Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](Br)=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[OH:1][C:2]1[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1cc(C)cc(-c2ccccc2)c1O
Temperature: 75 °C
Yield: 71.8 %

Procedure:
2′-Hydroxy-3′-bromo-5′methylacetophenone 233 (0.46 g, 2 mmol) and phenylboronic acid (0.24 g, 1 eq.) are dissolved in DME (10 ml) and placed under a nitrogen atmosphere. Na2CO3 (0.50 g, 3 eq.) in water (10 ml) is added, followed by Pd(Ph3)4 (0.12 g, 0.05 eq.) and the reaction mixture heated to 75° C. for 12-18 h. Most of the DME is removed in vacuo and the reaction mixture is diluted with ether, washed with water, brine, and dried (MgSO4), and concentrated in vacuo to give an oil. Purification by flash chromatography (5/95 EtOAc/hexanes) afforded 2′-Hydroxy-3′-phenyl-5′methylacetophenone 234 as a yellow solid (0.32 g, 71% yield) (Example 519, Table IIIa).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=1.[I-:17].[Na+].C1(C)C=CC=CC=1.CNCCNC>[Cu]I.O>[I:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Br)cc1S(C)(=O)=O
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(I)cc1S(C)(=O)=O
Yield: 64.5 %

Procedure:
To a mixture of ethyl 4-bromo-2-methanesulfonylbenzoate (13.88 g), sodium iodide (13.54 g) and copper(I) iodide (4.30% g) were added toluene (46 mL) and N,N′-dimethylethylenediamine (4.86 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give ethyl 4-iodo-2-methanesulfonylbenzoate (10.32 g). To a mixture of the obtained ethyl 4-iodo-2-methanesulfonylbenzoate (3.22 g), (R)-3-methylisothiazolidine 1,1-dioxide (1.23 g) described in Preparation Example 2, copper(I) iodide (4.30 g), N,N′-dimethylethylenediamine (0.92 mL) and potassium carbonate (2.52 g) was added toluene (9.2 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.7 g).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].BrBr.C(O)(=[O:16])C>>[OH:16][CH2:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: CC(=O)O
Reactant: Cc1[nH]c2ncccc2c1C
Agent: BrBr
Product: Cc1c(CO)[nH]c2ncccc12

Procedure:
2,3-dimethylpyrrolo[2,3-b]pyridine(0,2 g 0.0014 mol) was treated in 3 ml acetic acid with an equimolecular amount of bromine and after 5 min yellow precipitate was formed. The solid was filtered off and treated with 3 ml water for 60 min. The mixture was made alkaline with bicarbonate and extracted with methylene chloride. When the organic layer had been dried and evaporated the product was isolated as a yellow oil. (0,12 g, 53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:6])[CH3:5])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([S:15][C:16]2[CH:26]=[CH:25][C:19]([O:20]CC(O)=O)=[C:18]([Cl:27])[CH:17]=2)[CH:11]=[C:12]([OH:14])[CH:13]=1.O[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:6])[CH2:5][O:20][C:19]1[CH:25]=[CH:26][C:16]([S:15][C:10]2[CH:11]=[C:12]([O:14][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:13]=[C:8]([Br:7])[CH:9]=2)=[CH:17][C:18]=1[Cl:27])[CH3:2]
Reactant: OCCCN1CCOCC1
Reactant: O=C(O)COc1ccc(Sc2cc(O)cc(Br)c2)cc1Cl
Reactant: CCOC(C)=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethyl acetate (1.7 g; 4.07 mmol), N-(3-hydroxypropyl)morpholine (0.59 g; 4.07 mmol) and tributylphosphine (1.8 g; 7.33 mmol) were dissolved in THF (100 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (1.85 g; 7.33 mmol) dissolved in THF (50 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane). Yield: 1.1 g. HPLC-MS: m/z: 544.0 (M+); Rt: 1.78 min.
Reaction SMILES: [Br:1][C:2]([Br:19])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]COC)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.C(O)C>Cl.O1CCCC1.C(OCC)C>[Br:19][C:2]([Br:1])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COCOc1ccc(-c2ccc(C=C(Br)Br)s2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-c2ccc(C=C(Br)Br)s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.3 %

