Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl[CH:13]([CH2:18]Cl)[C:14]([O:16][CH3:17])=[O:15].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[N:30]([CH:31]=O)[CH:29](C(O)=O)[C:28]([CH3:37])([CH3:36])[S:27]2)[CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][C:28]1([CH3:37])[S:27][CH:26]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[N:30]2[CH:31]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:29]12
Reactant: COC(=O)C(Cl)CCl
Reactant: CC1(C)SC(c2cccnc2)N(C=O)C1C(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccn2c1C(C)(C)SC2c1cccnc1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a solution of p-toluenesulfonyl chloride (18 g, 95 mmol) and methyl 2,3-dichloropropionate (15 g, 95 mmol) in refluxing CH2Cl2 (125 mL) was added a mixture of 2-(3-pyridinyl)-3-formyl-5,5-dimethyl-4-thiazolidinecarboxylic acid (5.1 g, 19 mmol) and triethylamine (2.3 g, 22 mmol) in CH2Cl2 (125 mL). After one hour at reflux triethylamine (4.6 g, 44 mmol) was added and the reaction mixture was refluxed for a further 17 hours. The reaction mixture was cooled to ambient temperature and partitioned between cold 1N aqueous NaOH and ethyl acetate. The organic phase was washed with cold 1N aqueous NaOH and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was dissolved in 5% aqueous HCl and the solution was extracted twice with ether. The aqueous phase was neutralized with solid Na2CO3 and extracted twice with ethyl acetate. The combined ethyl acetate extracts where washed with brine, dried over MgSO4, and concentrated in vacuo. Chromatography on silica gel (150 g, 1:1 ethyl acetate, hexanes), afforded methyl 1,1-dimethyl-3-(pyrid-3-yl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylate (1.1 g, 20%) as an off-while powder.
Reaction SMILES: [Cl:1][C:2]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:3]=1[CH2:4][NH:5][C:6](=[O:44])[N:7]([C@H:9]([CH2:27][O:28][C:29](=[O:43])[NH:30][C:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[O:33][N:32]=1)[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:13])[CH3:8].Cl.O1CCOCC1>CO>[F:42][C:38]1[CH:37]=[C:36]([C:34]2[O:33][N:32]=[C:31]([NH:30][C:29](=[O:43])[O:28][CH2:27][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]3[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:2]=3[Cl:1])=[O:44])[CH2:10][CH2:11][C:12](=[O:13])[N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:35]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1cc(-c2cccc(F)c2)on1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc(-c2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(5-(3-fluorophenyl)isoxazol-3-ylcarbamoyloxy)pentanoyl)piperazine-1-carboxylate (0.3 g, 0.36 mmol, 1.0 equiv.) in MeOH (2 mL) at 0° C., was added HCl/dioxane (4 N, 0.9 mL, 3.6 mmol, 10 equiv.). The solution was stirred at RT for 1 h. The solvents were removed and the residue was purified on RP-HPLC using a mixture of acetonitrile and H2O with 0.1% TFA. The elute was diluted with EtOAc (10 mL) and then basified with saturated NaHCO3. The organic layer was dried and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl 5-(3-fluorophenyl)isoxazol-3-ylcarbamate (0.18 g, 90%). LRMS (M+H+) m/z 605.1.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:18]=[C:13]3[C:12]([C:23]3[N:24]=[C:25]([CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[S:26][CH:27]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>CCO>[CH2:19]([C:17]1[CH:18]=[C:13]2[C:12]([C:23]3[N:24]=[C:25]([CH:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)[S:26][CH:27]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1cnc2c(c1)c(-c1csc(C3CCN(C)CC3)n1)cn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1cnc2[nH]cc(-c3csc(C4CCN(C)CC4)n3)c2c1
Yield: 48.4 %

