Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[C:4]=1[CH3:12])=[O:2].[CH2:13]([C:15]1[CH:20]=[C:19]([C:21](=[NH:24])[NH:22]O)[CH:18]=[C:17]([CH3:25])[C:16]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[C:19]([C:21]2[N:22]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:12])[C:5]=3[CH3:11])[O:10][N:24]=2)[CH:18]=[C:17]([CH3:25])[C:16]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:14]
Reactant: Cc1c(C=O)sc(C(=O)O)c1C
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Product: CCc1cc(-c2noc(-c3sc(C=O)c(C)c3C)n2)cc(C)c1CCC(=O)O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-3,4-dimethyl-thiophene-2-carboxylic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid; LC-MS: tR=1.08 min; [M+1]+=399.05.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:23][CH3:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[CH:31]=[C:30]([N:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]([C:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=4)[CH:22]=3)[C:18]([S:23][CH3:24])=[N:19]2)[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CSc1n[nH]c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Product: CSc1nn(-c2cccc(F)c2)c2cc(C3=CCNCC3)ccc12

Procedure:
The title compound was prepared as a white solid by coupling 4-(3-methylsulfanyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 3-fluoro-phenyl boronic acid to yield an intermediate, which was de-protected to remove the N-Boc group.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[N:9]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:10]3=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]12([C:30](Br)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][CH:24]=[CH:23]2>>[C:22]12([C:30]([N:14]3[C:10]4=[N:11][C:12]5[C:7]([C:8](=[O:21])[N:9]4[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=4)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=5)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][CH:24]=[CH:23]2
Reactant: O=C(Br)C12C=CCC1CCC2
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc2[nH]c3ccccc3n12
Product: O=C(n1c2ccccc2n2c(=O)c3ccc([N+](=O)[O-])cc3nc12)C12C=CCC1CCC2

Procedure:
6-(Bicyclo[3.3.0]octenoyl)-3-nitrobenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-nitrobenzimidazo[2,1-b]-quinazolin-12(6H)one and bicyclo[3.3.0]octenoyl bromide.
Reaction SMILES: F[B-](F)(F)F.C(N([S+](F)F)CC)C.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2([C:28]#[N:29])[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[FH:30].[FH:31].F.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2([C:28]#[N:29])[CH2:26][CH2:25][C:24]([F:31])([F:30])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: N#CC1(c2ccc(Cl)nc2)CCC(=O)CC1
Reactant: F
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.1 %

Procedure:
To a stirred suspension of (diethylamino)difluorosulfonium tetrafluoroborate (16.5 g, 72.1 mmol) in DCM (150 mL) at room temperature under nitrogen atmosphere was added 1-(6-chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (4.2 g, 18 mmol) followed by triethylamine trihydrofluoride (8.68 g, 53.8 mmol). The reaction mixture was stirred for 6 hours at room temperature. The resulting mixture was then quenched by adding a saturated aqueous solution of sodium bicarbonate, stirred for 10 minutes, and the resulting mixture was extracted with DCM (3×25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (1:10 to 1:5 AcOEt/hexanes) to afford 1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (2.5 g, 54%). LC-MS (m/z) 257.0 (MH+). 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (d, J=2.2 Hz, 1 H), 7.79 (dd, J=8.4, 2.6 Hz, 1 H), 7.42 (d, J=8.4 Hz, 1 H), 2.09-2.41 (m, 8 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1C=CC=CC=1>[NH:1]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Nc1ccccc1)C(=O)OCC
Yield: 29.9 %

Procedure:
Aniline (18.6 g) was dissolved in dry benzene (125 ml), and diethyl bromomalonate (23.9 g) was added. The mixture was heated under reflux for 37 hours with stirring. The reaction mixture was washed with dilute hydrochloric acid to remove the unreacted aniline. The benzene layer was washed with water three times, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate (10:1) as an eluent to give 7.5 g (yield 30%) of diethyl anilinomalonate having the following NMR data.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17](=O)[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17](=[S:37])[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.9 %

