Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:9])[F:10])[C:3]=1[CH2:11][OH:12]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1nc(C(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
A solution of 7.2 g (37.0 mmoles) of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde dissolved in 100 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1 g (55.5 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.8 g (yield: 52.1%) of (5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26](ON3C(=O)CCC3=O)=[O:27])=[C:24]([CH2:36][OH:37])[N:23]=[C:22]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl.[NH2:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46].Cl>CN(C)C1C=CN=CC=1>[C:45]([CH2:44][NH:43][C:26]([C:25]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:22]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:23][C:24]=1[CH2:36][OH:37])=[O:27])([OH:47])=[O:46]
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCc1nc(CO)c(C(=O)NCC(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 53, but using 0.32 g of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in Example 52(a)], 0.11 g of t-butyl glycinate hydrochloride and 80 mg of 4-dimethylaminopyridine, 0.21 g of the hydrochloride of the title compound was obtained as an amorphous powder melting at above 110° C. (with softening).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C([Si]([O:41][CH2:42][CH2:43][C:44]1([CH2:50][CH3:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.Cl>O1CCCC1>[CH2:50]([C:44]1([CH2:43][CH2:42][OH:41])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)[CH3:51]
Reactant: CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCC1(CCO)CCCCC1
Reaction time: 2 h
Yield: 59.2 %

Procedure:
After adding a 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution (7.70 mL, 7.70 mmol) to a solution of tert-butyl-2-(1-ethylcyclohexyl)ethoxydiphenylsilane (3.02 g, 7.65 mmol) in tetrahydrofuran (20 mL) at room temperature, the mixture was stirred for 2 hours. A 1.0 M tetrabutylammonium fluoride tetrahydrofuran solution (7.70 mL, 7.70 mmol) was then added, and the mixture was stirred for 14 hours. After further adding 1N hydrochloric acid (20 mL) to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. After filtering and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (100 g Merck Art. 9385, hexane:ethyl acetate=6:1) to obtain the title compound as a colorless oil (708 mg) (3 steps, 57% yield).
Reaction SMILES: Cl.[F:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=2)[C:20]1=[O:33].CCN(C(C)C)C(C)C>CN(C=O)C>[F:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=3)[C:20]2=[O:33])[CH2:4]1
Reactant: COc1ccc([C@H]2CCNC[C@@H]2F)cc1F
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@@H]2F)cc1F
Temperature: 120 °C
Yield: 121.7 %

Procedure:
A mixture of (3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg, 0.114 mmol, from step K), 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.189 mmol, intermediate 6) and DIPEA (0.020 mL, 0.114 mmol) in DMF (3 mL) was heated to 120° C. for 90 min in the a microwave reactor. The solvent was then removed under reduced pressure to obtain 60 mg of 3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) which was used in the next step without further purification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[C:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C:29]([OH:39])=[O:28])=[CH:36][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(Cl)cccc23)c1
Product: O=C(O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(Cl)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-chloro-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 507.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22]O2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)[C:30](O)=[O:31].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.O1CCCC1CCN>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH:24]2[CH2:23][CH2:22][CH2:30][O:31]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: NCCC1CCCO1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(tetrahydro-2-furanyl)ethanamine.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C.O>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([O:1][C:2]2[CH:14]=[C:13]3[C:5]([C:6]4[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][C:11]=4[NH:12]3)=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(Oc3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 140 °C
Yield: 44.8 %

Procedure:
To a round bottom flask containing Compound 9 (80 mg, 0.268 mmol) in DMF (2 mL) was added potassium carbonate (74.1 mg, 0.536 mmol) and 4-fluoro-nitrobenzene (41.6 mg, 0.295 mmol). The reaction mixture was heated for 20 min at 140° C. After cooling down to rt, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic layers were dried, concentrated. The residue was purified on a silica gel column (EtOAc: Hexanes=3:7) to afford Compound 10 as a yellow solid (50 mg, 0.12 mmol, 44% yield). 1H NMR (400 MHz, CDCl3) δ: 8.22 (d, J=9.2 Hz, 2H), 8.10 (br, 1H), 8.00-7.90 (m, 3H), 7.12 (s, 1H), 7.06-6.90 (m, 4H), 6.70 (br, 1H), 1.56 (s, 9H); LRMS for C23H21N3O5+H+, calc'd: 420.2. found: 420.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][NH:10][CH2:11][CH2:12][C:5]=2[NH:4][C:3]1=[O:13].Cl[CH2:15][CH2:16][S:17][CH3:18].[Br-].[Li+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][N:10]([CH2:15][CH2:16][S:17][CH3:18])[CH2:11][CH2:12][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Reactant: CSCCCl
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCCN1CCc2[nH]c(=O)n(C)c(=O)c2C1
Yield: 45 %

