Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:39][CH:40]([N-]C(C)C)C.C1COCC1.ICC.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:39][CH3:40])[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1CCN([C@H]2CC[C@@]3(O)[C@H]4Cc5ccc(OCc6ccccc6)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)C1=O
Reaction time: 1 h
Yield: 66.6 %

Procedure:
In 5 mL of THF, 248 mg (0.50 mmol) of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1 was dissolved, and 4.1 mL (1.48 mmol) of 0.36N LDA/THF solution was added at 0° C., followed by stirring the mixture for 1 hour. Thereafter, 0.08 mL (0.99 mmol) of iodoethane was added thereto and the resulting mixture was stirred for 3 hours. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 176 mg (yield: 67%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2.[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]1[CH2:25][O:24]1)([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]([OH:24])[CH2:25][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2)([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: CCN1C(=O)Cc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21

Procedure:
5-Amino-1-ethyl-7-fluoro-1,3-dihydro-indol-2-one (2.25 g, 11.6 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (2.00 g, 11.6 mmol) and lithium trifluoromethanesulfonate (1.80 g, 11.6 mmol) in acetonitrile (12 ml) are heated at 90° C. for 20 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow-brown foamy solid. HPLC r.t. 3.95 min; MS for C 18H26FN3O4 m/z 368.3 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25])=[S:14].[CH3:26]O>>[ClH:1].[ClH:1].[ClH:1].[CH3:26][S:14][C:13](=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[N:5]=[CH:6][NH:7][C:3]=1[CH3:2])[NH:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25]
Reactant: CO
Reactant: Cc1[nH]cnc1CSCCNC(=S)NCCSCc1nc[nH]c1C
Agent: Cl
Product: CSC(=NCCSCc1nc[nH]c1C)NCCSCc1nc[nH]c1C

Procedure:
Dry hydrogen chloride was passed into a solution of N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea (7.7 g) in methanol at 80° for 5 hours. Concentration and re-evaporation with isopropyl alcohol afforded S-methyl-N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]isothiourea trihydrochloride (9.0 g), m.p. 212°-215° (isopropyl alcohol).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:29][C:30]1[CH:31]=[C:32]([C:36](=O)[CH3:37])[CH:33]=[N:34][CH:35]=1>C1COCC1>[Br:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32]([C:36]([CH3:37])=[CH:2][O:3][CH3:4])[CH:31]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1cncc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C(C)c1cncc(Br)c1
Temperature: -78 °C
Yield: 54.8 %

Procedure:
To a solution of methoxymethyltriphenylphosphonium chloride (20.57 g, 60 mmol) in THF at −78° C. was added slowly butyl lithium (1.6 M in hexanes, 37.5 mL). The resulting mixture was further stirred for 45 min to room temperature. After the reaction was cooled down to −78° C., 1-(5-bromopyridin-3-yl)ethanone (Aldich) (8 g, 40 mmol) in THF was added to the reaction mixture. The resulting solution was stirred from −78° C. to room temperature for overnight, then quenched with saturated aqueous NH4Cl solution, and extracted with diethyl ether three times. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and concentrated to a residue which was purified by flash column to give 3-bromo-5-(1-methoxyprop-1-en-2-yl)pyridine (E/Z mixture, 5 g). 1H NMR (300 MHz, CDCl3), d: 8.769 (m, 0.5H), 8.491 (m, 1.5H), 8.143 (m, 0.4H), 7.737 (m, 0.6H), 6.517 (m, 0.6H), 6.271 (m, 0.4H), 3.804, 3.773 (ss, 3H), 1.949 (m, 3H). The aldehyde was synthesized using the methods described herein.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:16])[CH3:13]
Reactant: Cc1ncoc1CSCCN
Reactant: CCN=C=S
Product: CCNC(=S)NCCSCc1ocnc1C

