Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)[CH:18]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:26]3[CH2:27][CH2:28][N:23]([C:19]4[CH:18]=[C:17]([Cl:16])[N:22]=[CH:21][N:20]=4)[CH2:24][CH2:25]3)=[O:30])[CH2:32][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(C1CCN(c2cc(Cl)ncn2)CC1)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2cc(Cl)ncn2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
4-Trifluoromethylphenylsulphonyl chloride (1.32 g) was added to a mixture 1-[1-(6-chloro-pyrimidin-4-yl)-4-piperidylcarbonyl]piperazine hydrochloride (2.60 g) and triethylamine (5.00 ml) in dichloromethane (100 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1.5% methanol in dichloromethane to give 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(6-chloro-pyrimidin-4-yl)-4-piperidylcarbonyl]piperazine (1.80 g) as a solid.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.C([Mg]Cl)(C)C.[Cl:22][C:23]1[CH:54]=[CH:53][C:26]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[N:37][CH:38]=2)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[C:32]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:42]=2)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:54]=[CH:53][C:26]([C:27]([OH:28])([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)[C:29]2[CH:30]=[C:31]3[C:36](=[N:37][CH:38]=2)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[C:32]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[CH:42]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1cnc2c(c1)c(-c1cccc(C#C[Si](C)(C)C)c1)cc(=O)n2C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To a solution of 5-bromo-1-methylimidazole (0.68 g, 4.26 mmol) in dry DCM (15 mL), DIPEA (0.77 mL, 4.47 mmol) and iPrMgCl (2.13 mL, 4.26 mmol, 2.0 M solution in THF) was added at 10° C. The reaction mixture was stirred for 1.5 h and a solution of compound J (0.5 g, 1.06 mmol) in DCM was added to it. The reaction mixture was refluxed for 2 h and quenched with saturated NH4Cl solution. The product was extracted with DCM (30 mL). The organic layer was dried, filtered and concentrated to give crude c. Purification of the crude product provided 210 mg (36%) of compound K.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(O)cc1Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(O)cc1Cl
Yield: 8.7 %

Procedure:
To a solution of methyl 2-chloro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 mL) was added N-chlorosuccinimide (9.8 g, 73.7 mmol). The solution was refluxed for 24 h and the solvent was evaporated under vacuo. The residue was taken up in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Methyl 2,3-dichloro-4-hydroxybenzoate precipitated out of ethyl acetate. Chromatography of the residue using ethyl acetate/hexane (1/9 to 3/7) afforded methyl 2,5-dichloro-4-hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4-hydroxybenzoate isomer (total of 8.4 g, 10%).
Reaction SMILES: C([O:3][C:4]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20])=[CH:11][CH:10]=1)[CH2:7][CH3:8])=[O:5])C.[OH-].[Na+]>CO.O>[C:4]([CH:6]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20])=[CH:13][CH:14]=1)[CH2:7][CH3:8])([OH:5])=[O:3]
Reactant: CCOC(=O)C(CC)c1ccc(N[C@@H](CCC(N)=O)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C(=O)O)c1ccc(N[C@@H](CCC(N)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
In 10 ml of methanol was suspended 1.68 g (0.005 mole) of N-[4-(1-ethoxycarbonyl-n-propyl)phenyl]-L-glutamine and a solution of 0.42 g of sodium hydroxide in 20 ml of water was added thereto and stirred for 1.5 hours at room temperature. The solvent was then distilled off in vacuo to about a half volume and the remaining solution was acidified to pH 4 with 5% hydrochloric acid. The precipitated crystals were collected by filtration, washed with cold water and dried in vacuo to give 1.16 g (0.0038 mole, 75% yield) of N-[4-(1-carboxy-n-propyl)phenyl]-L-glutamine, m.p. 166.5°-167.0° C.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[F:8][C:9]([F:30])([F:29])[C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH:20]([CH3:24])[C:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.[Na+].O.OP(O)(O)=O>C1(C)C(C)=CC=CC=1>[CH3:5][O:22][C:21](=[O:23])[CH:20]([O:19][C:18]1[CH:25]=[CH:26][C:15]([O:14][C:13]2[CH:12]=[CH:11][C:10]([C:9]([F:29])([F:30])[F:8])=[CH:28][CH:27]=2)=[CH:16][CH:17]=1)[CH3:24]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
63 g of dimethyl sulfate are added within 5 minutes and at 130° C. to 348 g of anhydrous sodium-2-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-propionate, suspended in 1,000 ml of xylene. After the addition, stirring of the mixture is continued for 1 hour, the mixture is cooled at 85° C., at said temperature 200 ml of water and 0.5 ml of H3PO4 are added and, for the separation of the inorganic salts, the mixture is stirred for 10 minutes. After separation of the water phase, the xylene is distilled off. 340 g of methyl-2-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-propionate are obtained melting at 142° C. under 0.05 torr. According to gas chromatogram the content of pure final product is 99.4%, the residual content of unreacted acid is 0.6%, which corresponds to a yield of 99.4%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[N:6][CH:7]=1.[CH3:31][C:32]1[C:36](B(O)O)=[C:35]([CH3:40])[O:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:31][C:32]1[C:36]([C:2]2[CH:3]=[C:4]([CH2:8][C:9]([P:21](=[O:30])([O:22][CH:23]([CH3:24])[CH3:25])[O:26][CH:27]([CH3:29])[CH3:28])([P:11](=[O:20])([O:16][CH:17]([CH3:18])[CH3:19])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[N:6][CH:7]=2)=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(Cc1cncc(Br)c1)P(=O)(OC(C)C)OC(C)C
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cncc(CC(F)(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)c1
Temperature: 80 °C
Reaction time: 36 h
Yield: 46.7 %