Procedure:
36.3 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]-pyrimidine-2,4-dione, 23 g of 1-chloro-2-methylsulfanylethane (97% pure), 17.4 g of lithium bromide and 27 g of ethyldiisopropylamine in 700 ml of dimethylformamide were stirred for 14 h at 50° C. After the reaction mixture had been concentrated under reduced pressure, the residue was taken up with 400 ml of water and 400 ml, of dichloromethane, the pH was adjusted to 8 with sodium bicarbonate, with stirring, and the mixture was worked up by extraction with dichloromethane and water. 23 g of 3-methyl-6-(2-methylsulfanylethyl)-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were obtained from the combined dichloromethane phases after drying, concentration and recrystallization of the residue from isopropanol.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18 mmol), triethylamine (0.028 mL, 0.2 mmol) and isobutyryl chloride (0.021 mL, 0.2 mmol) were dissolved in toluene (2.0 mL).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:9](O)(=[O:13])[C:10]([CH3:12])=[CH2:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: OCCCCCCO
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=C(C)C(=O)OCCCCCCO
Temperature: 90 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
1,6-Hexanediol (1000.00 g, 8.46 mol, Sigma-Aldrich) was placed in a 1-liter 3-neck flask equipped with a mechanical stirrer and a narrow tube blowing dry air into the flask. The solid diol was heated to 90° C., at which temperature all the solid melted. With continuous stirring, p-toluenesulfonic acid crystals (18.95 g, 0.11 mol) followed by BHT (2.42 g, 0.011 mol) and methacrylic acid (728.49.02 g, 8.46 mol). Heating at 90° C. with stirring was continued for 5 hours during which time vacuum was applied using tap water aspirator for 5-10 minutes after each half-hour reaction time. The heat was turned off and the reaction mixture was cooled to room temperature. The viscous liquid obtained was washed with 10% aqueous sodium carbonate twice (2×240 ml), followed by washing with water (2×240 ml), and finally with 100 ml of saturated NaCl aqueous solution. The obtained oil was dried using anhydrous Na2SO4 then isolated by vacuum filtration to give 1067 g (67.70%) of 6-hydroxyhexyl methacrylate, a yellow oil. This desired product was formed along with 15-18% of 1,6-bis(methacryloyloxyhexane). Chemical characterization was by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]2[O:33][CH2:11][O:12][C:13]=2[CH:14]=1)(=[O:28])=[O:27]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1Cl

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-chloro-3-methyl-5-aminoisoxazole (0.61 mmoles, 81 mg), NaH (1.5 mmoles), 61 mg), and 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (0.74 mmoles, 0.27 g) in THF (4 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes followed by recrystallization from ethyl acetate and hexanes, 0.23 g (81%) of a light brown solid, m.p. 178-181° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:42])[C:14]=3[CH:43]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:42])[C:14]=3[CH:43]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccc(Cl)nc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccc(Cl)nc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Ethyl 3-{[(4-{[{5-[(6-chloropyridin-3-yl)methoxy]-3-methyl-1-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (0.31 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.22 g, 74%) as a colorless solid.
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[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[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:24]=[CH:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=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: OCc1cccc(CBr)n1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CO)n3)C2=O)cn1
Yield: 35 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 6-bromomethyl-2-pyridinemethanol. Yield: 35%. MS M+H calculated 397.2; found 397.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.72 μM.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 4-(3-(acetamido)phenyl)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 4-(3-(acetamido)phenyl)-2-(4-fluoroanilino)benzoic acid 32 mg of pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:11](=[O:22])[NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:51]([CH2:53][NH2:54])[OH:52]>ClCCl.O>[C:1]1([CH:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:11](=[O:22])[NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:54][CH2:53][CH2:51][OH:52])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCO
Reactant: O=C(O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCCO)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Reaction time: 14 h

Procedure:
ylethyl)ureido]benzoic acid (obtained in Example 45) dissolved in dichloromethane are introduced into a 100 mL flask under an argon atmosphere, then HOBt (27 mg, 1.2 eq.), EDC (37 mg, 1.2 eq.), and ethanolamine (12 mg, 1 eq.) are added to the medium. After reacting for 14 hours, the mixture is neutralised with water, then with a saturated NaHCO3 solution and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with brine, then, dried over MgSO4 and concentrated. The crude product thus obtained is purified by silica column chromatography (eluent: CH2Cl2/MeOH 99/1 to 96/4). The desired amide, 3-[3-(3,3-diphenylpropyl)-3-(2-morpholin-4-ylethyl)ureido]-N-(2-hydroxyethyl)benzamide, is obtained in a yield of 52%. This procedure is hereinafter called method “J”, route 2.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[NH:19][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][CH:6]1[CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[NH:19][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CCN=[N+]=[N-])C4)C(=O)NC2=O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CCN)C4)C(=O)NC2=O)c2ccccc21
Yield: 10.6 %

