Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35](N[C@H](C(O)=O)C)=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CCOC(C)=O>[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35]([NH:3][C@H:4]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH2:5][C:6]([OH:8])=[O:7])=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Reactant: C[C@H](NC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](NC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O)c1cccnc1

Procedure:
Following the procedure described for 1-7, but substituting β-alanine ethyl ester hydrochloride (Aldrich) for ethyl 3-amino-3(S)-(3-pyridyl)propionate dihydrochloride, the title compound was prepared. Rf (silica, EtOAc)=0.3. ##STR37## N-{[7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetyl}--alanine (1-14)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][SH:11](=[O:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH:45]([N:58]1[CH2:61][CH:60](O)[CH2:59]1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCCC1>[CH:45]([N:58]1[CH2:61][CH:60]([N:10]([CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[SH:11](=[O:13])=[O:12])[CH2:59]1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=[SH](=O)NCc1cc(F)cc(F)c1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[SH](=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 20 h
Yield: 60.2 %

Procedure:
N-(1-Benzhydrylazetidin-3-yl)-N-(3,5-difluorophenyl)methylsulfonamide may be obtained by carrying out the procedure as in Example 13 (method 2) in the following manner: 0.86 g of N-(3,5-difluorophenyl)methylsulfonamide, 3.28 g of triphenylphosphine and then 2 ml of diethyl azodicarboxylate are added successively to a solution of 2 g of 1-benzhydrylazetidin-3-ol in 100 cm3 of tetrahydrofuran. An increase in the temperature, which passes from 22° C. to 29° C., as well as the formation of a precipitate immediately following the addition of the diethyl azodicarboxylate are observed. After 20 h at 22° C., the precipitate is removed by filtration and the filtrate is concentrated to dryness at 40° C. under 2.7 kPa. The residue is triturated with 5 cm3 of methanol for 20 minutes at 21° C., providing 1.07 g of N-(1-benzhydrylazetidin-3-yl)-N-(3,5-difluorophenyl)methylsulfonamide in the form of a white amorphous solid.
Reaction SMILES: C([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][O:17][CH2:18][O:19][CH3:20])(OCC1C=CC=CC=1)=O.[H][H]>CO.[C].[Pd]>[CH3:20][O:19][CH2:18][O:17][CH2:16][CH:12]1[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: COCOCC1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCOCC1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-carbobenzoxy-2-methoxymethoxymethylpyrrolidine (prepared in the above (2)) 3.9 g in methanol 80 ml is added palladium-carbon 1 g at argon atmosphere. Hydrogen gas is blown through the mixture and the mixture is stirred at room temperature for 3 hours. After reaction catalyst is removed by filtration and the filtrate is concentrated in vacuo to give 2-methoxymethoxymethylpyrrolidine 2.02 g.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[C:13]([F:33])=[C:14]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[CH3:10].CCCCCC>C(#N)C>[Br:1][C:27]1[C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[C:13]([F:33])[C:12]([O:11][CH2:9][CH3:10])=[C:29]([O:30][CH2:31][CH3:32])[CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Solvent: CCCCCC
Solvent: CC#N
Product: CCOc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Reaction time: 6 h
Yield: 0 %

Procedure:
N-bromosuccinimide (1.43 g, 8.07 mol) was added to a solution of 2-(3,4-diethoxy-2-fluorobenzyl)isoindol-1,3-dione (2.52 g, 7.34 mol) in acetonitrile (30 mL) on ice. The mixture was stirred on ice for ten hours, and then at room temperature for six hours. The reaction mixture was extracted after the addition of a 5% aqueous solution of sodium thiosulfate and ethyl acetate; then the resultant organic layer was washed sequentially with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (diethyl ether, no-hexane) to give 1.12 g of the title compound (yield: 36%) as white crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][NH:21][CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:38][NH:39][CH2:40][CH2:41]Cl>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][N:21]([CH2:41][CH2:40][NH:39][CH3:38])[CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: CNCCCl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3nsc4ccccc43)CC2)C1
Temperature: 70 °C