Procedure:
To a solution of tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g, 4.12 mmol) in tetrahydrofuran (15 ml) was added Lawesson reagent (1.70 g, 4.12 mmol), and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=8:1-5:1). Diisopropy ether was added to the obtained residue. The precipitated solid was collected by filtration and washed with diisopropy ether. The obtained solid was dried in vacuo to give tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-thiocarbamoylethyl]carbamate (540 mg, yield 34%).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.C([Li])CCC.[S].[S:27](=O)(=O)(O)O>CCCCCC.O1CCCC1>[Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[C:19]([SH:27])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:3][CH2:4]1
Reactant: OC(Cc1ccccc1Cl)(Cn1cncn1)C1(Cl)CC1
Reactant: O=S(=O)(O)O
Agent: [Li]CCCC
Agent: [S]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
At -20° C., a mixture of 3.12 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol and 45 ml of absolute tetrahydrofuran is admixed with 8.4 ml (21 mmol) of n-butyl-lithium in hexane and stirred at 0° C. for 30 minutes. The reaction mixture is subsequently cooled to -70° C., admixed with 0.32 g (10 mmol) of sulphur powder and stirred at -70° C. for 30 minutes. The mixture is warmed to -10° C., admixed with ice-water and adjusted to pH 5 by addition of dilute sulphuric acid. The mixture is extracted repeatedly with ethyl acetate and the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.2 g (93% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol) are obtained in the form of a solid substance which, after recrystallization, melts at 138-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9]C)[C:5]([NH2:6])=[CH:4][C:3]=1[CH3:11].B(Br)(Br)Br>C(Cl)Cl>[NH2:6][C:5]1[CH:4]=[C:3]([CH3:11])[C:2]([Br:1])=[CH:8][C:7]=1[OH:9]
Reactant: COc1cc(Br)c(C)cc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(N)c(O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 125 %

Procedure:
To a suspension of 4-bromo-6-methoxy-3-methylaniline (41) (500 mg, 2.3 mmol) in 6 ml DCM was added 1 M BBr3 in DCM (4.6 ml, 4.6 mmol). The reaction mixture was stirred at r.t. for 2 h, which turned to a brown solution and back to a brown suspension. After quenched with aq. sodium bicarbonate solution, the mixture was extracted with EA. The org. phase was washed with brine, dried over sodium sulfate, concentrated to dryness to give 581 mg 2-amino-5-bromo-4-methylphenol as dark oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:17]2([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[C:19]([NH2:27])=[N:18]2)[CH:14]=[CH:15][CH:16]=1>>[F:26][C:23]1[CH:24]=[C:25]2[C:20]([C:19]([NH2:27])=[N:18][C:17]2([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:13]2[CH:12]=[CH:11][CH:16]=[C:15]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[CH:14]=2)=[CH:21][CH:22]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cc(F)ccc21
Reactant: OB(O)c1cncnc1
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cncnc3)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared as described in Example 78 (Scheme #14, N) using pyrimidin-5-ylboronic acid and 1-(3-bromophenyl)-6-fluoro-1-pyridin-4-yl-1H-isoindol-3-amine (Example 82) (26% yield): 1H NMR (CDCl3) δ 9.19 (s, 1 H), 8.87 (s, 2 H), 8.55 (m, 2 H), 7.53-7.45 (m, 4 H), 7.36 (m, 1 H), 7.29-7.25 (m, 3 H), 7.20 (m, 1 H); MS (ESI) m/z 382 [M+1]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24]>>[CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCNc1cccc(-c2ccc(C=O)cc2)c1
Product: CCNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 77.1 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 900 mg (4 mmol) of 3′-ethylaminobiphenyl-4-carbaldehyde with 470 mg (4 mmol) of 2,4-thiazolidine dione, 1 g (77%) of the expected product are obtained in the form of an orange solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:11]1[S:12][C:13]([Br:16])=[CH:14][N:15]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:16][C:13]1[S:12][C:11]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[N:15][CH:14]=1
Reactant: CC(C)N1CCNCC1
Reactant: Brc1cnc(Br)s1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ncc(Br)s2)CC1
Temperature: 50 °C