Procedure:
A mixture of 2-(2,2-dibromoethenyl)-5-(4-methoxymethoxyphenyl)thiophene (8.8 g, 0.02 mole), prepared by the method of Example 6, ethanol (10 mL), and two drops of concentrated hydrochloric acid in tetrahydrofuran (50 mL) was stirred at room temperature for approximately 18 hours. Gaseous hydrogen chloride was bubbled into the mixture for several seconds, after which 10 mL of methanol was added. The resultant mixture was stirred at room temperature for two hours. This mixture was poured into an aqueous saturated ammonium chloride solution and extracted with diethyl ether. The ether extract was washed with an aqueous saturated ammonium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a solid residue. This residue was dissolved in diethyl ether, and approximately 50 g of silica gel was added to the solution. The mixture was stirred briefly and filtered. The filtrate was evaporated under reduced pressure, yielding 7.8 g of 2-(2,2-dibromoethenyl)-5-(4-hydroxyphenyl)thiophene as a solid (mp 99°-101° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][O:20]C(=O)C)[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26].C[O-].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)c(C=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=Cc1c(Br)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
5,6-Dichloro-2-bromo-3-formyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.136, 101 mg, 0.22 mmol) was dissolved in dry MeOH (10 mL) to which was added sodium methoxide (25 mg, 0.46 mmol). The solution was stirred at room temperature for 15 min, until the starting material was consumed (TLC). Water (30 mL) was added and the solution evaporated until the MeOH was completely removed. The residual aqueous suspension was extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine (20 mL), dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH and H2O to yield 43 mg (47%) of 4.137 as a pale tan powder: mp 210-211° C.; Rf0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 6.06 (d, 1H), 5.49-5.43 (m, 2H, D2O exch.), 5.31 (d, 1H, D2O exch.), 4.44 (q, 1H), 4.18 (m, 1H), 4.04 (d, 1H), 3.77-3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 185.53, 134.05, 128.85, 126.58, 126.47, 125.31, 120.56, 116.00, 114.68, 90.27, 86.55, 71.69, 69.62, 60.98. HRMS (EI) m/z calcd. for C14H12BrCl2NO5 422.9276, found 422.9271. Anal calcd for C14H12BrCl2NO5: C, 39.56; H, 2.85; N, 3.30. Found: C, 39.77; H, 3.03; N, 3.32.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:18]=O)[C:6]3[C:11]([C:12]=2[Cl:16])=[CH:10][C:9]([Cl:17])=[CH:8][CH:7]=3)[CH:3]=1.[NH2:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23]>>[ClH:1].[CH3:26][C:21]([NH:20][CH2:18][C:5]1[C:6]2[C:11]([C:12]([Cl:16])=[C:13]3[C:4]=1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14]3)=[CH:10][C:9]([Cl:17])=[CH:8][CH:7]=2)([CH2:24][OH:25])[CH2:22][OH:23]
Reactant: O=Cc1c2ccc(Cl)cc2c(Cl)c2ccc(Cl)cc12
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NCc1c2ccc(Cl)cc2c(Cl)c2ccc(Cl)cc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 2,6,10-trichloroanthracene-9-carbaldehyde (43B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-methyl-2-(((2,6,10-trichloro-9-anthracenyl)methyl)amino)-1,3-propanediol hydrochloride mp 275°-277° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.CN([C:17]([O:21][N:22]1N=NC2C=CC=C[C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C>>[CH3:17][O:21][N:22]([CH3:23])[C:10]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2nn[nH]c2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CON(C)C(=O)c1ccc2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1H-1,2,3-benzotriazole-6-carboxylic acid (Aldrich, 500 mg, 3.1 mmol), N,O-dimethylhydroroxylamine hydrochloride (Aldrich, 299 mg, 3.1 mmol), HBTU (1.5 g, 4.0 mmol) and trimethylamine (1.28 ml, 9.2 mmol) were added and the mixture was stirred for 18 hours at room temperature. Then, evaporation, purification through silica gel column chromatography eluting with DCM/MeOH (10:1) to give N-methoxy-N-methyl-1H-1,2,3-benzotriazole-6-carboxamide (LC-MS (MS (ESI) m/z 205 (M−H)−, 207 (M+H)+). To a THF (50 ml) solution of the product was added 0.96 M hexane solution of ethylmagnesium bromide (15 ml, 14.4 mmol) at 0° C., and the mixture was stirred for 16 hours at room temperature. Then the reaction was quenched with aqueous solution of ammonium chloride and the product was extracted with AcOEt, washed with brine, dried over magnesium sulfate. Then, evaporation in vacuo gave 1-(1H-1,2,3-benzotriazol-6-yl)propan-1-one (LC-MS (MS (ESI) m/z 174 (M−Hy, 176 (M+H)+).
Reaction SMILES: [NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH3:22])=[O:20])[CH:8](CC1C=CC=CC=1)[C:9](=[O:11])[OH:10])=[O:5])[CH3:2].C1(C[O:46][C:47]([C@@:49](C(Cl)=O)([CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:57])[NH2:56])[NH2:50])=O)C=CC=CC=1>C(O)(=O)C.O.[Pd]>[NH2:50][C@H:49]([C:47]([N:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:25])[CH3:22])=[O:20])[CH2:8][C:9](=[O:11])[OH:10])=[O:5])[CH3:2])=[O:46])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:56])[NH2:57]
Reactant: N=C(N)NCCC[C@](N)(C(=O)Cl)C(=O)OCc1ccccc1
Reactant: CNCC(=O)N[C@H](C(=O)N(C)CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CN(CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(=O)[C@H](CC(=O)O)NC(=O)CN(C)C(=O)[C@@H](N)CCCNC(=N)N
Reaction time: 15 h
Yield: 50.4 %

