Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:12][CH2:13][CH2:14]CC)(=O)C=C.C=CC1C=CC=CC=1.C(OO)(C)(C)C>O>[C:1]([O:6][CH2:7][CH:13]1[O:12][CH2:14]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CC(=O)OCCCC
Reactant: C=C(C)C(=O)OC
Agent: CC(C)(C)OO
Solvent: C=Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OCC1CO1
Temperature: 70 °C

Procedure:
An amount of 1300 g of an aqueous latex of a core polymer mainly comprising a styrene-butadiene rubber (containing 420 g of styrene-butadiene rubber particles) as obtained using the procedure described in Example 2 was charged into a 3 L glass vessel followed by addition of 440 g of pure water and stirring at 70° C. while replacing the atmosphere inside the vessel with nitrogen. A monomer mixture composed of 60 g of methyl methacrylate, 10 g of butyl acrylate, 35 g of styrene and 0.4 g of t-butyl hydroperoxide as a monomer mixture that is not the shell forming monomers (A) was added thereto over the course of 120 minutes to carry out graft polymerization. Following completion of the addition of the monomer mixture, stirring was further continued for 2 hours to complete the reaction and obtain minute polymer particles (CS-2C) in the form of an aqueous latex. The polymerization conversion rate was 99%. As a result of measuring the particle size in the same manner as in Example 2 after diluting the minute polymer particles in the form of an aqueous latex with water, the measured particle size was 0.1 μm, and a sharp, monodisperse particle size distribution nearly similar to that of Example 2 was shown.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C(OCC)(=O)C>[O:12]([C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][C:23]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:24][CH2:25]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1Oc1ccccc1
Temperature: 130 °C

Procedure:
Methyl 4-fluoro-2-phenoxybenzoate (2 g) and 1,4-dioxa-8-azaspiro[4.5]decane (1.279 g) were combined in dimethylsulfoxide O (12 mL) in a 250 mL round-bottom flask. Sodium carbonate (1.291 g) was added. The reaction flask was sealed and heated to 130° C. overnight. The reaction mixture was diluted with ethyl acetate, washed thoroughly with water and with brine, and dried over MgSO4, filtered and concentrated to obtain the desired product.
Reaction SMILES: C=O.[C:3](=[O:6])([O-])[O-].[K+].[K+].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH2:16](O)[CH3:17]>>[CH2:16]([O:6][CH2:3][N:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1)[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CCO
Reactant: CN1CCNCC1
Agent: C=O
Agent: [K+]
Product: CCOCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 67 h

Procedure:
To a suspension of paraformaldehyde and potassium carbonate in ethanol at about 0° C. was added 1-methylpiperazine dropwise. The mixture was stirred vigorously at room temperature for about 67 hours and filtered. The filter cake was washed with diethyl ether and the combined filtrates were concentrated under vacuum. The residue was distilled under reduced pressure (30° C. at 2.5 Torr) to provide the desired product. 1H NMR (500 MHz, DMSO-d6): δ 1.09 (t, J=6.8 Hz, 3H), 2.14 (s, 3H), 2.28 (m, 4H), 2.56 (m, 4H), 3.40 (q, J=6.8 Hz, 2H), 3.96 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([CH3:43])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][CH:42]=[C:12]23)[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[O:36]=[C:34]1[O:33][N:32]=[C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:15]3[C:16](=[O:17])[N:11]([C@H:8]4[CH2:9][CH2:10][C@H:5]([O:4][CH2:3][C:2](=[O:1])[CH3:43])[CH2:6][CH2:7]4)[C:12]4[N:13]([N:40]=[CH:41][CH:42]=4)[C:14]=3[CH2:37][CH2:38][CH3:39])=[CH:24][CH:23]=2)[NH:35]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Reaction time: 15 h

Procedure:
To a solution of 4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.38 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.55 g), and the mixture was stirred for 15 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.34 g, 90%).
Reaction SMILES: [NH2:1][C:2]1C(F)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.Cl[CH2:21][Cl:22]>>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: ClCCl
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Product: Nc1c(Cl)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 2-amino-3-fluorobenzoic acid (10.0 g, 58.5 mmol) in dichloromethane (150 mL) was added N-bromosuccinimide (10.4 g, 58.5 mmol), and the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The solid was filtered and washed with dichloromethane (100 mL×3) to give the title compound as a white solid (13.0 g, 89%), which was directly used in the next step without further purification. MS (ES+) C7H5BrClNO2 requires: 249, 251, found: 250, 252 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:16](=[O:17])[N:15]=[C:14]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([OH:12])[C@@H:6]3[O:13]2)[CH:3]=1>COCCO>[CH3:5][O:9][CH2:8][CH2:7][O:12][C@@H:6]1[C@H:7]([OH:12])[C@@H:8]([CH2:10][OH:11])[O:9][C@H:5]1[N:4]1[CH:3]=[C:2]([CH3:1])[C:16](=[O:17])[NH:15][C:14]1=[O:13]
Reactant: Cc1cn2c(nc1=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Solvent: COCCO
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 157.5 °C
Yield: 124.6 %