Procedure:
A sample of tetraisopropyl (2-(5-bromopyridin-3-yl)-1-fluoroethane-1,1-diyl)bis(phosphonate) (85 mg; 0.16 mmol), Pd(Ph3)4 (36.9 mg; 0.032 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (34 mg; 0.24 mmol) are added in a vial, the vial is capped with a septum and added DME (4 mL) is added. The mixture is immediately flushed with argon, potassium carbonate solution (2.5 eq.) is added and flushed again with argon. The reaction mixture is stirred at 80° C. for 36 h under argon. The mixture is cooled, diluted with EtOAc and filtered through Celite™, the Celite™ is rinsed 3× with EtOAc/MeOH (1:1). The combined filtrate is concentrated under vacuum and deposited on silica gel. Purification by column chromatography on silica gel (pre washed with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc, and then to 50% MeOH in EtOAc lead to the isolation of the product as a brown oil (41 mg; 47% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:16][CH2:17][CH2:18][CH3:19].[H-].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of 1 g (5 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine and 2.8 g (15 mmol) of 1-iodobutane in 5 mL of DMP was added 330 mg (11 mmol) of NaH (80% dispersion in mineral oil) and the mixture was heated to 40° C. After 5 h, 20 mL of H2O was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=4:1) to give 1-t-butoxycarbonyl-4-(butoxy)piperidine. Removal of the BOC protecting group was achieved as described in Example 4, Step 2 to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[C:16]([O:19][C@@H:20]1[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:33]([O:39][C:40](=[O:42])[CH3:41])[CH2:32][S:31][C@H:21]1[O:22][C:23]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:24]=1[Cl:30])(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:33]([O:39][C:40](=[O:42])[CH3:41])[CH2:32][S:31][C@H:21]1[O:22][C:23]1[CH:28]=[C:27]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:26]=[CH:25][C:24]=1[Cl:30])(=[O:18])[CH3:17]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)ccc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2cnn(C)c2)ccc1Cl

Procedure:
By carrying out the operation analogously to example 87, starting from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-2-chlorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation X, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccc(C#N)c1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and the product of Example 19A (64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.55 (s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.88 (dt, J=7.9, 1.4 Hz, 1H), 8.18 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.23 (ddd, J=7.9, 2.0, 1.2 Hz, 1H), 8.31 (t, J=1.6 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.98 (t, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:15][C:16]1[CH:17]=[C:18]([CH:19]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2cc(Cl)cc(Cl)c2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(3,5-dichlorophenoxy)-benzaldehyde in an analogous manner to that described in Example 1 to give 9-[3-(3,5-dichlorophenoxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow crystalline solid of melting point 254-255° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[C:21]([O:23][CH3:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 82, 0.090 g, 0.208 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 1.9 M solution of lithium hydroxide (1.5 mL, 2.8 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% methanol in ethyl acetate as the eluent to afford the title product as a white amorphous solid (0.062 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C[O:33]B(OC)OC.OO>O1CCCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[C:22]([OH:33])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3cc(F)ccc23)CC1
Agent: CC(C)[N-]C(C)C
Agent: OO
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3c(O)c(F)ccc23)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a stirred solution of 4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.13 mmol) in dry tetrahydrofuran (31.3 mL) cooled to −78° C. was added lithium diisopropylamide (1.72 mL, 3.35 mmoles). The resulting solution was stirred at −78° C. for 2 hours when trimethylborate (0.44 mL, 3.84 mmoles) was added. The resulting solution was stirred at −78° C. for 1 hour then was allowed to warm to room temperature over 3 hours when hydrogen peroxide (2.00 mL) and acetic acid (1.00 mL) were added. The resulting mixture was stirred at room temperature overnight when the mixture was quenched with saturated NH4Claq (20 mL) and 10% HClaq (20 mL). The resulting mixture was extracted with CH2Cl2 (4×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 0.619 g (59%) of the phenol as a white, crystalline solid, mp 169–170° C. Analysis calculated for C17H21N2FO4; 60.70% C, 6.29% H, 8.33% N. Found: 60.72% C, 6.15% H, 8.22% N.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9]Cl.[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][N:26]1[CH2:25][CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Product: Cc1nc2ccccn2c(=O)c1CCN1CCN(c2cccc(Cl)c2)CC1
Yield: 39.7 %

