Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=2[N:11]=[C:12]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[N:13]=1
Reactant: NC(CO)CO
Reactant: CC(C)n1c(=O)ccc2c(-c3ccccc3F)nc(S(C)(=O)=O)nc21
Product: CC(C)n1c(=O)ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc21

Procedure:
The product of Example 52, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 1.54 (m, 6H), 3.80 (m, 4H), 4.11 (m, 1H), 5.75 (m, 1H), 6.19 (d, 1H, J=9.8), 6.38 (br s, 1H), 7.01-7.21 (m, 2H), 7.30-7.49 (m, 3H). LC MS (m/e)=373 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4cccc(F)c4)cc(=O)[nH]c23)cc1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-amine and ethyl 3-(3-fluorophenyl)-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccccc2)CCN(C)C1
Temperature: 95 °C
Yield: 18.1 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), phenylboronic acid (51.7 mg, 0.423 mmol) and K3PO4 (149.7 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-biphenyl-2-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (18 mg). 1H NMR (Freebase, CDCl3) d (ppm): 7.58 (d, 1H), 7.44 (m, 2H), 7.30 (d, 1H), 7.18 (m, 4H), 6.98 (m, 3H), 6.82 (d, 1H), 3.70 (d, 1H), 3.60 (d, 1H), 3.64 (m, 1H), 2.50 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.[C:20]1([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:33]3[CH2:32][CH2:31][C:30]4([N:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:27][NH:28][C:29]4=[O:36])[CH2:35][CH2:34]3)[C:10](=[O:19])[NH:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)ccc21
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cc(Cl)ccc31)CC2
Yield: 25 %

Procedure:
A mixture of 4.9 parts of 5-chloro-1,3-dihydro-2-oxo-2H-benzimidazole-1-propanol methanesulfonate, 3.7 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.4 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated for 1 hour at 50°-60° C. The N,N-dimethylformamide is distilled off and the residue is taken up in water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue solidifies on triturating in 4-methyl-2-pentanone. The product is filtered off and crystallized twice: first from 2-propanol and then from a mixture of N,N-dimethylformamide and water, yielding 1.8 parts (25%) of 8-[3-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 233.7° C.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[Cl-].[Al+3:7].[Cl-].[Cl-]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:7].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:7]
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: O=S(=O)([O-])[O-]
Yield: 394.6 %

Procedure:
Concentrated sulphuric acid (17 g) was added to an aqueous solution of aluminium chloride (97 g). After standing, aluminium sulphate crystals precipitated from the over-saturated slurry obtained. The crystals were filtered off into a crystal take (31 g), leaving a saturated solution of aluminium sulphate (78 g) as a mother liquor.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.[NH2:25][C@H:26]([C:30]([NH:32][CH:33]([CH:42]([OH:45])[CH2:43][F:44])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])[CH:27]([CH3:29])[CH3:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:25][C@H:26]([C:30]([NH:32][CH:33]([CH:42]([OH:45])[CH2:43][F:44])[CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[O:31])[CH:27]([CH3:28])[CH3:29])=[O:24]
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF

Procedure:
DMAP (95 mg, 0.78 mmol) and EDAC (200 mg, 1.04 mmol) were added as solid to a solution of 1-methylindole-2-carboxylic acid (130 mg, 0.74 mmol) and N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (227 mg, 0.74 mmol) in methylene chloride (5 mL), and the resultant solution was stirred for 1 hour under a nitrogen atmosphere at 0° C. and then 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give a foam. The foam was triturated with ether to yield the title product as a slightly brown solid (224 mg, 65%). TLC: (methanol/methylene chloride, 1:9): Rf=0.46.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[O:29][C:30]([CH3:34])=[C:31]([CH3:33])[N:32]=1>ClC(Cl)(Cl)Cl>[Br:1][CH2:34][C:30]1[O:29][C:28]([CH3:27])=[N:32][C:31]=1[CH3:33]
Reactant: Cc1nc(C)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(C)c(CBr)o1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a mixture of 795 parts of dry tetrachloromethane, 40.1 parts of N-bromosuccinimide and a few parts of benzoylperoxide there were added 25 parts of 2,4,5-trimethyloxazole under a nitrogen atmosphere. The whole was stirred for 1 hour at reflux temperature. After cooling in an ice/salt bath, the reaction mixture was filtered and the filtrate was evaporated, yielding 42.7 parts (99.9%) of 5-(bromomethyl)-2,4-dimethyloxazole (interm. 9).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](O)=[O:29].CCN=C=NCCCN(C)C>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.ClCCl>[CH2:16]([O:15][C@H:3]1[C@@H:2]([NH:1][C:28]([C:24]2[NH:23][CH:27]=[CH:26][N:25]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCc2ccccc2)C1
Reactant: O=C(O)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc[nH]2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
tert-Butyl cis(±)-4-amino-3-(benzyloxy)piperidine-1-carboxylate obtained in Example (90d) (0.92 g, 3.0 mmol) was dissolved in DMA (10 mL). 1H-Imidazol-2-ylcarboxylic acid (0.19 g, 1.70 mmol), WSC (0.82 g, 0.43 mmol) and DMAP (60 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with dichloromethane, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1, 1/1, 1/3) to obtain 0.31 g of the title compound as a colorless solid (46%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+]>C(O)(=O)C.O>[I:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a stirred clear solution of 6-amino-3,4-dihydronaphthalen-1(2H)-one (15 g, 93 mmol) in acetic acid (150 mL) and water (150 mL) was added sulfuric acid (5.5 mL, 101 mmol) dropwise at 0° C. A solution of sodium nitrite (12.90 g, 187 mmol) in water (100 mL) was then added dropwise over 40 min at the same temperature. The mixture was stirred at 0° C. for 10 min before being added to a stirred solution of sodium iodide (55.8 g, 372 mmol) in water (600 mL) slowly over 2 h at 0° C. The resulting brown suspension was stirred at 0° C. for 30 min and at room temperature for 1 h. The mixture was extracted with ethyl acetate (400 mL, 2×100 mL). The combined ethyl acetate extracts were washed with water (60 mL), saturated aqueous Na2S2O3 solution until the brown color disappeared, and saturated aqueous K3PO4 (60 mL) solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Flash chromatography purification (330 g silica gel column, gradient elution from 5 to 15% ethyl acetate in hexanes) afforded 6-iodo-3,4-dihydronaphthalen-1(2H)-one (17.3 g, 63.6 mmol) as a solid. LC/MS M+1=273.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 87 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 87%). 1H NMR (200 MHz, CDCl3): δ 2.33 (s, 3H), 3.26-3.30 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 6.74-6.77 (m, 3H), 7.16-7.29 (m, 3H), 7.40 (dd, J=9.6 and 2.7 Hz, 1H), 7.78-7.81 (m, 1H).
Reaction SMILES: [Na].[CH2:2]([OH:7])[CH2:3][CH2:4][CH2:5][OH:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:21]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:7])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: OCCCCO
Reactant: CCCCCCCCCCCCCBr
Agent: [Na]
Product: CCCCCCCCCCCCCOCCCCO
Temperature: 150 °C
Reaction time: 5 h

Procedure:
2.3 g. Sodium are dissolved by warming in 44 ml. butane-1,4-diol, 38 ml. 1-bromotridecane are added thereto and the reaction mixture is stirred for 5 hours at a bath temperature of 150° C. After cooling, extraction is carried out with a mixture of diethyl ether-ligroin (1:2 v/v), the extract is evaporated and the residue is purified on a silica gel column by elution with ligroin which is subsequently replaced by diethyl ether-ligroin (1:1 v/v). The desired fractions are collected and evaporated. 19.4 g. (71% of theory) of thin layer chromatographically uniform 4-tridecyloxybutanol are thus obtained; m.p. 26°-29° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Product: O=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1

Procedure:
1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 4-bromo-1-bromomethyl-2-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[I-].[K+]>CN(C=O)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[C:20](=[O:21])[CH:5]([CH2:4][CH2:3][CH2:2][N:46]3[CH2:47][CH2:48][N:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:44][CH2:45]3)[CH2:6][CH2:7][C:8]=2[O:12][N:11]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2ccccn2)CC1
Temperature: 80 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (6.4 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.4 g), diisopropylethyl amine (5.4 ml), 1-(2-pyridyl)piperazine (4.8 ml) and potassium iodide (0.4 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 16 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water twice, then brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, 3% methanol) afforded 4.2 g of 6,7-dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyridyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one, as an oil which solidified upon standing. The product was recrystallized from ether, m.p. 94°-96° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][S:8][CH:9]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][S:8][CH:9]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCO)OC(C)=O
Solvent: c1ccccc1
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCCl)OC(C)=O