Procedure:
2,2′-Anhydro-5-methyluridine (195 g, 0.81 M), tris(2-methoxyethyl)boarate (231 g, 0.98 M) and 2-methoxyethanol (1.2 L) are added to a 2 L stainless steel pressure vessel and placed in a pre-heated oil bath at 160° C. After heating for 48 hours at 155-160° C., the vessel is opened and the solution evaporated to dryness and triturated with MeOH (200 mL). The residue is suspended in hot acetone (1 L). The insoluble salts are filtered, washed with acetone (150 mL) and the filtrate evaporated. The residue (280 g) is dissolved in CH3CN (600 mL) and evaporated. A silica gel column (3 kg) is packed in CH2Cl2/acetone/MeOH (20:5:3) containing 0.5% Et3NH. The residue is dissolved in CH2Cl2 (250 mL) and adsorbed onto silica (150 g) prior to loading onto the column. The product is eluted with the packing solvent to give 160 g (63%) of product.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:17][C:12]=2[S:11][C:10]=1[C:28]([O:30]CC)=[O:29])(C)(C)C.[OH-].[Na+].CCO.Cl>O.C1COCC1>[C:6]([CH2:7][O:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:17][C:12]=2[S:11][C:10]=1[C:28]([OH:30])=[O:29])([OH:33])=[O:5]
Reactant: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 3-(2-tert-butoxy-2-oxoethoxy)-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxylate (1.1 g), 1N NaOH (5 mL), EtOH (5 mL) and THF (10 mL) was stirred at 50° C. for 24 h. Water and 1N HCl (5 mL) were added to the mixture and the mixture was extracted with THF-EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with hexane to give the title compound (0.850 g). The obtained crystals were recrystallized from acetone-water.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:16])[CH:7]=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2].[S:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCOc1cc([C@@H]2CCCC[C@@H]2N)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc([C@H]2CCCC[C@H]2NC(=O)c2ccc(S(N)(=O)=O)cc2)ccc1OC
Reaction time: 8 h
Yield: 23.1 %

Procedure:
3.0 g of (+/-)-cis-2-ethoxy-1-methoxy-4-(2-aminocyclohexyl)benzene (compound B1) are dissolved in 40 ml of methylene chloride and 10 ml of triethylamine. A solution of 3.3 g of p-sulfamoylbenzoyl chloride in 60 ml of methylene chloride is added dropwise at RT, the mixture is extracted after stirring overnight with 100 ml each of water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of ethyl acetate/petroleum ether/methanol in the ratio 6/3/1. After concentration of the product fractions, 1.2 g of the title compound of m.p. 129-133° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=O)=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:43][C:44]1([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])[CH2:47][NH:46][CH2:45]1>CN(C=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([N:46]2[CH2:47][C:44]([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])([OH:43])[CH2:45]2)=[O:20])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Reactant: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C1(O)CN(C(=O)c2nn(C)c(=O)cc2Nc2ccc(I)cc2F)C1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a suspension of 4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.13 mmol) in DMF (2 mL), prepared using similar procedures to those described in Reference 4, at room temperature was added 1-hydroxybenzotriazole (36.3 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol) and the reaction was stirred for 2 hours. 1,1-Dimethylethyl [(1S)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (30 mg, 0.13 mmol), prepared using procedures similar to those in Example 28, and triethylamine (0.04 mL) were added and the mixture was stirred for 15 hours. The reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The organic layer was washed with 5% lithium chloride solution, saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product as yellow oil. The oil was purified by column chromatography (silica gel, ethyl acetate) to afford 1,1-dimethylethyl {(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate as a yellow oil (55 mg, 73% yield): 1H NMR (400 MHz, CDCl3): 10.24-10.23 (m, 1H), 7.52-7.50 (m, 2H), 7.12-7.07 (m, 1H), 6.10-6.09 (m, 1H), 5.13-5.09 (m, 1H), 4.91-4.82 (m, 1H), 4.60-4.39 (m, 2H), 4.10-4.08 (m, 1H), 4.00-3.87 (m, 2H), 3.70 (d, 3H), 1.43 (s, 9H), 1.24-1.20 (m, 3H); MS (EI) for C22H27FIN5O5: 588 (MH+).
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])(C)C)[CH3:12])(C)(C)C.C1(CN)CC1.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=1)C(N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CC1C=CC=CC=1)=O)([CH3:38])[CH3:37]>>[CH2:23]([C@H:8]([NH:7][C:6](=[O:30])[C:42]1[CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=[C:40]([O:39][CH:36]([CH3:38])[CH3:37])[CH:41]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH:16]1[CH2:17][CH2:20]1)[CH3:12])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Agent: NCC1CC1
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCC2CC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from cyclopropylmethylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.NN.[CH3:14][N:15]=[C:16]=[S:17].[CH3:18][C:19]1[N:20]=[C:21]([S:24][CH2:25][CH2:26][CH2:27][NH:28]C(N)=S)[O:22][CH:23]=1>>[CH3:14][NH:15][C:16]([NH:28][CH2:27][CH2:26][CH2:25][S:24][C:21]1[O:22][CH:23]=[C:19]([CH3:18])[N:20]=1)=[S:17]
Reactant: CN=C=S
Reactant: Cc1coc(SCCCNC(N)=S)n1
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Product: CNC(=S)NCCCSc1nc(C)co1