Procedure:
Also, reacting 5-[(2-aminoethyl)thiomethyl]-4-methyloxazole with ethyl isothiocyanate by the procedure of Example 1 gives N-ethyl-N'-[2-((4-methyl-5-oxazolyl)-methylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][N:2]([C:11]1[C:15]2[NH:16][C:17]([C:19]3[S:20][C:21]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:22][N:23]=3)=[CH:18][C:14]=2[S:13][C:12]=1[CH3:29])[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1>[C:37]([N:26]1[CH2:27][CH2:28][C:21]2([S:20][C:19]([C:17]3[NH:16][C:15]4[C:11]([N:2]([CH3:1])[S:3]([C:6]5[S:7][CH:8]=[CH:9][CH:10]=5)(=[O:5])=[O:4])=[C:12]([CH3:29])[S:13][C:14]=4[CH:18]=3)=[N:23][CH2:22]2)[CH2:24][CH2:25]1)(=[O:39])[CH3:38]
Reactant: Cc1sc2cc(C3=NCC4(CCNCC4)S3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)CN=C(c1cc3sc(C)c(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a mixture of N-methyl-N-[2-methyl-5-(1-thia-3,8-diazaspiro[4.5]deca-2-en-2-yl)-4H-thieno[3,2-b]pyrrol-3-yl]thiophene-2-sulfonamide (180 mg), triethylamine (78 μL) and tetrahydrofuran (5 mL) was added acetyl chloride (32 μL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-[5-(8-acetyl-1-thia-3,8-diazaspiro[4.5]deca-2-en-2-yl)-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl]-N-methylthiophene-2-sulfonamide (115 mg, yield 57%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 231° C.
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[CH3:25][C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([CH3:29])[CH2:27][CH3:28].FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=2)=[CH:32][CH:31]=1)([CH3:29])[CH2:27][CH3:28]
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: CCC(C)(C)c1ccc(C=O)cc1
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Yield: 94 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1,1-dimethylpropyl)-benzaldehyde (prepared as described in example S103) (88 mg, 0.50 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (94 mg, 0.50 mmol) and sodium borohydride (28 mg, 0.75 mmol). The desired product (163 mg, 94%) was isolated without further purification as a colorless oil. MS (ISP) 350.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CC(C)(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 2-(benzylthio)-2-methylpropylamine (0.47 g), 1H-1,2,3-benzotriazol-1-ol (0.35 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.86 g, yield 77%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:9-42:3, volume ratio). melting point 170-171° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][C:7]([Br:11])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.FC1C=CC(CCN2CCC(=[O:28])CC2)=CC=1>>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][C:7]([Br:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:28]
Reactant: O=C1CCN(CCc2ccc(F)cc2)CC1
Reactant: CC1(C)CNc2cc(Br)ccc21
Product: CC1(C)C(=O)Nc2cc(Br)ccc21
Yield: 89.2 %

Procedure:
3,3-Dimethyl-6-bromoindoline (3.10 g), 1-[2-(4-fluorophenyl)ethyl]-4-piperidone (2.81 g) and triacetoxylated sodium borohydride (5.70 g) were treated as in Example 16 to give the title compound (2.72 g) as a white amorphous solid (yield: 49.8%).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>ClCCCl>[Br:15][C:16]1[N:21]=[C:20]([CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=[CH:18][CH:17]=1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
NaBH(OAc)3 (68.5 g, 0.323 mol) was added to a solution of 6-bromopicolinaldehyde 62 (40 g, 0.22 mol) and morpholine 63 (20.9 g, 0.24 mol) in 1,2-dichloroethane (500 mL). The mixture was stirred at room temperature for 16 h. Saturated NaHCO3 (500 mL) was added and the mixture was extracted with EtOAc, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether:ethyl acetate (10:1) to give 64 (38 g, 68% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a stirred and cooled (0° C.) solution of tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) (0.10 g, 0.22 mmol) in dichloromethane (1.6 mL) was added trifluoroacetic acid (0.19 mL, 0.25 mmol), and the solution was allowed to warm slowly to ambient temperature and stirred overnight. The reaction mixture was concentrated, taken up in hexanes, and concentrated until a solid was obtained. The solid was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated sodium bicarbonate. The organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid (0.075 g, 97%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.18-8.07 (m, 2H), 7.83-7.74 (m, 2H), 7.41-7.29 (m, 4H), 3.02 (t, J=6.8 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 1.45-1.29 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −58.04.
Reaction SMILES: COC(=O)[C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Br:18])[C:12]=2[CH3:19])=[O:9])=[C:6](F)[CH:5]=1.[CH3:24][N:25](C)[C:26]1C=CC(C(Cl)=O)=CC=1>>[Br:18][C:13]1[C:12]([CH3:19])=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:20]=[CH:21][C:4]([N:25]([CH3:26])[CH3:24])=[CH:5][CH:6]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)Nc2cc(F)cc(Br)c2C)c(F)c1
Product: Cc1c(Br)cc(F)cc1NC(=O)c1ccc(N(C)C)cc1