Procedure:
To a stirred solution of 76 (155 mg, 0.31 mmol) in EtOH (4 mL) was added 10% aqueous NaOH (2 mL) and the reaction was heated at reflux for 1.5 h. The mixture was then cooled. Saturated aqueous NaHCO3 (25 mL) was added, and the solution was extracted with AcOEt (2×40 mL) The combined organic extracts were dried (MgSO4) and concentrated to afford a brown solid, which was purified by preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 77 as a white solid (54 mg, 0.15 mmol, 49%). 1H NMR (400 MHz, CDCl3) δ 0.96 (d, J=6.6 Hz, 2H), 1.94 (nonet, J=6.7 Hz, 1H), 2.07-2.19 (m, 2H), 2.25-2.35 (m, 2H), 2.41-2.52 (m, 5H), 2.64 (d, J=7.1 Hz, 2H), 3.14-3.24 (m, 3H), 7.26 (s, 1H), 7.83 (s, 1H), 8.10 (d, J=1.9 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 10.90 (br s, 1H). MS (CI) m/z 355 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CC(C)C1=O
Solvent: CO
Product: CC1CN(Cc2ccccc2)CC(C)C1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodiumboronhydride (121 mg, 3.2 mmol) is added to a solution of 44 (1.4 g, 6.4 mmol) in 15 ml of methanol and the mixture is stirred at room temperature for 30 min. The mixture is evaporated, and the residue is dissolved in ethyl acetate and washed with water.
Reaction SMILES: [NH2:1][OH:2].C(N(CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]3[CH:26]=[CH:27][C:28]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[C:29]([CH:32]=3)[CH:30]=O)=[N:21][CH:22]=2)=[CH:13][CH:12]=1.C(#N)C>O.C([O-])(O)=O.[Na+].CO>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]3[CH:26]=[CH:27][C:28]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[C:29]([CH:32]=3)[CH:30]=[N:1][OH:2])=[N:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: NO
Reactant: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: ON=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 85 °C

Procedure:
27 mg (0.38 mmol) hydroxylamine and 53 μL (0.38 mmol) triethylamine are added to a solution of 200 mg (0.35 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (Example 3.55b) in 2 mL of a 1:1 mixture of acetonitrile and MeOH. The reaction solution is heated to 85° C. After the reaction is complete the mixture is diluted with water and saturated NaHCO3 solution and the organic phase is extracted with DCM. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[O-:19][C:20]#[N:21].[K+].Cl>O.CO>[C:20]([NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10])(=[O:19])[NH2:21]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CNC(N)=O)c1ccccc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Of the compound from Example 113A, 330 mg (1.15 mmol) in 12 ml of water/methanol 1:1 were admixed at RT with 279 mg (3.44 mmol) of potassium cyanate. The mixture was heated at 40° C. for 1 h and then admixed with 1.15 ml of 1M hydrochloric acid (1.15 mmol) and stirred overnight at RT. A further 93 mg (1.14 mmol) of potassium cyanate were added and the mixture was stirred further at RT for 3 h. The entire reaction mixture was purified by preparative HPLC [Method 10]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 292 mg (80% of theory) of the title compound.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([CH:11]1[CH2:14][C:13](=[O:15])[CH2:12]1)=O.Cl.[Cl:17][C:18]1[C:19]([CH2:24][NH2:25])=[N:20][CH:21]=[CH:22][N:23]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:17][C:18]1[C:19]2[N:20]([C:9]([CH:11]3[CH2:12][C:13](=[O:15])[CH2:14]3)=[N:25][CH:24]=2)[CH:21]=[CH:22][N:23]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C1CC(C(=O)ON2C(=O)CCC2=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(c2ncc3c(Cl)nccn23)C1

