Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:6][C:5]([N:18]2[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]2)=[C:4]([F:28])[CH:3]=1>C(O)C.[Pt]=O>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:28])=[C:5]([N:18]3[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]3)[CH:6]=2)=[CH:14][CH:13]=1
Reactant: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=[Pt]
Solvent: CCO
Product: Cc1nn(-c2cc(Oc3ccc(N)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Yield: 79.7 %

Procedure:
Hydrogenation of 5.80 g (0.015 mole) of 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one dissolved in 100 mL of ethanol in the presence of a catalytic amount (0.30 g) of platinum oxide produced 4.6 g of 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 133°-135° C., Compound 3 of Table 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:9]([O:16][C:17]1[C:18]2[N:19]3[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26][CH3:27])=[C:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=1)[C:20]3=[C:42]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49]Cl)[CH:43]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C>CN(C)C=O.O>[CH2:9]([O:16][C:17]1[C:18]2[N:19]3[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26][CH3:27])=[C:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=1)[C:20]3=[C:42]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:43]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCNCC1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCl)cc3c(OCc4ccccc4)ccc1n32
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
Piperidine (0.104 g, 1.22 mmol) was dissolved in 50 ml of dry dimethylformamide under a nitrogen atmosphere and sodium hydride (60% in oil) 47 mg, 1.16 mmol) was added. The mixture was stirred for 1/2 hour. 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-((4-chlorobutoxy)methyl)-1-ethylpyrrolo[2,1,5-cd]indolizine (0.337 g, 0.583 mmol) was added and the mixture was stirred at 55-65° for 7 days. Ethanol (10 ml) was added dropwise, and the reaction mxiture was diluted with 250 ml of water. The organic material was extracted into ethyl acetate (3×100 ml), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was eaporated and the crude product was purified by column chromatography over silica gel 60, using 5% of methanol in dichloromethane as the eluent. Fractions containing the product were collected to afford 21 mg (5%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((4-piperidinobutoxy)methyl)pyrrolo[2,1,5-cd ]indolizine as an oil. MS(SP): m/z 640 (M+). 1H-NMR (DMSO-d6, 300 MHz) δ: 1.28-1.58 (m, 13H); 2.21-2.57 (m, 6H); 3.08 (q, 2H); 3.37-3.48 (m, 2H+H2O); 4.72 (s, 2H); 5.20 (s, 2H); 5.60 (s, 2H); 7.22 (d, 2H); 7.32-7.69 (m, 14H); 7.98 (d, 1H).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].Cl[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C)C=O>[S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[N:4]1[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:2])=[O:3]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 22.6g (0.11 mole) of sodium saccharin and 15g (0.1 mole) of tert-butyl α-chloroacetate in 150 ml of dimethylformamide is heated on a steam bath for 1 hour, allowed to stir at room temperature for 16 hours and poured into ice-water. The solution is dried over magnesium sulfate and the solvent is evaporated to give 24.9g of tert-butyl N-saccharinylacetate, m.p. 130°-132.5° C. This is refluxed with 300 ml of benzene and 1.4g (0.01 mole) of p-toluenesulfonic acid monohydrate to cause quantitative precipitation of 2-carboxymethylsaccharin, m.p. 212°-215° C. The completion of the reaction is established by passing a slow stream of nitrogen through the reaction mixture and into a solution of bromine in carbon tetrachloride. Failure to decolorize the bromine indicates that no more isobutylene is being evolved.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH:8]=[O:9].[C:10]([Mg]Cl)#[CH:11]>>[OH:9][CH:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1])[C:10]#[CH:11]
Reactant: COc1ccsc1C=O
Reactant: C#C[Mg]Cl
Product: C#CC(O)c1sccc1OC

