Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C:3]1[C:2]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:7]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(Cc2ccccc2)c1Cc1ccccc1
Product: Cc1ccccc1Cc1ccccc1

Procedure:
In the like manner as the example in the above reference, benzylchloride and toluene were reacted by using a catalyst of FeCl3 ; and benzyltoluene and dibenzyltoluene were obtained by distillation. These benzyltoluene and dibenzyltoluene in a weight ratio of 80:20 were mixed together. The contents of isomers of the benzyltoluene in the obtained mixture were o-isomer: 39.1 wt %, m-isomer: 5.4 wt % and p-isomer: 35.5 wt %, which were almost coincident with the analytical values of the above commercial sample JARYLEC C-100 of o-isomer: 36.2 wt %, m-isomer: 5.9 wt % and p-isomer: 37.8 wt %.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[C:9]([CH:14]([F:16])[F:15])=[N:10][N:11]([CH3:13])[CH:12]=1)=[O:7])[CH3:4].Br[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:23]1[C:18]([O:1][CH2:2][CH:3]([NH:5][C:6]([C:8]2[C:9]([CH:14]([F:16])[F:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[O:7])[CH3:4])=[N:19][CH:20]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:22]=1
Reactant: FC(F)(F)c1cnc(Br)c(Cl)c1
Reactant: CC(CO)NC(=O)c1cn(C)nc1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COc1ncc(C(F)(F)F)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
A solution of 2.3 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide (10.0 mmol, prepared as described in example P5a) and 2.6 g 2-bromo-3-chloro-5-trifluoromethyl-pyridine (10 mmol) in dimethylformamide (30 ml) is treated at ambient temperature with 2.8 g potassium carbonate (20 mmol). The resulting suspension is stirred at 100° C. for 3 hours, cooled to ambient temperature, poured onto water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers are washed with water (20 ml) and dried over Na2SO4. After removal of the solvent the residue (4.2 g in the form of an oil) is purified by flash chromatography over silica gel (eluent: cyclohexane/ethyl acetate 3:7). 1.4 g (34% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-1-methyl-ethyl]-amide (compound 1.239) is obtained in form of a solid (mp. 115-118° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:34](=[O:39])[NH:35][CH2:36][CH2:37][NH2:38])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:38]4[CH2:37][CH2:36][NH:35][C:34]4=[O:39])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNC4=O)ccc23)CC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (458 mg, 1.38 mmol), which was prepared as described in Example 12b, and (2-amino-ethyl)-carbamic acid benzyl ester hydrochloride (446 mg, 1.93 mmol) in DMSO (1.0 mL) was added K2CO3 (1.52 g, 11.04 mmol). The mixture was stirred at 115° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc as eluent) to afford the desired product as a white solid (400 mg, 73%). 1H NMR (CDCl3) δ 9.13 (s, 1H), 8.69 (dd, J=9.40 and 2.35 Hz, 1H), 8.08 (d, J=9.53 Hz, 1H), 7.42 (d, J=2.33 Hz, 1H), 5.25 (br, 1H), 4.31 (m, 2H), 4.09 (t, J=8.21 Hz, 2H), 3.69 (t, J=8.14 Hz, 2H), 3.63 (m, 1H), 2.95 (m, 2H), 1.77-2.04 (4H), 1.48 (s, 9H). Calcd for C21H28N5O3 (MH+) 398.3, found 398.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][S:32](N)(=[O:34])=[O:33])=[CH:27][CH:26]=1.Cl.[C:37]([O-])(O)=O.[Na+]>C(O)C>[ClH:1].[CH:17]([NH:16][C:14]1[N:13]([CH3:20])[C:12]2[CH:21]=[CH:22][C:9]([N:8]([CH3:23])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][S:32]([CH3:37])(=[O:34])=[O:33])=[CH:27][CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1)([CH3:19])[CH3:18]