Procedure:
Into a round bottom 1-neck flask (5L), 3-oxo-cyclobutanecarboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (217.2 g, 0.937 mol), C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (153.3 g, 0.852 mol), and THF (760 mL) were added. A solution of 10% NaHCO3 (1.07 kg) was then added and after 20 min, the layers were allowed to separate and the aqueous layer was removed. The aqueous layer was back extracted with EtOAc (1×700 mL, 1×300 mL). The combined organics were washed with brine (350 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. This solid was resuspended in ethyl acetate (915 mL) and DMF (132 mL) and the solution was put under an atmosphere of nitrogen and cooled to 10.5° C. Phosphorus oxychloride (159 mL, 1.70 mol) was then added over 15 minutes and the reaction was allowed to stir for 45 min. The reaction solution was then poured slowly into a 22% aqueous Na2CO3 solution at 10° C. Water (1 L) was added and the layers were allowed to separate. The organic layer was removed and the aqueous was back extracted with EtOAc (1×1 L, 1×0.5 L). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo until about 0.5 L of solvent remained. Heptane was added and the slurry was concentrated in vacua until most of the EtOAc was removed. The resultant slurry was filtered to give desired product 1H NMR. (400 MHz, CDCl3) δ 3.59-3.68 (m, 2H), 3.72-3.79 (m, 2H), 3.86-3.94 (m, 1H), 7.40 (d, 1H, J=5.2 Hz), 7.60 (d, 1H, J=5.2 Hz) and 7.85 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:12][CH:11]=1)C.[Li+].[OH-].Cl>C1COCC1>[C:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][NH:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:11][CH:12]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)CNCCOc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNCC(=O)O)cc1
Yield: 96.1 %

Procedure:
Compound 2 (0.28 g, 0.71 mmol) dissolved in THF (5 mL) was treated with LiOH (89 mg, 2.13 mmol, dissolved in 2 mL water) at room temperature overnight. The reaction mixture was neutralized with 2 N HCl aqueous solution to pH 5, and concentrated under vacuum. The resulting residue was co-evaporated with ethanol twice, and then loaded onto silica gel in a column. The product was eluted with a mixture of methanol (0-22%), ammonium hydroxide (0-2.2%) and dichloromethane (100-75.8%) to afford the desired product 11 (0.25 g, 96% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ 1.42 (s, 9H), 1.48 (m, 2H), 1.62 (m, 2H), 2.58 (t, 2H), 3.06 (m, 2H), 3.45 (m, 2H), 3.70 (s, 2H), 4.26 (m, 2H), 6.90 (d, 2H), 7.16 (d, 2H). m/z (ESI) 367.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]1=[O:20])#[N:2].Cl.N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>O>[S:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:2]=[C:1]1[CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]1=[O:20]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)CC1Sc2ccccc2N(CC#N)C1=O
Agent: Cl
Solvent: O
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3ccccc3s2)C1=O
Temperature: 180 °C
Yield: 68.7 %

Procedure:
A mixture of 208 mg of ethyl 2-(4-cyanomethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetate and 116 mg of 2-aminothiophenol hydrochloride was heated at 180° C. for 15 minutes to fuse them. After the mixture had been cooled, water was added, and then extracted with ethyl acetate. After the drying of the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The resulting oily matter was purified by silica gel chromatography to give 196 mg of the title compound. The structural formula and physical data of this compound are shown in Table 15.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[C:25]1([CH:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:25]1([CH:31]([NH:33][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: CC(N)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc2cnccc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1-phenylethylamine (56.1 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (78.7 mg, 99%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:12][C:13]1[C:7]2[C:5](=[CH:4][C:3]([S:2][CH3:1])=[CH:9][CH:8]=2)[N:6]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CSc1cccc(N)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(SC)ccc2c1O
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A neat mixture of 2.8 g of compound of 3-methylthioaniline and 4.0 g of diethyl ethoxymethylenemalonate is heated at 135° C. under a slow argon sweep for 1 h, then diluted with 25 mL of diphenyl ether and heated to 260° C., with maintenance of the argon sweep, and kept at that temperature for 90 min. The mixture is then cooled to ca 100° C. and added to 300 mL of stirred 1:1 ether-hexane. The precipitate is filtered, washed with hexane, and dried in vacuo to provide 1.35 g of crude material as a tan solid, which is recrystallized from acetic acid-water to afford 1.06 g of ethyl 4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1.[CH3:20][O:21][CH:22](OC)N(C)C>>[CH3:20][O:21]/[CH:22]=[C:15](\[C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)/[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)Cc1sc(C)nc1/C=C/c1ccccc1
Reactant: COC(OC)N(C)C
Agent: CO/C=C(/C(=O)OC)c1sc(C)nc1/C=C/c1ccccc1
Product: CO/C=C(/C(=O)OC)c1sc(C)nc1C=Cc1ccccc1
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
A mixture of 3 g of the product of Step A and 30 ml of dimethylformamide dimethyl acetal was refluxed for 5 hours and then allowed to return to 25° C. The mixture was evaporated to dryness and the residue was dissolved in 30 ml of tetrahydrofuran and 5 ml of a 2N hydrochloric acid solution. After standing for 3 hours at 25° C., 10 ml of water were added, followed by decanting and extracting with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in 50 ml of acetone and 6 g of potassium carbonate and then 12 ml of methyl iodide were added. The mixture was stirred for 16 hours at 20 to 25° C. and evaporated to dryness. The residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (7-3) to obtain 1.8 g of the desired product. Thin layer chromatography; Rf=0.20 [eluant: hexane-ethyl acetate (7-3)].
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=O.[N:7]1C=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:6]
Reactant: CN(C)C(=O)Cl
Reactant: c1ccncc1
Product: CN(C)c1ccccn1