Procedure:
3-Methoxy-2-thiophenecarboxadlehyde was prepared by adding n-butyllithium (10.56 mmol, 2.5M solution in hexane)(Aldrich), without cooling, to a solution of 3-methoxythiophene (1 g,8.8 mmol) (Aldrich) in dry diethyl ether (5 mL) over a period of 5 min. The mixture was gently heated at reflux for 2 h at which time the organolithium compound was transferred, via cannula, to a solution of DMF (23 mmol) in diethyl ether (5 mL) which was cooled in an ice bath. The reaction was stirred at room temperature for 14 h, at which time 1N HCl (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (3×25 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated to yield 3-methoxy-2-thiophenecarboxaldehyde as a pale, yellow solid. The 3-methoxy-2-thiophenecarboxaldehyde was then added to ethynylmagnesium chloride (Aldrich) according to Method A above to yield 3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propyne. (Yield 151 mg, 0.9 mmol).
Reaction SMILES: [CH2:1]([C:8]1[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][NH:14][CH:15]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]#[N:39]>>[CH2:1]([C:8]1[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:37][C:38]#[N:39])[CH:15]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(NCCCOc2ccccc2Cc2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCBr
Product: COc1ccc(C(c2ccc(OC)cc2)N(CC#N)CCCOc2ccccc2Cc2ccccc2)cc1

Procedure:
By following similar procedure as described in Preparation 93, N-alkylation of [3-(2-benzyl-phenoxy)-propyl]-[bis-(4-methoxy-phenyl)-methyl]-amine with bromoacetonitrile gives the title compound as oil. FABMS: m/z 506 (M)+, 507 (M+H)+.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1.[F:35][C:36]1[CH:41]=[C:40]([C:42]([NH:44]O)=[NH:43])[CH:39]=[CH:38][C:37]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O.CN(C)C=O>[F:35][C:36]1[CH:41]=[C:40]([C:42]2[N:43]=[C:30]([C:29]3[CH:28]=[CH:27][C:26]([CH2:25][OH:24])=[CH:34][CH:33]=3)[O:32][N:44]=2)[CH:39]=[CH:38][C:37]=1[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: N=C(NO)c1ccc(-c2ccccc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2nc(-c3ccc(-c4ccccc4)c(F)c3)no2)cc1
Temperature: 135 °C

Procedure:
1-Hydroxybenzotriazole hydrate (1.35 g, 0.01 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (1.95 g, 0.01 mol) are added to a stirred N,N-dimethylformamide solution (20 mL) of 4-hydroxymethylbenzoic acid (1.52 g, 0.01 mol). 2-Fluoro-N-hydroxybiphenyl-4-carboxamidine (2.3 g, 0.01 mol) is added to the reaction mixture which is then heated at 130-140° C. for 4 hrs. The reaction mixture is cooled to room temperature, Demineralized water (60 mL) is added and the aqueous layer is extracted with ethyl acetate (3×20 mL). Combined organic layers are washed with demineralized water (2×10 mL) followed by brine (1×20 mL) and finally dried over sodium sulphate. Removal of ethyl acetate under reduced pressure gives a crude liquid which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane 30:70) to furnish {4-[3-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazol-5-yl]phenyl}methanol.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[I-].[K+].C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][CH:2]([F:5])[CH2:3][NH:4][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: NCC(F)F
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNCC(F)F
Temperature: 25 °C
Reaction time: 25 h

Procedure:
2,2-difluoroethylamine (4.0 g) was added to a suspension of ethyl bromoacetate (5.4 mL), potassium iodide (0.82 g), diisopropylethylamine (9.8 mL) in acetonitrile (100 mL) and the mixture was stirred at RT for 25 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the sub-title compound (7.0 g) as a colorless oil; 1H NMR (300 MHz, CDCl3); 5.82 (1H, tt), 4.18 (2H, q), 3.46 (2H, s), 3.00 (2H, dt), 1.26 (3H, t).
Reaction SMILES: [CH:1]1([CH:6]([CH2:19][CH3:20])[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(O)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O)(=O)=O>C(O)(=O)C.[Pd]>[CH:1]1([CH:6]([CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:8][CH3:9])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(C1CCCC1)C(O)(CC)c1ccc(OC)cc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: CCC(c1ccc(OC)cc1)C(CC)C1CCCC1
Yield: 86.4 %

Procedure:
1,1 g (4 mmol) of 4-cyclopentyl-3-(p-methoxyphenyl)-3-hexanol was hydrogenated in an acidic medium for instance in acetic acid in the presence of some drops of methanesulfonic acid by using 10% Pd-C as a catalyst to yield 0.9 g (86%) of the oily product as a mixture of threo and erythro isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:26]/[C:25](=[N:27]/[NH2:28])/[CH2:24][O:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO[C:39](OC)(OC)[CH3:40]>>[CH3:39][C:40]1[N:26]2[C:21]3[CH:20]=[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH:7][C:6](=[O:36])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)=[N:29][C:22]=3[O:23][CH2:24][C:25]2=[N:27][N:28]=1
Reactant: COC(C)(OC)OC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N/C(=N/N)CO4)cc2)CCC1
Product: Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Yield: 47 %

