Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](OC)=O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1cccn1C
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccn3C)nc(=O)c1-2
Temperature: 25 °C
Yield: 36.9 %

Procedure:
Sodium spheres (1.0 g, 43.5 mmol) were dissolved in ethanol (50 mL) at reflux and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.2 g, 10 mmol), followed by methyl 1-methylpyrrole-2-acetate (3.06 g, 20 mmol) in ethanol (30 mL) were added. The reaction mixture was refluxed under argon overnight, cooled to room temperature and evaporated to dryness. The residue was dissolved in water, the solution was cooled and the resulting solid was collected by filtration to afford recovered starting material. The filtrate was chilled, a solid formed which was collected by filtration, slurried with water and acidified with 2N HCl. The mixture was cooled and the product was collected by filtration and dried at 110° C. in vacuo to afford 1.2 g of 1-cyclopentyl-3-ethyl-6-(1-methyl-2-pyrrolylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 214.5-216.5° C. Additional product (0.6 g) was also obtained by acidifying the filtrate with acetic acid, collecting the product by filtration and recrystallizing it from ethyl acetate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([Cl:15])[CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[N+:16]([O-])([O-:18])=[O:17].[Na+]>S(=O)(=O)(O)O>[C:12]([NH:11][C:10]1[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]([Cl:15])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(Cl)cc1NC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A solution of 5 g (22 mmol) of 3,4-diacetamido-1-chlorobenzene in 50 ml of concentrated sulfuric acid was cooled to 0° C., and 1.9 g (8.5 mmol) of sodium nitrate were added a little at a time, and the mixture was stirred at room temperature for 15 minutes. It was then poured into ice-water, and the crude product was filtered off with suction and washed with water. A yield of 63% of the product was obtained. Melting point 232° C.
Reaction SMILES: [CH3:1][N:2](C(OCC1C=CC=CC=1)=O)[NH:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>C(O)C.[Pd]>[CH3:1][NH:2][NH:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CN(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNNC(=O)OC(C)(C)C

Procedure:
A solution of 24.8 g (70.8 mmol) of 1-benzyl 2-tert-butyl 1-methylhydrazine-1,2-dicarboxylate in 500 ml of ethanol was hydrogenated in the presence of 1.24 g of palladium (10% on activated carbon) at RT and standard pressure. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure and dried. Yield: 12.3 g (purity 48%, 57% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22]=O)=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.CO.[CH3:32][NH2:33].[BH4-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][NH:33][CH3:32])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: CN
Reactant: COc1cc(Cl)cc(C)c1Nc1nc2cccc(-c3ccccc3C=O)c2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CNCc1ccccc1-c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
A mixture of 33 mg (0.0813 mmol) of 2-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl]benzaldehyde, 0.033 mL (0.325 mmol) of 40% methanol solution of methyl amine and 1 mL of ethanol was refluxed for 4 hours. After cooling, 9.2 mg (0.244 mmol) of sodium borohydride was added. The mixture was stirred at room temperature for 4 hours, and 15 mg (0.407 mmol) of sodium borohydride was added. After stirring at room temperature for 15 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC and basic silica gel column chromatography eluting with a 50-100% ethylacetate/n-hexane gradient mixture to give 5 mg (17%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]2[O:10][CH2:11][C:12]3[N:37]=[CH:36][CH:35]=[CH:34][C:13]=3[C:14](=[CH:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][C:21]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([OH:24])[C:20]([CH3:33])([CH3:32])[CH2:19]3)[C:8]=2[CH:7]=1.[OH-].[Na+]>CO.