Procedure:
Thionyl chloride (13.1 g., 0.11 mole) is added dropwise with stirring to a solution of ethyl 8-(2-hydroxyethylthio)-12 -acetoxyheptadecanoate (43.2 g., 0.10 mole) in benzene (150 ml.). The solution is heated at reflux for 2 hours. Then, the solvent and excess thionyl chloride are removed by evaporation in vacuo to leave the title compound as an orange yellow residual oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(F)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 was dissolved in N,N-dimethylformamide (3 ml). 1-Methylpiperazine (36 mg, 0.36 mmol), EDC (90 mg, 0.47 mmol) and HOBT (75 mg, 0.55 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (78 mg, Yield 64%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)[C:15](Cl)=[O:16]>C(Cl)CCl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:15]=[O:16])=[O:8])=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-(trifluoromethyl)benzamide (0.200 g, 1.05 mmol), EDC (10 mL) and oxalyl chloride (0.15 mL, 1.58 mmol) to afford 0.200 g of the product.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:11][C:12]([C:19]([F:22])([F:21])[F:20])([C:16](F)=[O:17])[C:13](F)=[O:14]>C(COC)OC>[CH3:11][C:12]1([C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[NH:4][C:2](=[O:3])[NH:1][C:13]1=[O:14]
Reactant: NC(N)=O
Reactant: CC(C(=O)F)(C(=O)F)C(F)(F)F
Solvent: COCCOC
Solvent: c1ccncc1
Product: CC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a suspension of 1.50 g (0.025 mol) of urea in 30 ml of glyme and 4.0 g (0.050 mol) of pyridine was added dropwise with stirring a solution of 5.0 g (0.026 mol) of methyltrifluoromethylmalonyl fluoride in 20 ml of glyme. Urea dissolved during a mildly exothermic reaction and the homogeneous solution was allowed to stand overnight. The mixture was then refluxed briefly, solvent was removed under vacuum, and the residue was stirred with 25 ml of water. Filtration and rinsing with water gave 3.80 g of 5-methyl-5-trifluoromethylbarbituric acid, mp 205°-206.5°C. A second crop, mp 205°-207°C, 0.84 g, brought the yield to 88% (4.64 g). Recrystallization from water gave an analytical sample, mp 205°-206°C; ir (KBr): 3.07 and 3.17 (NH), 5.67 shoulder and 5.80 (C=O), and 8-8.5 μ (CF); nmr ((CD3)2CO): 1H at ca. 7.0 (very broad, 2 (partly exchanged into acetone-d6), NH) and 1.72 ppm (quartet, JHF = 0.7 Hz, 3, CH3); 19F at -70.8 ppm (quartet, JHF = 0.7 Hz, CF3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])=[O:15]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
The reactant N-chloroacetyl 4-chlorobenzene sulfonamide was prepared by mixing 30.0 g of 4-chlorobenzene sulfonamide and 60.0 ml of chloroacetylchloride. The mixture was refluxed for 6 hours, allowed to cool, and stand at room temperature overnight. The crystalline product was removed by filtration, washed repeatedly with hexane, and dried. The product consisted of 32.5 g of reactant (m.p. 122°-124° C.). Structure was confirmed by IR and NMR.
Reaction SMILES: CO.[F:3][CH:4]([F:32])[O:5][C:6]1[C:11]2[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C:10]=2[C:9]([C:22]2[O:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=2)=[CH:8][CH:7]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]3[C:6]([O:5][CH:4]([F:3])[F:32])=[CH:7][CH:8]=[C:9]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=4)[C:10]=3[C:14]=2[CH:15]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc([N+](=O)[O-])cc4c23)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(N)cc4c23)n1
Yield: 87.5 %

Procedure:
A mixture of methanol (100 mL) and ethyl acetate (100 mL) was added to the ethyl 2-(4-(difluoromethoxy)-8-nitrodibenzo[b,d]furan-1-yl)1,3-oxazole-4-carboxylate (0.8 g, 1.91 mmol) from step 7 of example 47. To the reaction mixture, palladium-carbon (0.30 g) was added. The reaction mixture was transferred to the hydrogenation flask and hydrogenation was performed at room temperature (40 psi-hydrogen) for 2 hours. The reaction mixture was filtered through celite. The filtrate was evaporated at reduced pressure to give the desired product. Yield—87.5%. Rf—0.5 (Ethyl acetate:Hexane (1:1)
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:15])=[O:14])=[O:5].[NH3:34]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH2:34])=[O:28])(=[O:15])=[O:14])=[O:5]
Reactant: N
Reactant: O=C(Cl)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: c1ccccc1
Product: NC(=O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reaction time: 2 h

Procedure:
A solution of 2 g of 11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanoic acid chloride in 15 ml of anhydrous benzene is saturated with ammonia at 10° C. After stirring for two hours, the reaction medium is evaporated to dryness under vacuum, the residue is taken up with water and then extracted with ethyl acetate. After evaporation, the organic phase gives crystals which are recrystallized in benzene (1.22 g).