Procedure:
In a 50 mL round bottom flask, 1-isopropylpiperazine (224 mg, 1.74 mmol) was dissolved in 4 mL dioxane. 2,5-Dibromothiazole (650 mg, 1.5 eq.) and DIEA (670 mg, 3 eq.) were added and the reaction was heated to 50° C. overnight. Reaction mixture was cooled and extracted using ethyl acetate /brine. The organic layer was concentrated and purified via combiflash to give desired compound. LCMS-ESI+: calc'd for C10H17BrN3S: 290.0 (M+H+); Found: 290.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[Br:22]N1C(=O)CCC1=O>CN(C)C=O.COC(C)(C)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([Br:22])[C:9](=[O:12])[N:8]([C@H:13]3[CH2:14][CH2:15][C@H:16]([O:19][CH3:20])[CH2:17][CH2:18]3)[C:6]=2[N:7]=1
Reactant: CO[C@H]1CC[C@H](n2c(=O)ccc3c(C)nc(N)nc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](n2c(=O)c(Br)cc3c(C)nc(N)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (482 mg, 0.1.67 mmol) in dimethylformamide (15 mL) was added N-bromosuccinimide (300 mg, 1.69 mmol). After stirring for 1 hour at room temperature the solution was diluted with methyltertbutylether and washed with 50% sodium carbonate (2×) and brine. The combined aqueous layers were extracted with dichloromethane. The combined organics were dried (MgSO4) filtered and concentrated. The solids were triturated with diethyl ether to afford 2-amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (594 mg, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:19][CH:20]=[C:21]([CH3:23])[N:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[C:34](C1C=CC(F)=C([C@]23CO[C@@H](C4ON=C(C)C=4)C[C@H]2CSC(NC(=O)C2C=CC=CC=2)=N3)C=1)#[N:35]>>[C:34]([C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:19][CH:20]=[C:21]([CH3:23])[N:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9]3)[CH:7]=1)#[N:35]
Reactant: Cc1coc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)n1
Reactant: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Product: Cc1coc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)n1

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C40) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C37) in Example 10. The product was obtained as a white solid. Yield: 227 mg, 126%. LCMS m/z 477.2 [M+H+]. 1H NMR (400 MHz, CD3OH) δ 8.09 (br s, 2H), 7.83-7.86 (m, 2H), 7.61 (q, J=2.3 Hz, 1H), 7.55-7.65 (m, 2H), 7.40-7.51 (m, 3H), 4.91 (dd, J=11.8, 2.4 Hz, 1H), 4.35 (dd, J=11.9, 1.6 Hz, 1H), 4.00-4.13 (m, 2H), 2.97 (dd, J=13.1, 3.7 Hz, 1H), 2.82 (dd, J=13.2, 2.8 Hz, 1H), 2.38-2.47 (m, 1H), 2.15 and 2.01 (d, J=3.8 Hz, 3H), 2.03-2.07 (m, 1H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:18]=[CH:17][C:16]2[O:19][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(I)c1
Product: CC(C)(C)c1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-tert-Butyl-2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (398 mg, 80% yield). 1H NMR (300 MHz, CDCl3) δ 7.83 (dd, J=7.16, 2H), 7.57-7.56 (m, 1H), 7.44-7.38 (m, 3H), 7.34-7.30 (m, 2H), 6.96 (s, 1H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 155.99, 153.12, 145.92, 130.65, 128.88, 128.72, 128.33, 124.82, 122.23, 117.06, 110.42, 101.48, 34.68, 31.83. Anal. Calcd. for C18H18O: C, 86.36; H, 7.25. Found C, 86.34; H, 7.13. m.p.: 103-104° C. (lit., 7102-103° C.).
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[N:8][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:28][C:29](N(C)C)=[O:30]>O1CCCC1.CCCCCCC>[CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([C:29](=[O:30])[CH3:28])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc2ncn(COCC[Si](C)(C)C)c2cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(=O)c1nc2cc(C)c(C)cc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [5.01 g, Reference Example 4(a)] in dry tetrahydrofuran (55 mL), at −78° C., was treated with a solution of lithium diisopropylamide in a mixture of tetrahydrofuran and heptane (11.9 mL, 2M) over 10 minutes. The mixture was stirred for 15 minutes then treated dropwise with dimethylacetamide (2.15 mL) over 10 minutes. After stirring at −78° C. for a further 30 minutes the reaction mixture was poured into ice (50 g) and then left until all the ice had melted. This mixture was extracted with dichloromethane and the extracts were washed with brine, then with water, then dried over magnesium sulfate and then evaporated. The residual orange oil (5.91 g) was subjected to column chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give 1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone (3.93 g) as a yellow crystalline solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.[CH:23]1([CH2:29]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Na+].[Cl-]>C(OCC)(=O)C.CN(C)C=O>[CH:23]1([CH2:29][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCCCC1
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1ccc(OCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
A 1 L round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 28.4 g anhydrous potassium carbonate (pulverized with mortar and pestle), cesium carbonate (catalytic amount), 4-(hydroxy)phenyl acetonitrile (18.26 g.), cyclohexylmethylbromide (36.4 g.) and dimethylformamide (600 mL). The mixture was heated to reflux and maintained for one week at this temperature under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and saturated aqueous NaCl and ethyl acetate were added. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic fractions were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated in a rotary evaporator. The crude product was partitioned between equal volumes of hexane and 25% aqueous NaOH. This mixture was stirred under nitrogen atmosphere at room temperature for three days. The aqueous layer was drawn off, and the organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give 23 g of 4-(cyclohexylmethoxy)phenylacetonitrile as a yellow solid (73% yield). This material was homogeneous by TLC (CH2Cl2) and was carried on directly to the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C(N(CC)CC)C.[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>CN(C)C=O>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:40][C:39]4[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=4)[CH2:19][CH2:20]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)c21
Temperature: 90 °C
Reaction time: 10.5 h
Yield: 81.5 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (6.7 g), triethylamine (5.45 g), p-nitrobenzylbromide (5.8 g) and dimethylformamide (200 ml) was stirred at 90° C. for 10.5 hrs. The solvent was evaporated off and the residue was treated with water. The solid was filtered, washed with water, dried, and recrystallized from a mixture of dimethylformamide and ethanol to give 6.9 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[4-(p-nitrobenzyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid. mp: 241°-242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[CH2:13]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:19]1([OH:22])[CH2:20][CH2:21][N:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1
Reactant: FC(F)(F)c1ccc(Cl)c(I)c1
Reactant: CCCN1CCC(=O)CC1
Product: CCCN1CCC(O)(c2cc(C(F)(F)F)ccc2Cl)CC1

