Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[S:8][CH2:7][CH2:6]1)[CH3:3].[H-].[Na+].[CH:20](I)([CH3:22])[CH3:21].CCOCC>CN(C)C=O>[CH3:3][N:2]([CH2:4][CH:5]1[C:10]2[N:11]([CH:20]([CH3:22])[CH3:21])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[S:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: CC(C)I
Reactant: CN(C)CC1CCSc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)n1c2c(c3ccccc31)SCCC2CN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of 4-dimethylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.00 g) in dry dimethylformamide (25 ml) is mixed with 50% sodium hydride (293 mg) under stirring and the mixture is allowed to stand at 40° C. for 1 hour. Then, the reaction mixture is mixed with a solution of isopropyl iodide (1.63 g) in dimethylformamide (2 ml) and kept at 40° C. for 2 hours and further for 20 hours after addition of the reagent. The reaction mixture is mixed with ether and ice water successively at under 5° C. and the ether layer is separated. The aqueous layer is further extracted with ether. The combined ether layers are extracted with a dilute hydrochloric acid solution. The extract is made alkaline and extracted with methylene chloride. The extract is washed with water, dried and evaporated to give the title compound (910 mg) as an oil: Yield 77.8%.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=O)[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cn[nH]c1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cn[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 7 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and (1H-pyrazol-4-yl)-acetic acid methyl ester with heating for 15 days to afford the title compound as an off-white solid (12 mg, 7%). LC/MS (Method B) 3.60 min, [M+1]+ 475.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccccc2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 60 h
Yield: 48.3 %

Procedure:
To a suspension of 13.37 g (56 mmol) of 2,6-diphenyl-4(3H)-pyrimidinone and 200 mL glacial acetic acid was added 15.1 g (84.8 mmol) of N-bromosuccinimide and the mixture was left to stir at room temperature for 60 h. The reaction was poured onto 100 g crushed ice and vacuum filtered, washing well with water, then air dried to yield 8.85 g (48%) 5-bromo-2,6-diphenyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO) δ 7.55(6H,m); 7.75(2H,m); 8.15(2H,m).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[N:30]1>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]([CH3:28])[N:30]=2)=[O:39])[CH2:7]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2nn(C)c3ccccc23)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1-methyl-1H-indazole-3-carboxylic acid.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[N:12][C:11]2[NH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH:17]=[O:18].O>C1COCC1>[Cl:7][C:8]1[C:9]([CH:17]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[OH:18])=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: Br[Mg]C1CCC1
Reactant: O=Cc1c(Cl)cnc2[nH]ccc12
Solvent: O
Solvent: C1CCOC1
Product: OC(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Temperature: 25 °C

Procedure:
The solution of cyclobutylmagnesium bromide (0.28 M in THF, 56 mL, 63 mmol) was added to a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (0.908 g, 5.03 mmol, Adesis) in THF (30 mL) at about 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature and the reaction mixture was stirred for about 16 h. Water (10 mL) was added and the volatiles were removed under reduced pressure. The product was extracted into DCM (3×20 mL) and the combined organic phases were dried over anhydrous MgSO4, filtered, the solvent was removed under reduced pressure and the crude material was purified by column chromatography over silica gel using a 10 to 45% gradient of EtOAc in heptane as the eluent to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanol as an off white solid (0.42 g, 32%); LC/MS (Table 2, Method a) Rt=2.02 min; m/z: 237 and 239 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:30]3[CH2:33][CH:32]([C:34]([O:36]C(C)(C)C)=[O:35])[CH2:31]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:30]3[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (7C, 2.24 g, 4.06 mmol) in dichloromethane (4 mL) was added TFA (4 mL) slowly at room temperature. The reaction mixture was stirred at room temperature for 2 hr. The mixture was concentrated to remove dichloromethane and TFA (6 mL) was added. The mixture was stirred at room temperature till the starting material was observed to disappear. Dichloroethane (6 mL) was added and the mixture was concentrated under reduced pressure. The residue was mixed with water (10 mL), basified with 1 N aqueous NaOH to pH=8 and acidified with 1N aqueous HCl to pH=5. The mixture was sonicated for 30 min. The solid was filtered and washed with water (4×10 mL). The wet solid was mixed with methanol (40 mL), sonicated for 30 min, filtered, washed with methanol (3×10 mL), and dried to give 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid as a white solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:9]1[C:21]([CH2:22]O)=[C:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8].C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[CH2:7]([C:9]1[C:21]([CH2:22][C:5]#[N:6])=[C:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: CCc1nn2ccc3oc(C)cc3c2c1CO
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCc1nn2ccc3oc(C)cc3c2c1CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
Under an argon atmosphere, to a solution of boron trifluoride diethyl ether complex (0.563 mL, 4.44 mmol) and trimethylsilyl cyanide (0.789 mL, 5.92 mmol) in chlorobenzene (30 mL) was added a solution of (2-ethyl-8-methylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (340 mg, 1.48 mmol) in chlorobenzene (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 min. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (252 mg, yield 71%).
Reaction SMILES: [N+](C1C=C([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])C=CC=1N)([O-])=O.[N+:21]([C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][C:29]=1[NH2:30])([O-:23])=[O:22].C(N(CC)CC)C>CC(C)=O>[N+:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=1[NH:30][O:11][S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])([O-:23])=[O:22]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(OS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NOS(=O)(=O)c1ccccc1