Procedure:
Alpha-Phenylmethoxycarbonyl-L-Arginyl(HCL)-Sarcosyl-beta-benzyl-L-Aspartyl-Sarcosyl-L-Tyrosine amide (1.0 g) was dissolved in 100 ml of 75% aqueous acetic acid and reduced with 0.5 g of 10% Pd/C at 50 p.s.i. for 15 hours. The catalyst was removed by filtration and the solution lyophilized to give 0.8 g. The material was dissolved in 7 ml water, filtered through a 3μ multipore filter, adjusted to pH 5 with NH4OH(conc.) and chromatographed in an SP-C-25 column (2.5×100 cm) with 0.20 M NH4OAc, pH 5.0, 100 ml/hr, 20 ml/tube. Tubes 71 to 78 were pooled and lyophilized to give 0.35 g of Arg-Sar-Asp-Sar-Tyr-NH2.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:30]=[CH:31][C:32]3[C:33]([CH:44]=2)=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[O:35][N:36]=3)=[O:28])=[CH:23][CH:22]=1>C1COCC1>[Cl:43][C:39]1[CH:38]=[C:37]([C:34]2[O:35][N:36]=[C:32]3[CH:31]=[CH:30][C:29]([C:27]([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[OH:28])=[CH:44][C:33]=23)[CH:42]=[CH:41][CH:40]=1
Reactant: Cn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
Butyllithium in hexanes (10 ml) was added slowly at −70° C. under N2 flow to a solution of 1-methylimidazole (1.31 g) in THF (30 ml). The mixture was stirred at −70° C. for 45 minutes. Chlorotriethylsilane (2.7 ml) was added. The mixture was allowed to warm to 15° C. and cooled to −70° C. Butyllithium (10 ml) was added slowly. The mixture was stirred at −70° C. for 1 hour, allowed to warm to −15° C. and cooled to −70° C. A solution of intermediate (6-b) (4.9 g) in THF (60 ml) was added. The mixture was stirred at −70° C. for 30 minutes, then hydrolyzed with water, extracted with ethyl acetate and decanted. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue (8.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.2) and crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.5 g (25%) of (±)-3-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol (interm. 6-c).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Br:12].[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][C:16](=[O:17])[O:15]1.[CH:23](OCC)(OCC)OCC>C(O)(C)C>[Br:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:1][CH:23]=[C:18]1[C:19](=[O:20])[O:21][C:14]([CH3:22])([CH3:13])[O:15][C:16]1=[O:17])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c(Br)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)c(Br)c1
Temperature: 100 °C

Procedure:
To a suspension of methyl 4-amino-3-bromobenzoate (2 g, 8.69 mmol) in isopropanol (10 mL) was added Meldrum's acid (1.63 g, 11 mmol) and triethyl orthoformate (5.26 mL, 31.6 mmol). The resulting mixture was heated at 100° C. for 4 hr and cooled to room temperature. The resulting precipitates were filtered off and washed with 10% Et2O/hexanes to yield methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate. (M+Na)+: 408.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C([Li])CCC.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].[Cl-].[NH4+]>C1COCC1>[C:19]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: OCc1ccc2cc(O)ccc2c1
Reactant: C=C(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1ccc2cc(O)ccc2c1
Temperature: 5 °C
Yield: 56 %