Procedure:
Beginning with 4-chloro-3-iodobenzotrifluoride and 1-propyl-4-piperidone, the titled compound was recovered by the procedure described in Preparation 4, MS m/z (rel. intensity, 70 eV)) 321 (M+, 8), 294 (38), 292, (bp), 274 (52), 56 (35).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH3:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[C:12]=2[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:34][CH3:35])[CH2:18][CH3:19])=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(-c2cc3ccccc3o2)cc1
Agent: Cl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
When 2-(p-chlorophenyl)benzofuran is acylated with 4-(3-diethylaminopropoxy)benzoyl chloride hydrochloride by the procedure described in Example 6, the title compound is obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[C:10]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][C:8]=2[C:7]([Cl:26])=[CH:6][CH:5]=1.O.NN>[Pd].C(O)C>[ClH:26].[CH3:2][O:3][C:4]1[C:9]2[C:10]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(Cl)c2oc(-c3ccccc3)c(N3CCN(C)CC3)c12
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cccc2oc(-c3ccccc3)c(N3CCN(C)CC3)c12

Procedure:
The mixture of 6.0 g of 1-(4-methoxy-7 -chloro-2-phenyl-3-benzofuryl)-4-methylpiperazine hydrochloride, 45 ml of hydrazine hydrate, 250 ml of ethanol and 1.5 g of 10% palladium on charcoal is stirred at reflux for 2 hours. It is filtered, the filtrate evaporated, the residue taken up in methylene chloride and successively washed with 2 N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated. The residue is taken up in isopropanol, the solution acidified with ethereal hydrogen chloride and the precipitate collected to yield the 1-(4-methoxy-2-phenyl-3-benzofuryl)-4-methylpiperazine hydrochloride melting at 279°-282° with decomposition. This elimination of chlorine from said 7-position ensures that the process according to Example 1 provided said 4-methoxy-starting material (identified in Example 9, No. 33) unambiguously.