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:21]2([OH:24])[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]=[C:14]3[C:13]4[CH:34]=[CH:35][CH:36]=[N:37][C:12]=4[CH2:11][O:10][C:9]4[CH:38]=[CH:39][C:6]([O:5][CH2:4][C:3]([OH:40])=[O:2])=[CH:7][C:8]3=4)[CH2:19][C:20]2([CH3:32])[CH3:33])=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CN(CCC=C2c3cc(OCC(=O)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-acetic acid methyl ester (0.060 g, 0.107 mmol) was dissolved in methanol (1.5 mL). Sodium hydroxide (150 uL, 1N stock solution) was added and the resulting mixture was stirred at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo to give a yellow oil. The oil was suspended in water (2 mL) and then washed with ethyl acetate (3×3 mL). The aqueous layer was then acidified to pH=2 and extracted with ethyl acetate (3×5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a white solid (55 mg, 94%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:43])([F:42])[C:10]1[CH:11]=[C:12]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:13]([N:15]([CH:17]([CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][C:19]([OH:21])=O)[CH3:16])=[O:14].[CH:44]1([C:50]2[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:50]2[CH:51]=[CH:52][C:53]([NH:54][C:19](=[O:21])[CH2:18][CH:17]([N:15]([C:13](=[O:14])[C:12]3[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=[C:10]([C:9]([F:42])([F:8])[F:43])[CH:11]=3)[CH3:16])[CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:55][CH:56]=2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)Nc1ccc(C2CCCCC2)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A solution of 0.05 ml (0.362 mmol) of triethylamine and 37 mg (0.0726 mmol) of 3-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-4,4-diphenyl-butanoic acid in 0.5 ml of methylene chloride and a solution of 30.6 mg (0.289 mmol) of 1-propanephosphonic acid anhydride in 0.5 ml of methylene chloride are added in succession to 15.2 mg (0.087 mmol) of 4-cyclohexylaniline and the mixture is left to stand at room temperature for 24 hours. The reaction mixture is then washed with 0.5 ml of a 1N aqueous potassium carbonate solution. The organic phase is concentrated by evaporation in a vacuum centrifuge. The title compound is obtained in the form of a white foam. TLC: methylene chloride/methanol (95:5) Rf =0.44
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.[H][H]>[Ni].CO>[NH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:12]=[C:13]1[NH:14][CH2:15][CH2:16][NH:17]1
Reactant: Cc1cc(Cl)c(N=C2NCCN2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)c(N=C2NCCN2)c(Cl)c1

Procedure:
3.05 gm (0.012 mol) of 2-(2-chloro-4-methyl-6-nitrophenylimino)-imidazolidine were hydrogenated in a shaker autoclave at 25°-30° C. and atmospheric pressure in the presence of Raney nickel and in a 1:1 mixture of methanol and tetrahydrofurn until the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was separated by suction filtration, and the filtrate was evaporated in vacuo until the weight of the residue remained constant. Yield: 2.6 gm (96.5% of theory) of 2-(2-amino-6-chloro-4-methyl-phenylimino)-imidazolidine, an oily substance having an Rf -value of 0.3 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol and 5 parts concentrated ammonium hydroxide; carrier: silicagel G; visualization: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14](Cl)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24]([N:26]([CH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:40][CH:37]4[CH2:38][CH2:39][CH:34]([N:26]([CH2:24][CH3:25])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:35][CH2:36]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
For the preparation of the starting material compound 25.1, please refer to the experimental procedure for the synthesis of compound Example 25. To a solution of tert-butyl N-ethyl-N-(4-hydroxycyclohexyl)carbamate (intermediate 101.5, 322.68 mg, 1.33 mmol, 1.22 equiv) in distilled tetrahydrofuran (10 mL) was added sodium hydride (151.76 mg) slowly at 0° C. and the reaction mixture was stirred at room temperature for 30 min. Then (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (400 mg, 1.08 mmol, 1.00 equiv) in THF (5 mL) was added to the mixture via syringe and the resulting solution was stirred for 3 hr at ambient temperature. The reaction was then quenched by the addition of 40 mL of saturated aqueous NH4Cl and extracted with 3×80 mL of ethyl acetate. The combined organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to afford tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (570 mg, 91%) as a colorless oil. MS (ES): m/z 576 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:6]=[N:7][OH:8].ClN1C(=O)CCC1=O.Br[C:24]1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH:29]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:29]3[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=3[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc(C=NO)ccc1[N+](=O)[O-]