Procedure:
In 5 ml of pyridine was dissolved 101 mg of DC-89B2 obtained in Reference Example 2 and 3 mg of dimethylaminopyridine and 0.1 ml of dimethylcarbamyl chloride were added to the solution. After stirring at room temperature overnight, the reaction mixture was poured into 2 N hydrochloric acid and extracted with chloroform. After washing successively with aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, the chloroform layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (50 ml; eluted with chloroform) to give 64 mg of Compound 13 (yield, 57%).
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]1
Reactant: CC1CCCC1(C(=O)O)c1ccccc1F
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2F)CCCC1

Procedure:
To a solution of methyl 1-(2-fluorophenyl)cyclopentanecarboxylic acid (5.0 g, 24.01 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL), dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:33])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:21]2[C:20]([CH2:19][NH:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:33])=[CH:13][N:14]=3)=[C:24]([CH3:25])[O:23][N:22]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 410 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of isopropylamine (48 mg, 70 μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (70 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 5 h and then cooled to room temperature and then poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (53 mg, 70%) which was obtained as an off white foam. MS: m/e=369.4 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:23]([O:30][C:31]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 74 h
Yield: 495.6 %

Procedure:
t-Butyl 4-piperidinyloxyacetate (521 mg, 2.42 mmol) and triethylamine (0.40 ml, 2.9 mmol) were dissolved in methylene chloride (20 ml) and benzyloxycarbonyl chloride (0.41 mmol, 2.9 mmol) was added. The mixture was stirred at room temperature for 74 hours. A saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1). to give 710 mg of t-butyl [N-benzyloxycarbonyl-4-piperidinyloxy]acetate as a colorless oil (84%). Methylene chloride (30 ml) and trifluoroacetic acid (10 ml) were added to this oil (692 mg, 1.99 mmol) and the mixture was stirred at room temperature for 17 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give 555 mg of [N-benzyloxycarbonyl-4-piperidinyloxy]acetate as a colorless solid (96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[I-:25].[Na+]>[Cu]I>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([I:25])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: [I-]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Agent: [Cu]I
Agent: [Na+]
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)c(F)c3)CC2)c(C)c1
Yield: 70.5 %

Procedure:
Using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (760 mg) described in Preparation Example 125, sodium iodide (581 mg) and copper(I) iodide (184 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (600 mg) was obtained.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C(Cl)(Cl)Cl.Br.[Br:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[Br:12][CH2:13][CH2:14][NH:15][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: NCCBr
Reactant: C=C1CC(=O)O1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)CC(=O)NCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.4 g. (0.1 mole) of diketene in 150 ml. of chloroform is added 21 g. (0.11 mole) of 2-bromoethylamine hydrobromide in 30 ml. of water, and the resulting mixture stirred vigorously at 0° C. while 4.1 g. (0.11 mole) of sodium hydroxide in 20 ml. of water is added dropwise over a period of 20 minutes. The reaction mixture is allowed to stir at room temperature for 1 hour, after which the chloroform layer is separated, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to yield the intermediate, N-(2-bromoethyl)acetoacetamide, as a white crystalline residue.