Procedure:
A solution of (E)-tert-butyl(1-(4-(2-hydrazono-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.103 mmol) in 1,1,1-trimethoxyethane (1 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 100% ethyl acetate in n-hexanes) to give the title compound (24 mg, 47%). LCMS (Method A): RT=6.71 min, M+1=510. 1H NMR (500 MHz, CDCl3): 7.84 (1H, s), 7.37-7.33 (5H, m), 7.30-7.27 (2H, m), 7.24-7.19 (2H, m), 5.59 (2H, s), 2.87 (3H, s), 2.54-2.40 (4H, m), 2.13-2.02 (1H, m), 1.87-1.78 (1H, m), 1.45-1.27 (9H, br s).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:28]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:38][C:35]1[CH:36]=[CH:37][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-tert-butylphenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.55 g of p-tert-butylphenol in 75 ml of tetrahydrofuran at 80° C. for 18 hr to give the product as a gum.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:7][C:6]=2[CH:11]=1
Reactant: Nc1nc2cc(Br)c(F)cc2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Temperature: 80 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution of iii (0.36 g, 1.45 mmol) in 1,4-dioxane (25.0 mL) was added ethyl isocyanate (0.69 mL, 8.74 mmol) and the mixture heated at 80° C. for 15 h. The solvent was evaporated and the residue stirred with H2O at 60° C. for 5 h. The solution was filtered and washed with Et2O to obtain Intermediate 13 (0.30 g, 69%).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10][C@@H:2]12.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10][C@@H:2]12.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CC[C@H]2NCCO[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (4aR,8aR)-6-benzyl 1-tert-butyl hexahydro-1H-pyrido[3,4-b][1,4]oxazine-1,6(7H)-dicarboxylate (388 mg, 1.03 mmol) dissolved in DCM (2.8 mL) was added TFA (0.57 mL). The reaction was stirred at room temperature for 16 hours. The mixture was concentrated to afford benzyl (4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as a TFA salt. MS ESI calc'd. for C15H20N2O3 [M+H]+ 277. found 277.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[C:11](=[C:15](O)[CH2:16][O:17][CH3:18])[C:10](=[O:20])[CH2:9]1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[NH:23][N:22]=[C:15]([CH2:16][O:17][CH3:18])[C:11]=2[C:10](=[O:20])[CH2:9]1
Reactant: NN
Reactant: COCC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Solvent: O
Solvent: CCO
Product: COCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 25.3 %

Procedure:
A solution of 5-(2-chlorophenyl)-2-(1-hydroxy-2-methoxyethylidene)cyclohexane-1,3-dione (0.4 g) and hydrazine hydrate (0.072 g) in ethanol (15 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give 6-(2-chlorophenyl)-3-methoxymethyl-4,5,6,7-tetrahydroindazol-4-one (0.1 g) as oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37](OC1C=CC=CC=1)=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)Oc1ccccc1
Reactant: Nc1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)Nc1ccccn1
Yield: 67.1 %