Reactant: O=C([O-])O
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4ccc(CS(C)(=O)=O)cc4)n3)ccc2n1C
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 1-(4-aminophenyl)methane-sulfonamide (47 mg, 0.25 mmol) in ethanol (2.5 ml) was added a solution of HCl (0.25 ml, 1M in diethyl ether) and the reaction was heated to 70° C. After 20 hours, the reaction mixture was neutralized with the addition of solid NaHCO3. The mixture was filtered and the filtrate was purified with silica gel to give the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.16 (s, 1H), 7.78 (m, 3H), 7.19 (d, J=8.1 Hz, 3H), 7.09 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.1 and 1.8 Hz, 1H), 6.75 (s, 2H), 6.49 (d, J=7.8 Hz, 1H), 5.62 (d, J=6.0 Hz, 1H), 4.15 (s, 2H), 4.02 (m, 1H), 3.51 (s, 3H), 3.44 (s, 3H), 1.24 (d, J=6.6 Hz, 6H) ppm. MS (ESI) m/z=481 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]2[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:20][N:21]1[C:25]([CH2:26]O)=[CH:24][C:23]([C:28]([F:31])([F:30])[F:29])=[N:22]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:20][N:21]1[C:25]([CH2:26][O:14][C:12]2[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:19])=[CH:6][S:7][C:8]=3[CH:13]=2)=[CH:24][C:23]([C:28]([F:29])([F:31])[F:30])=[N:22]1
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: COC(=O)Cc1csc2cc(O)cc(C(F)(F)F)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1COc1cc(C(F)(F)F)c2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a mixture of methyl(6-hydroxy-4-(trifluoromethyl)-1-benzothiophen-3-yl)acetate (60 mg) and THF (dry) (3 mL) were added (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (37.2 mg), ADDP (62.6 mg) and tri-n-butylphosphine (0.071 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). To the mixture of the crude material and THF (1 mL) was added 1N NaOH (1 mL) at room temperature for 12 h. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The solid was crystallized from EtOAc-hexane to give the title compound (64.0 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=3[CH3:15])[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 80.4 %

Procedure:
Using 4-bromo-2-methanesulfonylbenzoic acid (1 g) and 1-(2,4-dimethylphenyl)piperazine (684 mg) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (1.3 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]1([CH3:49])[CH:45]=[CH:44][CH:43]=[C:42](B(O)O)[CH:41]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:42]3[CH:41]=[C:40]([CH3:49])[CH:45]=[CH:44][CH:43]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3cccc(C)c3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 3-tolylboronic acid replacing phenylboronic acid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])[N:8]=1.Cl.[CH3:24][OH:25]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[NH:19])[O:25][CH3:24])[N:8]=1
Reactant: N#CCCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 60 h

Procedure:
The above nitrile (3 g.) was dissolved in dry chloroform (40 ml.) and MeOH (20 ml.), cooled to 0° and saturated with hydrogen chloride gas. The mixture was kept at 0° for 60 hours then volatile material was evaporated in vacuo. The residue was shaken with cold aqueous potassium carbonate solution (50 ml.) and extracted with chloroform (3×50 ml.). The combined extracts were dried (MgSO4) and evaporated in vacuo to give methyl 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valerimidate as a gum which was used without further purification.