Procedure:
In order to prepare 2-nitro-4-phenylsulfonyloxy-aniline, 15.4 g of 3-nitro-4-amino-phenol in 100 ml of acetone were mixed with 14 ml of triethylamine, and 17.6 g of benzane-sulfonic acid-chloride dissolved in 30 ml of acetone were added dropwise, while stirring, at an internal temperature not exceeding 20° C in an ice bath. The mixture was continued to be stirred for another 3 hours at room temperature, the triethylamine-hydrochloride was filtered off, and the filtrate was evaporated to dryness. The residue was then stirred with 50 ml of methanol and was filtered. After washing with methanol and drying, 18.2 g of 2-nitro-phenylsulfonyloxy-aniline were obtained, which has a melting point of 140° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O=C1C=CC=CN1CC1C=CC(OC(=O)N(C)C2C=CC=CC=2)=CC=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Oc1ccccn1
Agent: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCOc2ccccn2)cc1)c1ccccc1
Yield: 50 %

Procedure:
The title compound was prepared in 50% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyridine. In addition 29% of the isomeric methyl-phenyl-carbamic acid 4-(2-oxo-2H-pyridin-1-ylmethyl)-phenyl ester was isolated, see characterization above. 1H NMR (400 MHz; CDCl3): δ 3.08 (t, 2H), 3.41 (br s, 3H), 4.49 (s, 2H), 6.73 (d, 1H), 6.88 (dd, 1H), 7.05 (br d, 2H), 7.22-7.42 (m, 7H), 7.61 (dt, 1H), 8.18 (dd, 1H); HPLC-MS: m/z=349.2 (M+1); Rt=3.97 min.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(Cl)cc1Cl
Yield: 79.4 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (7.50 g, 36.2 mmol) and 2,4-dichloroaniline (5.30 g, 32.6 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (9.09 g, 72%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]1[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc(Cl)c1-n1cccc1
Yield: 83.3 %

Procedure:
A mixture of 5 g of 2,6-dichloroaniline, 4.5 g of 2,5-dimethoxytetrahydrofuran and 30 ml of acetic acid was heated to reflux for 10 hours. The reaction mixture was allowed to cool, poured into water, and extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 5.45 g of 1-(2,6-dichlorophenyl)-1H-pyrrole of the formula:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CC)CC)C.CCOCC>[C:7]1([S:13][CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CC(=O)OC
Reactant: Sc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C=CSc1ccccc1
Reaction time: 24 h

Procedure:
A solution of 2.45 g (24.54 mmol) methyl propiolate and 20 ml ether is treated with 2.7 g (24.54 mmol) benzenethiol with 4 drops triethylamine in 25 ml ether over 15 min at 20°. After stirring for 24 hr, the reaction mixture is rotoevaporated to yield methyl 3-phenylthio-2-propenoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24]2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:22])[CH2:20][OH:21])[CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>CCCCCC.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[NH:27]2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@H:19]([OH:22])[CH2:20][OH:21])[CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(C(C(=O)c1cccc(C(O)CO)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Solvent: CCCCCC
Solvent: CCO
Product: O=C(C(C(=O)c1cccc([C@H](O)CO)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1

Procedure:
Resolution of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-[3-(1,2-dihydroxyethyl)phenyl]propane-1,3-dione was carried out in the usual way using a chiral column: CHIRALCEL OD-H (trade name, Daicel Chemical Industries) and an eluent: hexane/ethanol 3:1. 1-(3,5-Difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1S)-1,2-dihydroxyethyl]phenyl}propane-1,3-dione (Example 13-1) was obtained as the isomer having shorter retention time.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: C1CSCCN1
Product: CC(=O)N1CCSCC1