Procedure:
A mixture of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35.0 mg, 0.0803 mmol), cesium carbonate (105 mg, 0.321 mmol) and 2-methylaminoethyl chloride hydrochloride (41.8 mg, 0.321 mmol) in acetonitrile (0.8 ml) was heated at 70° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave title compound (19 mg, 48%) as off-white solid. MS m/e: 493 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].Cl>>[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=[C:2]([Cl:1])[N:3]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCc1cccc(I)c1
Agent: Cl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-methyl-β-D-ribofuranosyl)-purine (61, 372 mg, 0.89 mmol) and 3-iodobenzylamine.HCl (1.34 mmol, 360 mg). The mixture was purified by column chromatography (eluens 2% MeOH in CH2Cl2). Yield 383 mg (0.72 mmol, 81%), mp 84–86° C.; Rf 0.59 (10% MeOH in CH2Cl2). The product was recrystallised from CH3COCH3; 1H NMR (DMSO-d6) δ 8.89 (bs, 1H, NH), 8.35 (s, 1H, H-8), 7.73 (s, 1H, CCHCI), 7.60 (d, 1H, J=5.83 Hz, CCHCHCH), 7.33 (d, 1H, J=6.12 Hz, CCHCH), 7.12 (t, 1H, J=7.55 Hz, CCHCH), 5.82 (d, 1H, J=5.15 Hz, H-1′), 5.54 (d, 1H, J=5.84 Hz, OH-2′), 5.30 (d, 1H, J=5.49 Hz, OH-3′), 4.61–4.51 (m, 3H, NHCH2, H-2′), 4.09–4.00 (m, 2H, H-3′,4′), 3.56–3.52 (m, 2H, H-5′), 3.28 (s, 3H, OCH3); MS m/z 532 (M+H)−; Anal. (C18H19ClIN5O4.0.3 CH3COCH3) C, H, N.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.ClCCl.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(OCC)(=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC(N)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 0.570 g (0.00477 mole) of 4-amino-1-methylpiperidine, 1.5 mL of ethyldiisopropylamine and 20 mL of dichloromethane at 0 degrees, was added 1.000 g (0.00451 mole) of 4-nitrobenzenesulfonyl chloride. The mixture was stirred for 1 hour and then diluted with 100 mL of ethyl acetate and washed successively twice with 20 mL of saturated sodium bicarbonate solution, twice with 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.23 g of N-(1-methyl-piperidin-4-yl)-4-nitro-benzenesulfonamide as a yellow solid. The material was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:27]([F:29])[F:28])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:9]2[C:10]([CH3:17])=[N:11][C:12]3[C:7]([C:8]=2[O:26][CH:27]([F:29])[F:28])=[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[CH:24][CH:23]=1
Reactant: COC(=O)COc1ccc(F)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-4-difluoromethoxy-8-fluoro-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.18 g), methanol (3.5 mL), water (2.0 mL), tetrahydrofuran (3.5 mL) and lithium hydroxide solution (0.036 g) was stirred at room temperature for 30 minutes. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid, extracted with ethyl acetate and the combined extracts dried over sodium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse-phase HPLC, using a gradient over 30 minutes of acetonitrile in water, gave title compound as a yellow solid, 0.088 g.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[NH2:16][C:17]1[S:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1>C(#N)C>[CH3:3][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)=[O:15])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Nc1nc(-c2ccccc2)ns1
Solvent: CC#N
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1nc(-c2ccccc2)ns1
Yield: 46.4 %

Procedure:
2,6-Diisopropylphenylisocyanate (1.9 g, 9.4 mmol) was added to a refluxing solution of 5-amino-3-phenyl-1,2,4-thiadiazole (1.5 g, 8.5 mmol) in acetonitrile (60 mL). The mixture was refluxed for 18 hours, allowed to cool, filtered, and the filtrate concentrated, taken up in ethyl acetate (150 mL), and washed with water (3×50 mL). The organics were dried over Na2SO4, filtered, concentrated, and the resulting solid washed with hexane and recrystallized from acetonitrile to give a white solid (1.50 g, 46%), m.p. 180°-183° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[C:9]([NH2:13])(=[O:12])[CH:10]=[CH2:11].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:11][CH2:10][C:9]([NH2:13])=[O:12]
Reactant: C=CC(N)=O
Reactant: CN(C)CCO
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOCCC(N)=O
Yield: 60 %