Procedure:
200 mg of the pyrroledione product of Example 16 in 70 ml of methanol containing 40 mg of 10% Pd/C were shaken under a hydrogen atmosphere at a pressure of 3 atmospheres for 48 hours. The supernatant was decanted and evaporated. The residue was treated with 50 ml of a saturated solution of hydrogen chloride in ethyl acetate and was then purified by chromatography on silica gel with dichloromethane/methanol/acetic acid/water (60:18:2:3). Crystallization from ethyl acetate gave 20 mg of 3-[8-(2-aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 160°-165° C.
Reaction SMILES: O(CC(N)C)C1C=CC=CC=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(N)=NC=2Cl)(=O)C.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.C([O:60][C@@H:61]1[C@H:65]([O:66]C(=O)C)[C@@H:64]([CH2:70][O:71]C(=O)C)[O:63][C@H:62]1[N:75]1[C:94]2[N:93]=[C:92]([NH2:95])[N:91]=[C:79]([NH:80][CH:81]([CH3:90])[CH2:82][O:83][C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C:78]=2[N:77]=[CH:76]1)(=O)C.N>O1CCOCC1>[NH2:95][C:92]1[N:91]=[C:79]([NH:80][CH:81]([CH3:90])[CH2:82][O:83][C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[C:78]2[N:77]=[CH:76][N:75]([C:94]=2[N:93]=1)[C@@H:62]1[O:63][C@H:64]([CH2:70][OH:71])[C@@H:65]([OH:66])[C@H:61]1[OH:60]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(C)COc4ccccc4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(N)COc1ccccc1
Agent: N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CC(COc1ccccc1)Nc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
1-Phenoxy-2-propylamine (2.90 g, 19.2 mmol) and 9-(2,3,5-tri- O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-9H-purine (6.94 g, 16.2 mmol) were dissolved in dioxan (50 ml) and triethylamine (4.5 ml, 33.2 mmol) was introduced. After stirring the reaction mixture for 18 h at room temperature, diisopropylethylamine (2.08 g, 16.1 mmol) was added and the solution was heated at 80° C. for 100 h. Following column column chromatography, a 1.3 g sample of the resultant 2',3',5'-tri- O-acetyl-2-amino- N-(1-phenoxy-2-propyl)adenosine was deprotected using saturated methanolic ammonia (50 ml). The reaction mixture was evaporated, and the residue dissolved in in a mixture of ethyl acetate (150 ml) and water (150 ml). The phases were separated and the ethyl acetate phase was washed with water (2×150 ml). The ethyl acetate phase was then extracted with pH 2 dilute hydrochloric acid, and this acidic aqueous phase was washed with ethyl acetate (2×100 ml), and basified with sodium bicarbonate solution before extraction with ethyl acetate (100 ml). The ethyl acetate phase was was dried (MgSO4) and evaporated to give the title compound (0.43 g, 33%) a mixture of diastereoisomers as an amorphous foam, 1H NMR (DMSO-d6)δ 1.28 (3H, d, --CH3), 3.49-3.57 (1H, m, H-5'a), 3.61-3.68 (1H, m, H-5'b), 3.85-3.94 and 4.07-4.15 (4H, 2m, m, H-4', H-3' and --CH2 --), 4.50 (1H, q, H-2'), 4.68 (1H, br, --C HCH3), 5.11, 5.36 (2H, 2d, 2'- and 3'-OH), 5.40 (1H, t, 5'-OH) 5.73 (1H, d, H-1'), 5.83 (1H, br, --NH2), 6.88-6.96 (3H, m, Ar--H), 7.22-7.31 (2H, t, Ar--H), 7.95 (1H, s, H-8).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9](=S)[NH:10][C:11]2[NH:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:33])[C:31]=1[F:32])[CH2:27][NH2:28].Cl.C(N=C=NCCCN(C)C)C>CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6](/[N:8]=[C:9](/[NH:28][CH2:27][C:26]2[CH:29]=[C:30]([F:33])[C:31]([F:32])=[C:24]([F:23])[CH:25]=2)\[NH:10][C:11]2[NH:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(Cl)cc1
Reactant: NCc1cc(F)c(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: O=C(/N=C(/NCc1cc(F)c(F)c(F)c1)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-N-((3-(trifluoromethyl)-1H-pyrazol-5-yl)carbamothioyl)benzamide (500 mg, 1.43 mmol) was dissolved in methanol (5 mL) and 3,4,5-trifluorobenzylamine (462 mg, 2.87 mmol) was added followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (550 mg, 2.87 mmol). The reaction was stirred at 50° C. for 30 minutes. The crude mixture was then partitioned between water and ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate, then purified by chromatography (gradient: 95:5 hexanes:EtOAc to 7:3 hexanes:EtOAc). (Z)-4-Chloro-N-(((3,4,5-trifluorobenzyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)benzamide was obtained as a solid (221 mg, 32% yield). MS (ES+) 475.8.