Procedure:
The product of Example 30 was followed using thiomorpholine and acetic anhydride giving the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30]Cl)[CH3:27]>>[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:7])=[CH:24][CH:25]=1)[CH3:27]
Reactant: CCN(CC)CCCl
Reactant: Cc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxybenzoyl)-2-(4-tolyl)benzofuran with 2-diethylaminoethyl chloride by the procedure of Example 1 gives the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[N:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:36])([CH3:35])[CH2:33][OH:34])[CH2:28][CH2:27]1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:34][CH2:33][C:32]([OH:36])([CH:29]2[CH2:30][CH2:31][N:26]([C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][N:18]=3)[CH2:27][CH2:28]2)[CH3:35])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1cc2ncnc(N3CCC(C(C)(O)CO)CC3)c2cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(N3CCC(C(C)(O)COS(=O)(=O)c4ccc(C)cc4)CC3)c2cc1OC
Reaction time: 3 h

Procedure:
Toluene-4-sulphonylchloride (0.285 g) was added at 0° to a stirred solution of 2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]propane-1,2-diol (0.35 g) in pyridine (3 cm3) and the mixture was stirred for 3 hours. The mixture was poured into a mixture of chloroform (20 cm3) and saturated sodium bicarbonate solution (20 cm3) and the dried (MgSO4) chloroform layer was evaporated. The residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give an oil which was crystallised from ethyl acetate to afford 1-[4-toluenesulphonyloxy]-2-hydroxy-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]propane, m.p. 120°-124° (0.285 g).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6]1[C:11]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14](C(=O)C(F)(F)F)[CH2:13]2)=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:24])C>CO.O.[OH-].[K+]>[NH:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:11]2[C:6]3[NH:5][C:4](=[O:3])[NH:24][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:13]1
Reactant: CCOC(=O)Nc1c(N)cccc1C1CCCN(C(=O)C(F)(F)F)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c2cccc(C3CCCNC3)c2[nH]1
Yield: 50.9 %

Procedure:
4 g of the product of Step E in 80 ml of methanol, 16 ml of water and 16 ml of potassium hydroxide were taken to 80° C. for 4 hours with stirring under an inert atmosphere. After evaporating the methanol under reduced pressure, adding 30 ml of water, adjusting the pH to 6-8 by acetic acid and taking to dryness under reduced pressure, the residue was purified by chromatography on silica, (eluent: methylene chloride-methanol-triethylamine (6-3-1) to obtain 2.15 g of crude product. The latter was triturated in ethyl ether, separated, dried and crystallized from ethanol to obtain 1.23 g of 1,3-dihydro-4-(3-piperidinyl)-2H-benzimidazol-2-one melting at about 260° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[SH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][S:34][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)[CH3:40]
Reactant: CCOC(=O)CS
Reactant: CN(c1cccc2cc(C3=NCC(CCCl)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CSCCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of N-{2-[5-(2-chloroethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (100 mg) in N,N-dimethylformamide (3 mL) were added potassium carbonate (65 mg) and ethyl mercaptoacetate (50 μL), and the mixture was stirred overnight at 50° C. Potassium carbonate (20 mg) was added to the reaction mixture, and the mixture was stirred at 50° C. for 3 hr, and cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (60 mg, yield 50%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS:524(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH3:15])=[O:12])=[CH:10][C:2]=2[Cl:1])=[O:5])[CH2:30]1
Reactant: NCCC1CCCNC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC(CCN)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-3-(2-aminoethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.88 minutes; C24H27Cl2N5O2 (488.42); mass spectrum: (M−H)−=487/489/491 (chlorine isotope).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][O:5][C:6](=[O:17])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH3:9].[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][O:5][C:6](=[O:17])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH3:9])[C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COC(=O)N(CC)Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Benzyl-ethyl-carbamic acid 2-bromo-5-trifluoromethyl-benzyl ester (0.354 g, 0.85 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.300 g, 0.94 mmol), and potassium carbonate (0.410 g, 2.98 mmol) were combined in a deoxygenated solution of DME (8 mL) and H2O (4 mL). Tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.09 mmol) was added, and the reaction was stirred at 75° C. for 2 hours. After work-up, the crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: BrBr.[CH2:3]([N:10]1[CH:17]=[C:16](Br)[C:14](=[O:15])[NH:13][C:11]1=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CS(C)=O.CN(C)C=O>[CH2:3]([N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=c1[nH]c(=O)n(Cc2ccccc2)cc1Br
Agent: BrBr
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=c1ccn(Cc2ccccc2)c(=O)[nH]1

Procedure:
This experiment was performed to verify the role of DMSO solvent in the generation of the bromine electrophile. Thus, this synthesis was done following the same procedure as for the synthesis of 1-benzyl-5-bromouracil, with the sole exception that DMSO was replaced by dimethylformamide (DMF), as solvent. Extraction was done by water-EtOAc and crystallization was done from EtOAc-Hexanes. After filtration, washing with hexanes and drying under high vacuum, 1.4 g of pure 1-benzyluracil, was isolated, as clean white crystals with properties shown below.