Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].CC([O-])=O.[K+]>CC(O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:17][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23]([OH:25])=[O:24])=[CH:18][CH:19]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(CCCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(O)c1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)c1ccccc1Nc1ccc(CCCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a slurry of 4-[3-(4-nitrophenyl)propyl]aniline (4.08 g, 15.9 mmol) and 2-bromobenzoic acid (3.52 g, 17.5 mmol) in i-PrOH (100 mL) was added Cu(OAc)2 (87 mg, 0.478 mmol) and KOAc (3.44 g, 35.0 mmol) at room temperature. The resulting mixture was allowed to heat under reflux for 23 hours, then cooled to room temperature. After removing the solvent under reduced pressure, the residue was diluted with water (100 mL) and basified with aqueous 1.0 M-NaOH solution to pH 9.0. The aqueous layer was washed with Et2O (20 ml, twice) and acidified with aqueous 1.0 M-HCl solution to pH 3.0. The precipitate formed was filtered by suction and dried at 60° C. in vacuo, affording the title compound as a beige solid (5.75 g, 96% yield). mp 150-153° C. MS (Fab): 376 (MH+).
Reaction SMILES: O[CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][C:4]2[CH:10]=[CH:11][S:12][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:8][C:6]1([CH3:9])[O:5][C:4]2[CH:10]=[CH:11][S:12][C:3]=2[CH:2]=[CH:7]1
Reactant: CC1(C)CC(O)c2sccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)C=Cc2sccc2O1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.3 g, 7.06 mmol), p-toluenesulfonic acid (0.11 g, 0.58 mmol) and ground molecular sieves (1.3 g) was stirred at -5° C. for 1.5 h. The mixture was washed with 1.0N aqueous sodium hydroxide and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product, 1.17 g (99%), as a red oil: IR (neat): 2976, 1504 and 1531 cm-1 ; MS: m/z 167 (MH30 ); 1H NMR (CDCl3): δ1.45 (s, 6H), 5.27 (d, J=9.8 Hz, 1H), 6.30 (d, J=9.8 Hz, 1H), 6.60 (d, J=5.3 Hz, 1H) and 6.99 (d, J=5.3 Hz, 1H). This oil was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>CN(C=O)C.N1C=CC=CC=1.O>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:18])[CH:16]=[CH2:17]
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CC(=O)Nc1ccc2cc(C(=O)O)ccc2c1
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a stirred solution of 2-Amino-6-naphthoic acid (0.3 g, 1.6 mmol) in DMF (2 mL) and pyridine (0.3 mL) was added at 0° C., acryloyl chloride (0.15 g, 1.6 mmol). The resulting mixture was allowed to come to rt and stirred further for 2 h. After that it was poured in water (5 mL) and the solid separated was filtered and dried under reduced pressure to get the desired product (160 mg, 41.5%) as a pale brown solid. This solid was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ncccc23)Oc2c(CN3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0292 g, 0.0633 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (aminopropyl silica was used, chloroform/methanol) to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0132 g, 58%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:13]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][C:21]2[S:20][C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:23][CH:22]=2)[CH:10]=1
Reactant: Cc1cc(C)c(C(=O)O)cc1Br
Reactant: c1ccc(-c2cccs2)cc1
Product: Cc1cc(C)c(Cc2ccc(-c3ccccc3)s2)cc1Br

Procedure:
2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100 ml), and thereto were added oxalyl chloride (6.8 ml) and N, N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (200 ml). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2,4-dimethylbenzoate as pale yellow oil, which was used in the subsequent step without further purification. (2) To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g) and activated aluminum neutral oxide (120 g) was added dropwise bromine (9.25 ml) while stirring at room temperature. The mixture was stirred at room temperature for 8 hours, and diluted with diethyl ether (1000 ml). Insoluble materials were filtered off, and washed with diethyl ether (500 ml). The combined filtrate was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol (40 ml) to give methyl 5-bromo-2,4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H). (3) The above methyl 5-bromo-2,4-dimethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2,4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z 227/229 (M−H) (4) The above 5-bromo-2,4-dimethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 357/359 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][C@H:11]([CH3:14])[CH2:12][OH:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: C[C@@H](N)CO
Reactant: Clc1ncc(I)c(Cl)n1
Product: C[C@H](CO)Nc1nc(Cl)ncc1I
Yield: 88 %

