to yield tert-butyl 2-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-ylamino)ethyl(methyl)carbamate as a beige powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=[O:19])[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (20.0 g), 3-hydroxy-4-methoxybenzaldehyde (13.97 g), potassium carbonate (13.96 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzaldehyde as colorless crystals (19.4 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([O:20][C:21]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br)[CH3:19].Cl>CN(C)C=O>[C:12]([O:11][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:21]=1[O:20][CH2:18][CH3:19])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CCOc1c(CBr)cccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A mixture of iminodicarboxylic acid di-t-butyl ester (3.23 g), dimethylformamide (50 ml) and sodium hydride (0.57 g) was stirred under ice cooling for 1 h and then a mixture of the compound (3.51 g) obtained in Example 417c and dimethylformamide (20 ml) was added under ice cooling. The reaction mixture was stirred at room temperature for 14 h and, after addition of 2 N HCl, subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:9) to give 5.09 g of the titled compound (yield, 95%).
Reaction SMILES: [CH3:1][N:2]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[C:29]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41]=1[O:42][CH3:43])[C:36](O)=[O:37])([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:41]=1[O:42][CH3:43])[C:36]([N:26]1[CH2:27][CH2:28][C@@H:24]([N:2]([CH3:1])[C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:25]1)=[O:37])([CH3:47])([CH3:46])[CH3:45]
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Reactant: CN(C(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)[C@@H]1CCNC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1c(C(C)(C)C)cc(C(=O)N2CC[C@@H](N(C)C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of (R)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid methyl-pyrrolidin-3-yl-amide (0.78 g, 2.02 mmol) in dry CH2Cl2 (30 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.53 g, 2.02 mmol) under nitrogen. To the reaction was added EDC (0.77 g, 4.04 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give 1.1 g of desired product.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[N:15]=[C:16]([NH:18][CH2:19][CH3:20])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:21][F:22])[C@H:10]1[O:23]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl>C(Cl)Cl>[CH2:19]([NH:18][C:16]1[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:21][F:22])[C@@H:10]([OH:23])[C@H:9]([OH:8])[C@H:14]2[N:15]=1)[CH3:20]
Reactant: CCNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CF)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-N-ethyl-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-2-amine (209 mg, 0.507 mmol) in DCM (5 mL) at −78° C. was added a solution of BCl3 in DCM (1.0 M, 1.27 mL, 1.27 mmol). The mixture was slowly warmed up to 0° C. and stirred at this temperature for 5 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (10 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 5%-15% 2 M NH3 MeOH solution in DCM to give the product (3aR,4R,5R,6S,7aS)-2-(ethylamino)-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (86.0 mg, 73%) as a white solid. MS m/z 233.2 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 4.60 (dd, J=9.0 Hz, 4.4 Hz, 0.5H), 4.45-4.51 (m, 2H), 4.35 (dd, J=9.0 Hz, 2.5 Hz, 0.5H), 3.47 (t, J=7.1 Hz, 1H), 3.13-3.22 (m, 2H), 3.06-3.12 (m, 2H), 2.12-2.21 (m, 1H), 1.65-1.80 (m, 2H), 1.06 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, MeOD) δ 163.88, 84.63 (d, J=165.6 Hz), 80.81, 80.65, 71.86 (d, J=4.8 Hz), 68.43, 39.40 (d, J=18.6 Hz), 38.23 (d, J=2.4 Hz), 28.14 (d, J=3.8 Hz), 15.24.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH3:9]C([OH:12])C.C(OCC)(OCC)OCC.[ClH:23]>O>[OH2:4].[OH2:12].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CC(C)O
Agent: Cl
Solvent: O
Solvent: CCOC(OCC)OCC
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
Under the nitrogen atmosphere, 5.00 g of 2-aminomalonamide was added to 100 mL of 2-propanol. After heating to 80° C., 17.7 mL of triethyl orthoformate was added dropwise to the mixture over 30 minutes. Subsequently, the reaction mixture was stirred for 7 hours and 50 minutes at 83 to 84° C. Subsequently, after cooling to 50 to 60° C., the reaction mixture was added with an aqueous solution prepared with 4 mL of conc. hydrochloric acid and 5 mL of water. After cooling the mixture to 20 to 30° C., the crystal was collected by filtration and then washed with 25 mL of acetone to give 8.04 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a pale yellow crystal.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[C:15]([N:16]3[N:20]=[CH:19][CH:18]=[N:17]3)=[CH:14][CH:13]=[C:12]([CH3:21])[N:11]=2)=[O:9])[C@@H:3]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.[H-].[Na+].[CH3:36]I>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[C:15]([N:16]3[N:17]=[CH:18][CH:19]=[N:20]3)=[CH:14][CH:13]=[C:12]([CH3:21])[N:11]=2)=[O:9])[C@@H:3]1[CH2:22][N:23]([CH3:36])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][N:25]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN(C)c2ccc(C(F)(F)F)cn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (0.0215 g, 0.047 mmol) in DMF (0.5 mL) at rt was added NaH (60%, 0.006 g, 0.141 mmol). The mixture was stirred at rt for 1 h, then MeI (0.013 g, 0.094 mmol) was added. The reaction was stirred at rt for another 1 h. The crude was purified via preparative-HPLC to obtain the title compound. ESI-MS (m/z): 474 [M+1]+.