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26].[I-].[K+]>CC(C)=O>[C:25]([CH:24]=[CH:23][CH2:22][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=1)([O:27][CH3:28])=[O:26]
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C=CCOc1ccc(CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 4-hydroxyphenylpropan-2-one ethylene ketal (3.0 g) and potassium carbonate (2.13 g) in acetone (50 ml) was treated with methyl 4-bromocrotonate (2.77 g) and a trace of potassium iodide. After heating under reflux for 12 hours, the solution was filtered, the solvent evaporated and the residue dissolved in methanol (50 ml) and 2.5 N hydrochloric acid (25 ml). The solution was stirred at ambient temperature for 2 hours, the solvent evaporated, the residue extracted with ether, washed with 2 N sodium hydroxide, water and dried (MgSO4). Removal of the solvent gave the title compound as an oil (2.3 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:20].Cl.[NH2:22][CH2:23][CH2:24][O:25][NH2:26].N1C=CC=CC=1.C(O)C>[OH-].[Na+].C(OCC)(=O)C>[ClH:20].[ClH:20].[NH2:22][CH2:23][CH2:24][O:25][N:26]=[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCn1ccnc1)c1cccc(C(F)(F)F)c1
Reactant: NCCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCn1ccnc1)c1cccc(C(F)(F)F)c1
Yield: 53.5 %

Procedure:
A mixture of 3-(1-(1H)-imidazolyl)-1-(3-trifluoromethylphenyl)-1-propanone (4.60 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (3.07 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was stirred under reflux, under nitrogen, for three hrs. The reaction mixture was diluted with 10% sodium hydroxide solution and ethyl acetate. The layers were separated. The aqueous phase was extracted with ethyl acetate, the organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was flash chromatographed (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added to the solution. The solid was collected and recrystallized twice from absolute ethanol/ether to give 2.2 g (32%) of product, mp 223°-225° C. (dec.)
Reaction SMILES: C(O[C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:6])(C)C.[CH3:31][NH2:32]>>[CH3:31][NH:32][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:6]
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CN
Product: CNC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
0.57 g of 1-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester ( ) was stirred in 20 mL methyl amine (40% wt in water) at 100° C. in a sealed tube for 5 days. The methyl amine was allowed to evaporate and the residual aqueous solution was left to stand overnight uncapped. The following morning, a white precipitate was present, which was collected by vacuum filtration. The precipitate was washed with water and hexanes. The original aqueous solution was then extracted twice with ethyl acetate. The organic layer was then dried over sodium sulfate and concentrated in vacuo to afford more product. 0.31 g of the title compound was collected as a white solid; mp 137-139° C.; 1H NMR (CDCl3) δ 1.52-1.72 (m, 5H), 1.81 (t, J=5.82 Hz, 4H), 2.15-2.20 (m, 1H), 2.86 (d, J=4.95 Hz, 3H), 3.08-3.55 (m, 1H), 3.49-3.55 (m, 4H), 4.00 (s, 4H), 6.89-6.94 (M, 2H), 6.99-7.01 (m, 1H), 7.61-7.73 (m, 2H); MS (ES) m/z 410.0 (MH+); HRMS for C19H27N3O5S: 410.1740.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:40])([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:25][CH:26](Cl)[CH3:27]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCOC(=O)OC(C)Cl
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Product: CCCCCCCCCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl decyl carbonate (4.79 g, 18.1 mmol) were converted to chromatographed title product, 4.46 g white foam (8.0 mmol, 88.0%) which gave white crystals from isopropyl alcohol: mp 84°-86° C.: IR (KBr) 1764, 1679 cm-1 ; 1H NMR (CDCl3) delta 0.89 (t, J=7 Hz, 3H), 1.09-1.41 (m, 14H), 1.41-1.60 (br m, 2H), 1.75 (d, J=6 Hz, 3H), 3.11 (s, 3H), 4.00 (t, J=7 Hz, 2H), 6.36 (q, J=6 Hz, 1H), 7.07-7.17 (m, 1H), 7.63-7.96 (m, 5H), 8.30-8.40 (m, 2H), 9.40 (br s, 1H); precise mass calcd for C28H37N3O7S m/e 559.2352, found 559.2346.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([C:16]([F:19])([F:18])[F:17])=[C:10]([CH2:12][CH2:13][CH2:14][OH:15])[N:11]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([O:15][CH2:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=3)[O:8][C:9]=2[C:16]([F:18])([F:19])[F:17])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-c2nc(CCCO)c(C(F)(F)F)o2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2nc(CCCOS(=O)(=O)c3ccc(C)cc3)c(C(F)(F)F)o2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