Procedure:
In the reaction of 2,4-dichloro-5-iodopyrimidine (3.0 g, 10.9 mmol) with (R)-2-amino-1-propanol (884 mg, 11.8 mmol) according to procedure 2, the desired product is obtained in 88% yield (1.6 g) after chromatographic purification (silica gel, dichloromethane/methanol (0% to 20% methanol)).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]([OH:27])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH:39]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](Cl)=[O:51])=[CH:45][CH:44]=1)([CH3:41])[CH3:40]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]([O:27][C:50](=[O:51])[CH2:49][C:46]2[CH:47]=[CH:48][C:43]([O:42][CH:39]([CH3:40])[CH3:41])=[CH:44][CH:45]=2)[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CCCCCC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O
Reactant: CC(C)Oc1ccc(CC(=O)Cl)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)Oc1ccc(CC(=O)Oc2cc(C(=O)CNC(C)(C)C)ccc2OC(=O)CCCCCC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(7,7-dimethyloctanoyloxy)-phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with p-isopropoxyphenylacetyl chloride there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O>CN(C=O)C>[C:30]([C:6]1[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]=2[CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)[NH:8][CH:7]=1)#[N:29]
Reactant: CCc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CCc1cc(C)c2[nH]cc(C#N)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-((5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (15 mg, 0.048 mmol) in DMF (1 mL) was added chlorosulfonyl isocyanate (17 μL, 0.191 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1.5 h. The mixture was allowed to warm up to room temperature with stirring. After 13.5 h, the reaction was quenched by 28% aq. NH4OH. The mixture was stirred for 0.25 h and then extracted with EtOAc/2,2,2-trifluoroethanol (c.a. 9/1). The organic layer was washed with H2O and brine, dried over Na2SO4, and filtered. After concentration, the resulting residue was purified by silica gel flash column chromatography [CH2Cl2/(2M NH3 in MeOH)=98/2, isocratic] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 10.22 (br. s., 1H), 8.07 (dd, J=1.00, 1.10 Hz, 1H), 7.91 (d, J=3.16 Hz, 1H), 7.71-7.85 (m, 2H), 7.15 (s, 1H), 5.02 (s, 2H), 2.71 (q, J=7.60 Hz, 2H), 2.54 (d, J=0.63 Hz, 3H), 1.14 (t, J=7.58 Hz, 3H). HRMS calcd. for C21H17N5 (M+H)+ 340.1557. found 340.1556.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1.Cl[CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]=1[CH3:29].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:13][O:14][C:15]1[CH2:20][CH2:19][CH:18]([CH2:23][C:24]2[N:25]=[CH:26][N:27]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:28]=2[CH3:29])[C:17](=[O:21])[CH:16]=1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=CC(=O)CCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC1=CC(=O)C(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CC1
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
n-Butyllithium (1.58M in hexane; 21 ml) was added at -78° under nitrogen to a stirred solution of diisopropylamine (4.6 ml) in dry THF (75 ml) and the solution was stirred at 0° for 30 min. The solution was cooled to -78° and added to a solution of 3-methoxy-2-cyclohexen-1 one (3.4 g) in dry THF (25 ml) at -78° under nitrogen with stirring. After stirring for 1 h at -78° and for 30 min. at 0° the solution was cooled to -78° and a solution of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (10 g) in dry THF (100 ml) was added dropwise with stirring under nitrogen. The solution was stirred at -78° for 3 h and at 0° for 30 min., treated with 8% aqueous sodium bicarbonate (400 ml) and extracted with ethyl acetate (2×300 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 13 g) which was purified by SPCC eluting with System A (967:30:3) to give the title compound (3.28 g), m.p. 145°-148°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)[NH2:5].C([Sn](CCCC)(CCCC)[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)[NH2:5]
Reactant: Nc1cc(Br)cc(-c2ncccn2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc(-c2ncccn2)cc(-c2ncccn2)c1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
The mixture of 3-bromo-5-(pyrimidin-2-yl)aniline (140 mg, 0.56 mmol),), 2-tributylstannylpyrimidine (420 mg, 1.12 mmol), Pd(Ph3P)4 (65 mg, 0.056 mmol) in 20 mL toluene and 5 mL dioxane was degassed with argon stream and stirred at 110° C. in argon atmosphere for two days. It was cooled to RT, diluted with EtOAc, filtered through celite, concentrated in vacuo, and subjected to silica flash column to isolate 3,5-di(pyrimidin-2-yl)aniline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Cl)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1ccc(-c2ccccc2)cc1C
Yield: 82.8 %