Procedure:
To a 3-necked, 500-mL round bottomed flask equipped with an overhead stirrer, a digital thermometer and a 250-mL constant-pressure addition funnel with a nitrogen inlet was added 25 g (0.14 mol) of 6-hydroxymethyl-2-naphthol and 100 mL of anhydrous THF. The addition funnel was charged with 190 mL (0.3 mol) of n-butyllithium (1.6 M in hexane). The flask was cooled to 5° C. and the butyllithium was added slowly while maintaining a temperature of less than 15° C. The resulting suspension was stirred for 1 h at which time a solution of 14.9 g (0.15 mol) of methacryloyl chloride in 100 mL of anhydrous THF was slowly added while maintaining a temperature of less than 10° C. Stirring was continued with cooling for 6 h at which time the reaction mixture was poured into 300 mL of saturated ammonium chloride with vigorous stirring. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried and evaporated. The resulting residue was chromatographed on silica gel with 35% ethyl acetate in hexane. The fractions containing the pure product were combined and evaporated to yield 19 g (56%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.Cl.[NH2:8][C:9]1[CH:10]=[C:11]([C:17](=[O:38])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH2:36][CH3:37])[CH2:22][CH2:21]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].C(N(CC)CC)C>O1CCCC1>[ClH:5].[CH2:36]([O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=2)=[O:38])[CH2:21][CH2:22]1)[CH3:37]
Reactant: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(N)c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(NS(C)(=O)=O)c2)CC1
Reaction time: 12 h

Procedure:
Methanesulfonyl chloride (0.108 ml) was added to a solution of 1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy)ethyl]-4-piperidinyl}-1-propanone dihydrochloride (300 mg) obtained in Example 327 and triethylamine (0.195 ml) in tetrahydrofuran (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (30 ml) and ethyl acetate (40 ml) were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as a colorless oil (291 mg). The free base compound (290 mg) was treated with a hydrogen chloride-ethanol solution to give the title compound (277 mg) as colorless amorphous powders.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]2[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:25][C:9]([CH2:10][C:11]3[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[N:16]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)ccc3o2)[nH]1

Procedure:
The product is prepared according to the procedure described in Stage 2 of Example 2, using 700 mg of N-(5-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide and 292 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After purification by silica gel column chromatography, elution being carried out with a mixture of CH2Cl2/MeOH: 98/02, then CH2Cl2/MeOH: 95/05, followed by recrystallization from methanol, 188 mg of 2-[(5-fluoro-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a brown solid, the characteristics of which are the following:
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.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=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]=[C:22]([F:21])[CH:23]=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: Fc1cccc(CCBr)c1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3cccc(F)c3)C2=O)cn1
Yield: 22 %

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 10-1) and 3-fluorophenethyl bromide. Yield: 22%. 1H NMR (DMSO-d6, 400 MHz):2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 4.06 (s, 2H), 5.17 (s, 2H), 6.85 (dt, J=8.4, 2.0 Hz, 1H), 7.11 (t, J=8.4 Hz, 2H), 7.32 (q, J=7.8 Hz, 1H), 7.73 (s, 1H), 8.12 (s, 1H). MS M+H calculated 398.2. found 398.1. Melting point: 110-111° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:28])=[CH:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:27])[C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:5]=2[N:4]=[C:3]1SC.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:28])=[CH:10][N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19](=[O:27])[C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[C:5]=2[N:4]=[CH:3]1
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c(=O)n1C
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Solvent: COCCOC
Product: Cc1cn(Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c2ncn(C)c(=O)c12
Temperature: 40 °C
Yield: 76.1 %

Procedure:
In a mixture of DME (100 ml) and ethanol (10 ml) was dissolved 3,5-dimethyl-7-[4-(4-fluorobenzoyl) benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (755 mg) followed by addition of acetic acid (560 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (512 mg).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].C(Cl)(Cl)[Cl:16]>>[ClH:16].[CH3:12][CH:11]([NH:14][CH2:9][CH2:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: BrCCOc1ccccc1
Reactant: CC(C)N
Reactant: ClC(Cl)Cl
Product: CC(C)NCCOc1ccccc1
Product: Cl

Procedure:
Following the procedure of Preparation 1, 2-bromoethyl phenyl ether and isopropyl amine were reacted (in refluxing chloroform) overnight and the reaction mixture processed to yield an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride to form the hydrochloride salt in 68.3% yield, m.p. 152°-154.5° C.