Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5].[N+:19]([C:22]1[C:23]([CH:35]=O)=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][CH:27]=1)([O-:21])=[O:20].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[OH-].[Na+]>[CH:13]1([CH:2]([NH:1][CH2:35][C:23]2[C:22]([N+:19]([O-:21])=[O:20])=[CH:27][N:26]=[C:25]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:24]=2)[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)CCNC(=O)CC(N)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture 3-amino-3-cyclohexyl-N-(3,3-dimethyl-butyl)-propionamide (0.57 g, 2.24 mmol), 5-nitro-2-phenoxy-pyridine-4-carbaldehyde (0.57 g, 2.35 mmol), and dichloroethane (100 mL) was stirred for 12 hrs. Sodium triacetoxyborohydride (1.09 g, 5.15 mmol) was added and the resulting mixture was stirred 4 hours at room temperature. Sodium hydroxide solution ([0.1N], 100 mL) was added, the organic layer was separated, treated with MgSO4, filtered and the solvent evaporated under reduced pressure to yield an oil. The oil was purified by column chromatography (10%-40% ethyl acetate/heptane) to yield a residue.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22]C)=O)[N:19]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][Mg+].[Br-]>C1COCC1>[C:5]1([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([C:20](=[O:22])[CH3:30])[N:19]=2)[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: C[Mg+]
Reactant: COC(=O)c1coc(-c2c(-c3ccccc3)cnnc2-c2cccc(OC)c2)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of compound 26 (50 mg, 0.14 mmol) in THF (4 mL), MeMgBr (0.7 mL, 0.70 mmol) was added at −40° C. and the reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate (25 mL), washed with brine (1×10 mL) and dried over Na2SO4. Evaporation of the solvent under reduced pressure gave the crude product which was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-hexane) to furnish 1-(2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)ethanone (20 mg, 42%) as an off white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(c2ccc(Cl)cc2Cl)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)piperidine-4-carboxylate hydrochloride (2.8 g, 8.63 mmol) was diluted with DCM (24.18 mL). DIPEA (3.76 mL, 21.56 mmol) and methyl carbonochloridate (0.815 mL, 10.35 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, then washed with 3×0.1 M HCl and brine. Filtered through a phase separator. Evaporated to yield dimethyl 2-(2,4-dichlorophenyl)piperidine-1,4-dicarboxylate (2.78 g, 93%) as an oil. MS m/z 346 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,3,4-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.9 mg) with purity >90%. MS (pos) m/z 429.0, 431.0, 433.0.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=O)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.[NH+:34]1([O-:40])[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][N+:34]5([O-:40])[CH2:39][CH2:38][S:37][CH2:36][CH2:35]5)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: [O-][NH+]1CCSCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(C[N+]4([O-])CCSCC4)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (300 mg) in tetrahydrofuran (20 mL) were added thiomorpholine monooxide hydrochloride (149 mg), sodium triacetoxyborohydride (270 mg) and triethylamine (177 μL) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (87 mg, yield 24%) as a pale-yellow amorphous solid. MS: 575 (MH+).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:12]Br>Br>[BrH:12].[Br:12][CH:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]1=[O:11]
Reactant: BrBr
Reactant: O=C1CCCc2ncccc21
Agent: Br
Product: O=C1c2cccnc2CCC1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 159.7 %

Procedure:
To a warm solution of 5.00 g (33.52 mmol) of 7,8-dihydro-5(6H)-quinolinone, prepared in Example 1, in 25 ml of 48% hydrobromic acid, was added dropwise 6.0 g (37.54 mmol) of bromine. The solution was stirred at room temperature for 1 hour, then concentrated to a yellow-white solide. Recrystallization from absolute ethanol afforded 9.20 g (88.5%) of 6-bromo-7,8-dihydro-5(6H)-quinolinone hydrobromide as a white solid; mp 187°-189° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@H:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1)(=O)C.O>CO>[OH:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@H:24]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(OC(C)=O)c2)[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Potassium carbonate (1.46 g, 0.0105 mol, 3 eq) was added to a solution of 5a (1.49 g, 0.0035 mol, 1 eq) in methanol (15 mL) (see FIGS. 2 and 3). The suspension was stirred under nitrogen for 2 h. Water (200 mL) was added and the suspension was extracted with ethyl acetate (200 mL). The organic solution was washed with brine (100 mL), separated and dried over sodium sulfate. Evaporation of the solvent afforded the methyl ester 6a as a solid (1.17 g, 87% yield). Rf 0.30 (hexane/EtOAc=8:2). 1H NMR δ (CDCl3) 0.70 (d, 3H), 1.25 (s, 3H), 1.51 (d, 1H), 1.94 (m, 1H), 2.20-2.50 (m, 3H), 2.60-3.00 (m, 5H), 3.55 (s, 3H), 6.64 (d, 2H), 6.75 (s, 1H), 6.85 (s, 1H), 7.10-7.35 (m, 7H); [M+H]+382.2,: tR=3.42 min; purity: 99%. (Chiral purity determination; HPLC conditions: column Chiralcel OD 4.6×250 mm; flow: 1 mL/min; mobile phase: 92.5% hexane/7.5% isopropanol; λ=254 nM; Inj. Vol: 20 μL; 6a (reference standard): tR=27.97 min; 6b (reference standard): tR=25.36 min; result: 6a/6b=98.7/1.3 (% area pic calculation)].
Reaction SMILES: [S:1]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23]CC)=[O:22])([CH3:4])(=[O:3])=[O:2].O>[OH-].[Na+]>[S:1]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([OH:23])=[O:22])([CH3:4])(=[O:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Nc1c(CC(=O)O)cccc1Oc1ccccc1Cl
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
Ethyl 2-[2-mesylamino-3-(2-chlorophenoxy)phenyl]-acetate (0.8 g) was dissolved in 1N-sodium hydroxide (10 ml) by heating, and the solution was allowed to stand at room temperature for 10 minutes. To the reaction mixture was added water (20 ml), and the mixture was washed with diethyl ether. The aqueous solution was adjusted to pH 2 with conc. hydrochloric acid. The precipitating crystals were collected by filtration, washed with water and recrystallized from benzene to give 2-[2-mesylamino-3-(2-chlorophenoxy)phenyl]acetic acid (0.58 g). mp 159°-163° C.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.17 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.64 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.11 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.9 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[O:33][CH3:32])[CH2:45][CH2:44]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: COc1ccccc1N1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=621.98 (M+H+); retention time=0.95 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[CH2:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]=[C:19](S([O-])(=O)=O)[O:20][C:16]=2[CH:15]=1.[K+].Cl.[NH2:29][C:30]([NH2:32])=[NH:31].[OH-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[CH2:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]=[C:19]([NH:31][C:30]([NH2:32])=[NH:29])[O:20][C:16]=2[CH:15]=1
Reactant: Cc1ccn2c(C)c(CCc3ccc4nc(S(=O)(=O)[O-])oc4c3)nc2c1
Reactant: N=C(N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccn2c(C)c(CCc3ccc4nc(NC(=N)N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
Potassium 6-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-benzoxazolesulfonate (1.10 g) was added to a mixture of guanidine hydrochloride (257 mg) and potassium hydroxide (150 mg) in N,N-dimethylformamide (12 ml). After being stirred for 4 hours at ambient temperature, the reaction mixture was mixed with water (110 ml) and ethyl acetate (20 ml). The resulting precipitate was collected, washed with water and recrystallized from ethanol to give 6-[2-(3,7-dimethylimidazo[1,2-a]-pyridin-2-yl)ethyl]-2-guanidinobenzoxazole (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][C:6]2[CH:5]=[CH:4][C:3]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([Cl:1])[CH:7]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: CS(=O)(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(Cl)c2)c2c(c1)OC(C)(C)C2
Temperature: 80 °C
Yield: 91.9 %

Procedure:
A mixture of 2-chloro-4-fluoro-1-(methylsulfonyl)benzene (939 mg, 4.50 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.00 g, 4.50 mmol) and Cs2CO3 (2.93 g, 9.00 mmol) in DMF (5 mL) was heated to 80° C. for 1.5 h, cooled to room temperature, quenched with H2O and extracted with 3× EtOAc. The organic layers were washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 25-50% EtOAc in hexanes to give a white solid (1.70 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.84 Hz, 1 H) 7.31 (d, J=1.26 Hz, 1 H) 7.25 (d, J=1.26 Hz, 1 H) 7.10 (d, J=2.27 Hz, 1 H) 6.88-7.03 (m, 1 H) 3.89 (s, 3H) 3.28 (s, 3 H) 2.88 (s, 2 H) 1.50 (s, 6 H); LCMS for C19H19ClO6S m/z 411.00 and 413.00 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=O.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+].CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(C(=O)c2nc3ccccc3s2)c1
Reactant: CN1CCC(N)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C(=NC2CCN(C)CC2)c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (benzothiazol-2-yl)(m-tolyl)methanone (1.06 g) and 4-amino-1-methylpiperidine (0.456 g) in tetrahydrofurane (4 mL) is added titanium tetraisopropoxide (1.42 g). The mixture is stirred at room temperature for 1 h, then polymethyl hydrosiloxane (1.2 mL) is added. The mixture is stirred for one day at room temperature, diluted with ethyl acetate (50 mL), hydolysed with 3N sodium hydroxide (30 mL). The organic phase is separated by decantation, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is crystallised by trituration in diisopropyl oxide. A second crop can be obtained form the mother liquor by chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 95/5) to give [(benzothiazol-2-yl)(m-tolyl)methylene](1-methylpiperidin-4-yl)amine meting at 125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:30][CH:31]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (415 mg), 3-(4-chloromethylphenoxymethyl)pyridine (554 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 80.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (340 mg, yield: 55%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-(3-fluoro-4-methoxylphenyl)-2-naphthol (1 g, 3.73 mmol) and NCS (748 mg, 5.60 mmol) in THF (35 mL) according to method A to yield 780 mg (69%) of brown solid: mp 137-139° C.; 1H NMR (DMDO-d6): δ 3.89 (3H, s), 7.26-7.33 (2H, m), 7.61 (1H, d, J=8.63 Hz), 7.71 (1H, dd, J=13.08 Hz, J=2.16 Hz), 7.84 (1H, d, J=8.93 Hz), 7.92 (1H, dd, J=8.92 Hz, J=1.80 Hz), 8.06 (1H, d, J=8.86 Hz), 8.19 (1H, d, J=1.55 Hz), 10.52 (1H, s); MS (ESI) m/z301/303(M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[CH:35][CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:37][CH2:36][CH:35]=[CH:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C=CCN
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1C=CCNC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg (0.416 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 81.4 mg (0.499 mmol) of 3-(2-methoxyphenyl)-allylamine were dissolved in 10 ml of dichloromethane. 120 mg (0.624 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 63.7 mg (0.416 mmol) of 1-hydroxybenzotriazole were added to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 hours. Dichloromethane was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the product was washed with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O>C1COCC1>[Br:14][C:6]1[S:7][CH:8]=[CH:9][C:5]=1[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(CC)Cc1ccsc1
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccsc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To 150 mL of THF solution of (9-4) (5.3 g, 26.9 mmol), N-bromosuccinimide (4.8 g, 26.9 mmol) was added portionwise at 0° C. and the mixture was stirred at 0° C. overnight. The organic fraction was extracted with water and CHCl3, washed with NaHCO3 aq., and dried over anhydrous Mg2SO4. The crude product was further purified by column chromatography using hexane as the eluent give (9-5) as a colourless liquid (6.9 g, 93%). 1H NMR (CDCl3, 300 MHz, ppm): 7.18 (d, 1H, J=5.7 Hz), 6.76 (d, 1H, J=5.7 Hz), 2.50 (d, 2H, J=7.2 Hz), 1.55-1.62 (m, 1H), 1.25-1.34 (m, 8H), 0.85-0.90 (m, 6H).