Procedure:
The general procedure described in Example 3 was used with 3,4-dimethyl-chlorobenzene (0.140 mL, 1.00 mmol), phenylboronic acid (157 mg, 1.20 mmol), Pd(OAc)2 (4.5 mg, 0.020 mmol, 2 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (20.0 mg, 0.040 mmol, 4 mol %), K2CO3 (276 mg, 2.00 mmol), water (1.0 mL), 10 h, room temperature. The product was isolated as a colorless oil (151 mg, 99%). 1H NMR (400 MHz, CDCl3) δ: 7.82 (d, 2H, J=7.6 Hz), 6.81-7.55 (m, 6H), 2.24 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH:29]=O)=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:29][CH2:28][S:27][C:21]2[CH:22]=[N:23][C:24]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:16][CH3:15])=[CH:26][CH:25]=3)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(SCC=O)cc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (3.4 g, 17.15 mmol, 1.0 eq) is added at room temperature to a stirred solution of (6-methoxy-quinolin-3-ylsulfanyl)-acetaldehyde (4.0 g, 17.15 mmol, 1.0 eq) in 1,2-dichloroethane (200 mL), followed by sodium triacetoxyborohydride (2.06 g, 34.3 mmol, 2.0 eq). After 1 hour stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×50 mL) and a saturated sodium hydrogen carbonate aqueous solution (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 20:1 to 10:1, v/v) to give a yellow solid that is further recrystallized with ethyl acetate:hexane (1:6, v/v) to afford {1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a yellow oil (724 mg, 10% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si](C(C)C)(C(C)C)C(C)C)[C:14]=3[O:30][CH3:31])[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:61][O:62][C:63](=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70]Br)[CH:65]=1>C(#N)C>[CH3:61][O:62][C:63](=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:11]3[N:10]([C:32](=[O:33])[C:34]4[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=4[F:40])[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:12]3)[C:14]=2[O:30][CH3:31])[CH:65]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: COC(=O)c1cccc(COc2cccc(C3SC(c4ccc(F)cc4)=NN3C(=O)c3c(F)cc(F)cc3F)c2OC)c1
Reaction time: 0.5 h

Procedure:
[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (0.02 mmol) is treated with tetrabutylammonium fluoride (1 M in THF) (0.04 mmol) at room temperature for 30 minutes. 3-Bromomethyl-benzoic acid methyl ester (0.04 mmol) is then added. After 30 minutes, the reaction is complete as determined by LC/MS. The mixture is diluted with acetonitrile and purified by preparative LC/MS (20-100% MeCN/H2O) to give 3-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoic acid methyl ester as white solid after evaporation of solvent: 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.47-7.55 (m, 4H), 7.01-7.07 (m, 3H), 6.94 (t, J=8.3 Hz, 2H), 6.77 (t, J=8.5 Hz, 2H), 5.16 (s, 2H), 4.07 (s, 3H), 3.94 (s, 3H). LC/MS (ES+): (M+1) 610.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>>[S:17]([CH2:20][CH2:14][CH2:15][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][CH2:10]1)([OH:19])(=[O:18])=[O:16]
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=S1(=O)CCCO1
Product: O=S(=O)(O)CCCN1CCN(c2ccccc2Cl)CC1

Procedure:
The reaction is conducted in the same manner as in Example 4 except that 4.2 g (21.4 mmols) of 1-(o-chlorophenyl)piperazine and 3.2 g (26.2 mmols) of 1,3-propanesultone are used. The resulting product is recrystallized from water.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:26][OH:27].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[OH:27])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccccc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccccc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-1-(2-methylpyridin-4-yl)-3-phenyl-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=331.2 ([M+H]+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[CH:19]=[CH:18][O:17][CH:16]=2)=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[N:22]=[CH:23][CH:24]=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[CH:29]=[C:25]([C:26]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[CH:19]=[CH:18][O:17][CH:16]=3)[N:11]=2)=[O:27])[CH:24]=[CH:23][N:22]=1
Reactant: Nc1nc(-c2ccoc2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccoc2)c(C(=O)C2CCOCC2)s1)c1ccnc(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
Compound 610 (100 mg, 0.359 mmol) was dissolved in pyridine (3 mL), and 6-chloroisonicotinoyl chloride (560 mg, 3.18 mmol) and DMAP (4.40 mg, 0.0360 mmol) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=3:1), followed by recrystallizing from a mixed solvent of ethanol and water to afford the entitled Compound 616 (54.5 mg, 36%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][NH:28][C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[N:33]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:29]([NH:28][CH3:27])[S:30][CH:31]=2)=[CH:41][CH:40]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CNc1nc(-c2ccc(CN)cc2)cs1
Product: CNc1nc(-c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)cs1
Yield: 21.3 %

Procedure:
Use a method similar to the General Procedure 1-3, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.48 g, 1.14 mmol) and 4-(2-methylamino-thiazol-4-yl)-benzylamine (0.4 g, 1.8 mmol), to obtain 7-chloro-6-[4-(2-methylamino-thiazol-4-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (0.12 g, 21%). MS (ES+) m/z: 495 (M+H)+.