Procedure:
A 100 ml 3 neck round bottom flask was fitted with the following: magnetic stirrer, reflux condenser, air bubbler, and a temperature controlled oil bath. The flask was charged with 22.25 g of 2-dimethylamino ethanol. Sodium hydride, 0.05 g, was then added carefully to 2-dimethylamino ethanol solution with stirring. After stirring at a constant rate for two minutes, 17.75 g of acrylamide was added. The reaction mixture was stirred at 45° C. for 6 hours. The mixture was cooled to ambient temperature and neutralized with 0.11 g of concentrated sulfuric acid. The resulting mixture was filtered through a Celite layer. The filtrate was collected for foam application. Quantitative 1H NMR shows that the product had ˜90% purity. The product could be further purified by reduced pressure distillation. Fraction collected at 135° C./1 mm Hg gives a colorless needle shape crystal (60% yield, >96% in purity).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([OH:34])(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:15]([O:14][C@H:10]1[C@H:11]([O:13][C:15](=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@@H]1CN(Cc2ccccc2)C[C@H]1OC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Compound VI-9 (1.85 g, 98.8%) was obtained in the same manner as that in Reference Example 2, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 500 mg, 2.59 mmol) and oleic acid (Tokyo Chemical Industry Co., Ltd.; 1.61 g, 5.69 mmol).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]([NH:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1)=[O:16].[NH2:32][OH:33].[OH-].[Na+].Cl>CO>[OH:33][NH:32][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][CH2:19][CH2:18][NH:17][C:15]([C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][O:4][CH2:3][C:2]([F:31])([F:30])[F:1])=[O:16])=[CH:22][CH:23]=1
Reactant: O=C([O-])c1ccc(OCCNC(=O)c2oc3ccccc3c2COCC(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NO)c1ccc(OCCNC(=O)c2oc3ccccc3c2COCC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
4-{2-[3-(2,2,2-Trifluoroethoxymethyl)benzofuran-2-yl-carbonylamino]-ethoxy}-benzoate was dissolved in MeOH and excess aqueous hydroxylamine solution and NaOH(aq) were added to give pH 10-11. After stirring overnight, the reaction mixture was neutralized reaction to pH 7-8 with aqueous hydrochloric acid. The reaction mixture was concentrated in vacuo to give a solid which was collected and washed with water, then dissolved in acetonitrile and water and purified with prep HPLC to give the title compound (35 mg). 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.95 (t, J=5.6 Hz, 1H), 8.89 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.00 (d, J=9.2 Hz, 2H), 5.25 (s, 2H), 4.18 (m, 4H), 3.67 (m, 2H). EM (calc.): 452.1; MS (ESI) m/e (M+1H)+: 453.0, (M−1H)−: 451.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>O1CCCC1.O>[Cl:11][C:12]1[N:17]=[C:16]([NH:10][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH3:9])[CH:15]=[CH:14][N:13]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Nc1ccnc(Cl)n1)c1ccc(F)cn1
Temperature: 55 °C
Yield: 10.1 %

Procedure:
A solution of (S)-1-(5-fluoropyridin-2-yl)ethanamine (prepared as described in WO2006/123113, 235 mg, 1.68 mmol) in tetrahydrofuran (2 mL) was added to a stirred solution of 2,4-dichloropyrimidine (250 mg, 1.68 mmol) in tetrahydrofuran (2 mL) at ambient temperature. A solution of triethylamine (0.23 mL, 1.68 mmol) in tetrahydrofuran (2 mL) was then added dropwise and the reaction mixture was heated overnight at 55° C. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (43 mg, 10%) as an oil.
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[O:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=1)=[O:8])(=[O:5])[CH3:4]>ClCCl>[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[O:12][C:13]([C:16](=[O:18])[CH2:17][Br:1])=[CH:14][CH:15]=1)=[O:8])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)NC(=O)NCc1ccc(C(C)=O)o1
Solvent: ClCCl
Product: CC(=O)NC(=O)NCc1ccc(C(=O)CBr)o1
Reaction time: 1.5 h

Procedure:
A solution of bromine (0.23 ml) in dichloromethane (5 ml) was dropwise added to a mixture of 1-acetyl-3-(5-acetylfuran-2-ylmethyl)urea (1.0 g) in dichloromethane (20 ml) at ambient temperature for 20 minutes and the mixture was stirred at the same temperature for 1.5 hours. The solvent was removed by concentration and residue was triturated with isopropyl ether to give 1-acetyl-3-[5-(bromoacetyl)furan-2-ylmethyl]urea (1.27 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)Cl>[CH2:18]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)[CH2:19][CH2:20][CH3:21]
Reactant: OCCN1CCNCC1
Reactant: CCCCBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN1CCN(CCO)CC1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
2-(1-Piperazinyl)ethanol (12.2 g) was dissolved in chloroform (60 ml), triethylamine (13.0 ml) and 1-bromobutane (14.1 g) were successively added at room temperature, and the mixture was stirred overnight. The reaction solution was successively washed with a 10M aqueous solution of potassium hydroxide (15 ml), water (50 ml×2), saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (methylene chloride:methanol:aqueous ammonia=90:10:0.5) to give the title compound (10.8 g) as a pale yellow oily substance. Yield=62%.
Reaction SMILES: C(O)C.[CH:4]1([CH3:14])[CH2:9][CH2:8][CH:7]([CH:10]([CH3:12])[CH3:11])[CH:6]([OH:13])[CH2:5]1>O>[CH3:14][C@H:4]1[CH2:5][C@@H:6]([OH:13])[C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8][CH2:9]1
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: CCO
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Yield: 0.1 %