3-[2-(p-Tolyl)-5-trifluoromethyloxazol-4-yl]-1-propanol (6.40 g) synthesized according to the method of Kawase et. al. (Chem. Pharm. Bull., 46, 749–756 (1998)) was dissolved in 35 ml of dichloromethane. To the solution were added sequentially 293 mg of 4-(dimethylamino)pyridine, 4.7 ml of triethylamine and 5.13 g of p-toluenesulfonyl chloride, and stirred for 3 hours at room temperature. To the reaction solution was added ethyl acetate, and washed with water, 10% hydrochloric acid and an aqueous solution of saturated aqueous sodium hydrogen carbonate solution sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 10.08 g of the objective compound as pale brown crystals. M.p. 57–58° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH:33]([CH3:35])[CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].O.[OH-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH:33]([CH3:34])[CH3:35])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC(C)C)C3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)O)c4s3)C[C@H]2OC(C)C)nc1Cl
Yield: 97.5 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-isopropoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (148b) (0.140 g, 0.269 mmol) was dissolved in tetrahydrofuran (5 mL). The solution was subjected to the same operation as in Example (1i) using lithium hydroxide monohydrate (0.135 g, 3.23 mmol) and water (5 mL), to obtain 0.129 g of the title compound as a white solid (98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([CH:26]=O)[C:18]=2[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:35][OH:36].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:18]([CH3:28])=[C:19](/[CH:26]=[N:35]\[OH:36])[C:20]([CH3:25])=[C:21]([CH3:24])[C:22]=2[OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:18]([CH3:28])=[C:19](/[CH:26]=[N:35]/[OH:36])[C:20]([CH3:25])=[C:21]([CH3:24])[C:22]=2[OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1c(C)c(C=O)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(C)c(/C=N/O)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Product: Cc1c(C)c(/C=N\O)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O

Procedure:
To a solution 7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (1.3 g) in ethanol (13 ml) were added sodium acetate (1.3 g), hydroxylamine hydrochloride (0.26 g) and water (2.6 ml) and the mixture was refluxed for 4 hours. The solvent was distilled off under reduced pressure. To the residue were added water and 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain (Z)-7-(4-fluorophenyl)-7-(2-hydroxy-5-hydroxyiminomethyl-3,4,6-trimethylphenyl)heptanoic acid (0.55 g) and (E)-7-(4-fluorophenyl)-7-(2-hydroxy-5-hydroxyiminomethyl-3,4,6-trimethylphenyl)heptanoic acid (0.75 g) (Compounds 47 and 48). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: Cl[C:2]1[C:3]([F:24])=[CH:4][C:5]2[C:6]([CH:23]=1)=[N:7][C:8]1[N:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:24][C:3]1[C:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][C:6]2=[N:7][C:8]3[N:9]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Yield: 64.4 %

Procedure:
The reaction is carried out under the conditions of Reference Example 5 but starting from 1.7 g of 8-chloro-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.3 g of piperazine in 20 cm3 of pyridine. The pure product is obtained after a single recrystallization from 20 cm3 of dimethylformamide. 1.25 g of 7-fluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are isolated in the form of a yellow solid melting at 290° C., solvated by 4.5% of water.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2].ClN1C(=[O:19])CCC1=O>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:19])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(=O)c1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 12.57 g. (79 mmoles) of 7-acetylindole in 187 ml. of methylene chloride was added 11.07 g. (82.9 mmoles) of N-chlorosuccinimide and the reaction allowed to stir at room temperature for 2 hours. The solvent was removed in vacuo and the residue treated with 155 ml. of acetic acid and heated to 80° C. Phosphoric acid (80 ml.) was added and the reaction mixture heated to reflux for 9 hours. The mixture was cooled, the acetic acid removed under vacuum and the residue poured into 500 ml. of ice and water. The product was extracted with methylene chloride, 11.91 g. (65% yield), 174°-175° C.