Procedure:
Intermediate 46 was prepared analogue to Intermediate 34 by replacing Intermediate 33 with 4-dimethylamino-benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([Mg]Br)[CH:17]=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: COc1ccc(F)cc1[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)c1cccc(Br)c1F
Temperature: -78 °C
Yield: 100 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (5-fluoro-2-methoxyphenyl)magnesium bromide in THF (11.82 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, then allowed to warm to room temperature. The reaction mixture was then re-cooled to 0° C. and additional (5-fluoro-2-methoxyphenyl) magnesium bromide in THF (11.82 mL, 5.91 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl and diluted with CH2Cl2. The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 20 min, tr=17.5 min) gave the title compound (1.62 g, 4.92 mmol, 100% yield) as a colorless liquid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[CH2:20]2)=[O:17])[NH:13][C:12]1=[O:37])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:45]([C:48]1[CH:58]=[CH:57][C:51]([CH2:52][O:53][CH2:54][CH2:55]Cl)=[CH:50][CH:49]=1)([O-:47])=[O:46].P([O-])([O-])([O-])=O>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[CH2:20]2)=[O:17])[N:13]([CH2:55][CH2:54][O:53][CH2:52][C:51]2[CH:57]=[CH:58][C:48]([N+:45]([O-:47])=[O:46])=[CH:49][CH:50]=2)[C:12]1=[O:37])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
57.7 mg (0.105 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-([(S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl)-2-azetidinone and 33 mg (0.33 mmole) of triethylamine were dissolved in 3 ml of methylene chloride. To the solution were added 73 mg (0.30 mmole) of p-nitrobenzyloxyethyl chloride, with ice-cooling under a nitrogen atmosphere. The mixture was stirred for 1 hour and then poured into a 0.1M phosphate buffer solution (pH 7.2). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride. The solvent was distilled off and the residue was purified by column chromatography through 1.3 g of silica gel, to give 67.8 mg (yield 83%) of the desired product as an oil from the fraction eluted with mixtures of benzene and ethyl acetate in volume ratios from 12:1 to 4:1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH:18]([OH:19])[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)[C@H](CCc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cooled solution of [(5)-3-(4-bromo-phenyl)-1-formyl-propyl]-carbamic acid tert-butyl ester (7.3 g) in THF (40 ml) and Et2O (30 ml) at 0° C. was added dropwise over 30 min a solution of methylmagnesium bromide (20.0 ml, 3 M solution in Et2O). The reaction mixture was then stirred at room temperature for 4 hours before being quenched by dropwise addition of water (gas formation!). The reaction mixture was then poured into EtOAc, the layers were separated and the organic layer was washed sequentially with diluted aq. HCl (pH 5) and saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 80% EtOAc in hexane) to afford {(1S,2RS)-1-[2-(4-bromo-phenyl)-ethyl]-2-hydroxy-propyl}-carbamic acid tert-butyl ester as a colourless amorphous solid comprising a mixture of epimers (5.1 g, 66%). MS (EI): 303 ([{81Br}M−C4H8]+), 301 ([{79Br}M−C4H8]+), 258 ([{81Br}M−C4H8—CO2H]+), 256 ([{79Br}M−C4H8—CO2H]+), 214, 212, 171, 169, 57 ([C4H9]+).
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.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[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]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccc(F)cc3)C2=O)cn1
Yield: 33 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-fluorobenzene. Yield 33%. MS M+H calculated 384.1; found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an I IC50 of 0.05 uM.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].CN1CCOCC1>CO>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CN(C)CCN
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCN(C)C)cc2s1
Yield: 9.6 %

Procedure:
the title compound (11 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N1,N1-dimethylethane-1,2-diamine (67 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 381.4 (M+1, 50%). Yield=9%.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)=[O:14])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:29]1[C:1]([C:3]2[C:4]([NH:9][C:10]3[CH:11]=[C:12]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=3)=[O:14])=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:2][N:31]=[N:30]1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Nc1ncccc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Nc1ncccc1-c1nnn[nH]1
Temperature: 130 °C

Procedure:
To 3-(3-cyanopyridin-2-ylamino)-N-(3-isopropylphenyl)-4-methylbenzamide (11 mg, 0.03 mmol), sodium azide (21 mg, 0.30 mmol) and ammonium chloride (17 mg, 0.30 mmol) was added DMF (0.5 mL). The mixture was heated to 130° C. in the microwave for 10 minutes. The reaction was quenched with saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 3-(3-(1H-tetrazol-5-yl)pyridin-2-ylamino)-N-(3-isopropylphenyl)-4-methylbenzamide. MS m/z [M+H]+=414; Calc'd for C23H23N7O: 413.49.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][OH:6].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.[OH-].[Na+]>CN(C)C(=O)C>[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][O:6][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1
Reactant: OCC(F)(F)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred suspension of sodium hydride (3.9 g, 96 mmol, 60% in oil) in N,N-dimethylacetamide (160 mL) is added dropwise 2,2,3,3,3-pentafluoropropan-1-ol (6.4 mL, 64 mmol) at 0° C. After stirring for 10 minutes, a solution of methyl 6-chloronicotinate (5.5 g, 32 mmol) in N,N-dimethylacetamide (10 mL) is added dropwise at 0° C., and the mixture is stirred for 30 minutes at room temperature. Then, the mixture is stirred at 90° C. for 2 hours. After cooled to room temperature, 2M aqueous sodium hydroxide is added (pH is around 6). The mixture is extracted with n-hexane/ethyl acetate (1:2, 200 mL). The organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure, and the residue is purified by column chromatography on amine gel eluting with n-hexane/ethyl acetate (30:1) to give 3.1 g (34% yield) of the title compound as brown oil. MS (ESI) m/z: 286 (M+H)+.