Procedure:
A mixture of 1.1 g of 2-methyl-3-(2-chloroethyl)-4H-pyrido[1,2-a)pyrimidin-4-one, 2.95 g of 1-(m-chlorophenyl)piperazine and 15 ml of toluene was refluxed with heating for 30 hours. After completion of the reaction, the reaction mixture was filtered while hot. The filtrate was concentrated under reduced pressure, and the residue was purified by means of column chromatography using alumina. The product was then recrystallized from a mixture of benzene - n-hexane to give 0.75 g of the desired compound as colorless needles, m.p. 112° - 113°C.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12](Cl)=[O:13].[CH3:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:16]([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1F
Reactant: CC(CC(C)(C)C)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CC(C)(C)C)c1ccccc1NC(=O)c1c(C(F)(F)F)nn(C)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
At from 0° C. to −10° C., a solution comprising 8.1 g (42.4 mmol) of 5-fluoro-1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl chloride in 80 ml of tetrahydrofuran is added dropwise to a solution comprising 6.5 g (28.3 mmol) of 2-(1,3,3-trimethylbutyl)phenylamine and 5.7 g (56.6 mmol) of triethylamine in 200 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 1 h. For work-up, the mixture is filtered through silica gel and concentrated. Purification on silica gel (petroleum ether/ethyl acetate 3:1) gives 10.1 g (94% of theory) of [5-fluoro-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[2-(1,3,3-trimethylbutyl)phenyl]carbox-amide of log P (pH 2.3)=4.14.
Reaction SMILES: [C:1]1([C:7](=[N:38][O:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:21])=[C:15]([CH2:18][CH3:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]1([C:7](=[N:38][O:39][CH2:40][C:41]([OH:43])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[S:21])=[C:15]([CH2:18][CH3:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3ccccc3)[C@H]2SC1
Yield: 97.1 %

Procedure:
The solution of benzhydryl 7-[2-phenyl-2-tertbutoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.0 g) and anisole (2.0 ml) in trifluoroacetic acid (8 ml) was stirred for 90 minutes at ambient temperature. The resultant solution was evaporated under reduced pressure and the residual oil was dissolved in an aqueous solution of sodium bicarbonate. After the solution was washed with ethyl acetate, the solution was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (100 ml). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 7-[2-phenyl-2-carboxymethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid (syn isomer, 1.3 g), mp. 103° to 107° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:16]>>[NH2:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N
Reactant: Cc1cccc2cc([N+](=O)[O-])c(Cl)nc12
Product: Cc1cccc2cc([N+](=O)[O-])c(N)nc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
1.6 g of 2-chloro-8-methyl-3-nitroquinoline (compound C1) is dissolved in 70 ml of ethanolic ammonia solution and stirred at 130° C. for 18 h in an autocave. After cooling to room temperature, the reaction mixture is concentrated in vacuo and the residue recrystallized from ethyl acetate. 1.2 g of the title compound are obtained as red solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: ClCCNCCCl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Yield: 53.7 %

Procedure:
50 ml of a solution of 5 g of 3-nitroaniline and 6.46 g of bis(2-chloroethyl)amine hydrochloride in 1-butanol was heated under reflux for 25 hours. After adding 3.84 g of sodium carbonate, the mixture was further heated under reflux for 60 hours. After allowing to cool, the insoluble matters were collected by filtration, suspended in an aqueous solution of sodium hydroxide and extracted with chloroform. The extract was successively washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=100:3). Thus 4.03 g of the title compound was obtained in the form of a red oily product.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3]>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a solution of 3-(aminosulfonyl)benzoic acid (Fluorochem) (150 mg, 0.746 mmol) in THF (1 mL) was added dropwise at 0° C. Borane-THF complex (3.73 mL, 3.73 mmol). The resulting solution was stirred 10 min at 0° C., and then at room temperature overnight. The reaction mixture was carefully quenched with 10 mL of water at 0° C. The reaction mixture was diluted with 30 mL of EtOAc and 20 ml of water. The aqueous layer was further extracted with 30 mL of EtOAc. The combined organic solutions were washed with brine (30 mL), dried over an hydrophobic frit and concentrated under reduced pressure. The residue was loaded in dichloromethane to a silica cartridge (20 g), and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (86.4 mg, 62%) as a gum. LCMS (System A) RT=0.41 min, ES+ve m/z 188 (M+H)+.
Reaction SMILES: [CH3:1][O:2]C1C=CC(N)=C([N+]([O-])=O)C=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26](C(F)(F)F)=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(OCC)(=O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:2][CH3:1])=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.