Procedure:
A 0.1% 1-menthol solution is prepared by mixing 30 g of ethyl alcohol, 1.2 g of a surface active agent, 145.65 g of distilled water and 0.15 g of menthol. The mixed solution is diluted twice with distilled water to prepare a control solution. A separate test solution is prepared by dissolving 0.15 g of menthyl glucoside in 100 g of distilled water.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[S:3])[NH2:2].[CH:15]([C:18]1[CH:27]=[CH:26][C:21]([C:22](=O)[CH2:23]Br)=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH:23]=2)=[CH:26][CH:27]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1cccc(C(N)=S)c1
Product: CCOC(=O)c1cccc(-c2nc(-c3ccc(C(C)C)cc3)cs2)c1
Yield: 46 %

Procedure:
In the same manner as in Example 74, ethyl 3-thiocarbamoylbenzoate was reacted with 4-isopropylphenacyl bromide to obtain ethyl 3-[4-(4-isopropylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 46%. Pale yellow prisms. Melting point: 91 to 92° C.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[Br:5][CH2:6][CH2:7]Br.C#C.[C:11](Br)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[Cl-].[Na+].O>[Br:5]/[CH:6]=[CH:7]/[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: BrCCBr
Reactant: CCCCCC(=O)Br
Agent: C#C
Agent: [Al+3]
Agent: [Br-]
Solvent: O
Product: CCCCCC(=O)/C=C/Br
Temperature: 0 °C

Procedure:
A mixture of 300 g. of aluminum bromide and 250 ml. of 1,2-dibromoethane, cooled in an ice bath and protected from moisture, is saturated with acetylene. To the mixture is added with ice cooling 150 g. of hexanoyl bromide (Example 991) over a period of 20 minutes and the resulting mixture is treated with acetylene until gas uptake ceases. The reaction mixture is poured onto 500 ml. of saturated brine and 500 g. of ice. The resulting mixture is extracted twice with 500 ml. of ether. The combined organic extracts are washed twice with 500 ml. of saturated brine and dried with anhydrous sodium sulfate. To the organic phase is added 5 g. of hydroquinone and the solvent is evaporated in vacuo to yield the crude 1-bromo-trans-1-octen-3-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([NH2:36])[CH3:35]>>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([NH:36][C:24]([C:21]1[O:22][C:23]2[C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=[CH:18][C:19]=2[CH:20]=1)=[O:26])[CH3:35]
Reactant: CC(N)c1ccccn1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: CC(NC(=O)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1)c1ccccn1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 1-(pyridin-2-yl)ethanamine (23 mg, 0.19 mmol). Yield: 20 mg (25%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14](C)[C:12]=3[N:13]=2)=[C:4]([F:19])[CH:3]=1.BrC1C=CC(NC2SC3C=C(OC(F)(F)[F:39])C=CC=3N=2)=C(F)C=1.ClC1SC2C=C(F)C=CC=2N=1.FC1C=C(Br)C=CC=1N>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([F:39])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:19])[CH:3]=1
Reactant: Cc1cccc2sc(Nc3ccc(Br)cc3F)nc12
Reactant: Fc1cc(Br)ccc1Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: Fc1ccc2nc(Cl)sc2c1
Agent: Nc1ccc(Br)cc1F
Product: Fc1ccc2nc(Nc3ccc(Br)cc3F)sc2c1
Yield: 78 %

Procedure:
In a similar manner to that described above for the preparation of N-(4-bromo-2-fluorophenyl)-4-methyl-1,3-benzothiazol-2-amine and N-(4-bromo-2-fluorophenyl)-N-(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amine, using 2-chloro-6-fluoro-1,3-benzothiazole and 2-fluoro-4-bromoaniline, was prepared the desired product as a white solid (78% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.60 (t, 1H), 7.80 (d, 1H), 7.60 (m, 2H), 7.40 (d, 1H), 7.20 (m, 1H).