Procedure:
Treatment of the phthalimide compound (3.0 g.) with hydrazine (1.53 g.) followed by reaction of the product directly with methyl isothiocyanate (0.73 g.) using the conditions described in Example 132 afforded N-methyl)-N-[3-(4-methyl-2-oxazolyl)thiopropyl]thiourea (1.0 g.). m.p. 73°-74° (from ethanol-ether-n-hexane).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26](CC3C=CC(OC)=CC=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[C:22]([CH3:24])[N:23]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[C:22]([CH3:24])[N:23]=4)[C:8]=3[CH:25]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4nc(C)c[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c(-c2c(-c3ccc(F)cc3)oc3cc(NS(C)(=O)=O)c(C4CC4)cc23)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1O using the compound prepared in Example 2B, (0.64 g, 1.17 mmol) and 20% trifluoroacetic acid in CH2Cl2. The title compound was isolated as a yellow solid (0.18 g, 35%). MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=O)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:22])([F:21])[F:1])=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12
Product: FC(F)(F)Oc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-(4-trifluoromethoxyphenyl)isoquinolin-1-one (3.01 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-(4-trifluoromethoxyphenyl)isoquinoline, which was then reacted as it was with N-ethylpiperazine (40 ml) at 90° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 3.65 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[N:33]=[CH:32]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[F:26][C:24]([F:27])([F:25])[C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15]([C:14]2[CH:13]=[C:12]([CH:30]=[CH:29][CH:28]=2)[O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36]([C:34]4[N:33]=[CH:32][O:31][CH:35]=4)=[O:37])[S:3][C:4]=3[CH:10]=2)=[O:16])=[CH:23][CH:22]=1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Reactant: O=C(O)c1cocn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), 1,3-oxazole-4-carboxylic acid (113 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol), 1-hydroxybenzotriazole (135 mg, 1.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (260 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (90 mg, 34%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:33]2[C:27]3[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Product: CC1(C)Cc2cccc(C(=O)NC[C@@H]3[C@H]4C[C@H]4CN3C(=O)c3nc(N)sc3-c3cccc(F)c3)c2O1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:50]([S:53]([CH2:56][CH2:57][NH2:58])(=[O:55])=[O:54])[CH2:51][CH3:52]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([NH:58][CH2:57][CH2:56][S:53]([CH2:50][CH2:51][CH3:52])(=[O:55])=[O:54])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34]
Reactant: CCCS(=O)(=O)CCN
Reactant: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)CCNC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Yield: 18.3 %

Procedure:
Prepared according to Procedure I utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.23 g, 0.42 mmol), carbonyldiimidazole (0.21 g, 1.27 mmol), and n-propanesulfonylethylamine (0.16 g, 0.85 mmol) in DMF to afford the title compound (0.05 g) after purification by chromatography. Electrospray MS m/z 649 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]#[N:21])=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CCCCCC>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2([C:20]#[N:21])[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: N#CC1(c2cn(Cc3ccccc3)c3ccccc23)CCCC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 2.26 g, 56 mmol) was added a solution of 1-benzyl-1H-indol-3-ylacetonitrile in DMSO-ether (10MI: 80 mL) dropwise and the mixture was stirred for 5 hours at 20° C. Water and hexane were added. Solid was collected by filtration and washed with water and hexane to give 1-(1-benzyl-1 H-indol-3-yl)cyclopentanecarbonitrile (5.3 g). MS (ES): 301 (MH+).
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][C:4]([O:6]CC)=O.Cl.[NH2:16][OH:17].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:23]([NH:18][C:4](=[C:3]1[C:4](=[O:6])[O:17][N:16]=[C:2]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:2][CH2:9][CH2:10][CH3:11])[CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCC(=O)CC(=O)OCC
Reactant: NO
Reactant: c1ccncc1
Agent: Cl
Product: CCCCCCC1=NOC(=O)C1=C(CCCCC)NCCCCC

Procedure:
3-n-Hexylisoxazol-5(4H)-one is obtained in 99% yield as a reddish liquid by holding ethyl 3-oxo-pelargonate at reflux temperature for 1 hour with one equivalent of hydroxylamine hydrochloride and one equivalent of pyridine and thereafter working-up in the usual manner.