Procedure:
A solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(phenoxycarbonylamino)pentanoyl]oxyhexadecanamide (1.70 g) and 2-aminopyridine (2.56 g) in pyridine (10 ml) was stirred at 70° C. for 64 hours, and then poured into a mixture of ethyl acetate (100 ml) and 1N hydrochloric acid (100 ml). The organic phase was washed with 1N hydrochloric acid (100 ml), 0.5N hydrochloric acid (100 ml), saturated aqueous sodium bicarbonate (100 ml), and brine (50 ml) successively, dried over magnesium sulfate, and evaporated to dryness. The residue was chromatographed on silica gel (300 cc) eluting with a mixture of dichloromethane and acetone (2:1 - 1:1) to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-{3-(2-pyridyl)ureido}pentanoyl]oxyhexadecanamide (1.14 g).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=O)OC(C)(C)C)[CH2:9][CH2:8]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:7]1[CH2:8][CH2:9][CH:10]([NH:13][CH3:14])[CH2:11][CH2:12]1
Reactant: CN(C)CCC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CCN(CCCN(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
A solution of tert-butyl [1-(3-dimethylaminopropionyl)piperidin-4-yl]carbamate (2.73 g) in tetrahydrofuran (30 ml) was stirred in an ice bath, and lithium aluminum hydride (1.04 g) was gradually added thereto. The mixture was stirred under a nitrogen atmosphere, for 15 minutes in an ice bath and for 15 minutes at room temperature. It was further heated to reflux for 7 hours under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath, and then water (1.0 ml), 5N aqueous sodium hydroxide (1.0 ml) and water (5.0 ml) were added thereto in that order and stirring was carried out on ice. The insoluble portion was filtered. The filtrate was concentrated to provide the title compound (1.51 g, 83.2%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([OH:11])[CH:9]([C:12]([OH:14])=[O:13])[CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=[O:4].C1([C@@H](N)C)C=CC=CC=1.CC(O)C.CCCCCC>CO.CC#N>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([OH:11])[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(C(=O)O)C1O
Agent: C[C@H](N)c1ccccc1
Solvent: CCCCCC
Solvent: CC#N
Solvent: CC(C)O
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C(=O)O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3R,4S,5S), and (3S,4R,5R), -N-tert-Butyloxycarbonyl-4-hydroxy-piperidine-3,5-dicarboxylic acid 3-methyl ester (96% ee) (78 g, 0.26 mol) is dissolved in MeOH (500 mL) and (S)-(−)1-phenylethylamine (33 mL, 0.26 mol) at room temperature is added. The mixture is stirred for 30 min at room temperature and concentrated under reduced pressure to provide a salt as a colorless amorphous. The resulting residue is dissolved in CH3CN (1.3 L) at 70° C. and stirred vigorously at room temperature for 20 h. A white crystalline salt is collected by filtration, washed with Et2O. After repeating the same recrystallization procedure (dissolution in CH3CN and stirring at room temperature) two or three times the resulting salt is dissolved in water, acidified to pH 3 with 5N and 1N HCl, and extracted with AcOEt. The combined organic phases are dried over Na2SO4. Concentration under reduced pressure gives enantiomeric pure (3R,4S,5S)-starting material-G as a white solid: ES-MS: M+H=304: CtRet=2.37 min. chiral HPLC: >99.9% ee, AD-H, 7.5% i-PrOH/Hexane/0.1% TFA, flow 0.75 mL/min, 210 nm, tRet=24 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>[Pt](=O)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)NCc1ccnc(Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-cyanopyridine (1.9 g), platinum dioxide (0.3 g), acetic anhydride (50 ml) and acetic acid (50 ml) was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between chloroform and dilute aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated to give N-(2-chloropyrid-4-ylmethyl)acetamide (1.5 g), as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH2:25][CH2:26]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[O:22][CH3:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1ccccc1CCBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1ccccc1CCN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 52 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 6) and 2-methoxyphenethyl bromide. Yield: 52%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.51 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 4.03 (s, 2H), 5.17 (s, 2H), 6.85 (t, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.16-7.21 (m, 2H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 410.2. found 410.1. Melting point: 97-98° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([O:26]CC2C=CC([N+]([O-])=O)=CC=2)=[O:25])[CH2:8][N:7]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O.[H][H]>O1CCCC1.P([O-])([O-])([O-])=O.[OH-].[OH-].[Pd+2]>[F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([OH:26])=[O:25])[CH2:8][NH:7]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](COCCF)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCF)C3)[C@H](C)[C@H]12
Yield: 45.2 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.80 g) in a mixture of tetrahydrofuran (50 ml) and 0.1M phosphate buffer (pH 5.8) (50 ml) was stirred at ambient temperature for 5 hours in the presence of 20% palladium hydroxide on carbon (0.3 g) under atmospheric pressure of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran. The resulting aqueous solution was washed with ethyl acetate (50 ml×2) and evaporated to remove the organic solvent. The residual solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (trademark, made by Mitsubishi Chemical Industries) (50 ml) and eluted with a mixture of acetone and water (5:95 V/V). The fractions containing the desired compound were combined and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.20 g).