Reactant: O=C1CCCC=C1Br
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2noc3c2CCCC3=O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 3-methoxy-4-nitrobenzaldehyde oxime (5.0 g, 25.5 mmol) in DMF (60 ml) at 0° C. was added N-chlorosuccinimide (4.088 g, 30.61 mmol). The reaction mixture was stirred for 15 min at 0° C., and 1.5 hr at ambient temperature. To the reaction flask was added as solids 2-bromocyclohex-2-enone (6.66 g, 38.2 mmol, prepared as in Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem. (1982), 47(26), 5088-93) followed by sodium bicarbonate (4.29 g, 51 mmol), and the mixture was stirred overnight. The reaction mixture was partitioned between water and dichloromethane, the organic phase was washed with water, sat. NaHCO3, and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel using hexanes/ethyl acetate mixture as eluent to furnish 4.95 g of the title product. 1H NMR (CDCl3) δ: 7.97 (d, J=8.6 Hz, 1H), 7.60 (s, 1H), 7.32 (dd, J=8.4, 1.4 Hz, 1H), 4.05 (s, 3H), 2.99 (t, J=6.1 Hz, 2H), 2.75 (t, J=6.3 Hz, 2H), 2.31 (quin, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1](OC(=O)C(OCC)=O)C.[H-].[Na+].[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH3:14].C=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1C=CC=CC=1.O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17](=[CH2:1])[C:16]([O:15][CH2:13][CH3:14])=[O:26])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a solution of oxalic acid diethyl ester (18.8 ml, 0.14 mol) in tetrahydrofuran (10 ml) and benzene (10 ml) was added sodium hydride (80% oil suspension, 6.5 g, 0.22 mol) and then stirred for 10 minutes under argon atmosphere. A benzene solution (100 ml) of 2-(p-methoxyphenyl)acetic acid ethyl ester (1) (27.0 g, 0.14 mol) was added to the resulting solution and stirred for 3 days at room temperature. The reaction solution was quenched with aqueous 2N HCl solution and extracted with ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. Thus, 48.0 g of the crude product was obtained. The obtained crude product was dissolved in water (150 ml) and 37% formalin (25 ml, 0.31 mol) was added dropwise thereto. To the reaction mixture was added dropwise aqueous potassium carbonate solution (24 g, 0.17 mol, 100 ml) and then stirred for 24 hours. The reaction solution was extracted with ether, and the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The obtained crude product was then purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 27.0 g (yield: 94%) of ethyl α-(4-methoxyphenyl)acrylate (2).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])[CH2:5][CH2:4][O:3]1.[CH3:14][CH2:15][Mg+].[Br-].[NH4+].[Cl-].O>C(OCC)C>[CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH:9]([OH:10])[CH2:14][CH3:15])[CH3:11])[CH2:5][CH2:4][O:3]1
Reactant: CC[Mg+]
Reactant: CC1(C)OCCC(C(C)(C)C=O)O1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(O)C(C)(C)C1CCOC(C)(C)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 268 mg (1.44 mmol) of aldehyde 45 in 4 ml of diethyl ether is mixed at 0° C. with 528 μl (1.58 mmol, 1.1 equivalents) of a 3 M solution of EtMgBr in ether. It is allowed to stir for 2 hours at 0° C., heated to room temperature and allowed to stir for another hour. For working-up, it is mixed with saturated aqueous NH4Cl solution, and then water is added steadily until the precipitate goes into solution. The aqueous phase is extracted with ether, the combined organic phases are dried on MgSO4 and concentrated by evaporation. The residue is purified by column chromatography with pentane:ether=1:1. 251 mg (1.16 mmol) of alcohol 46, corresponding to a yield of 80%, is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([CH:8]=[CH2:9])[CH:7]=1.[Se](=O)=[O:18]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[N:12][C:13]([CH:16]=[O:18])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([CH:8]=[CH2:9])[CH:7]=1
Reactant: C=Cc1cnc(-c2ccc(C)nc2)c(Cl)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: C=Cc1cnc(-c2ccc(C=O)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
4.0 g of 3-chloro-6′-methyl-5-vinyl-2,3′-bipyridine (14) (17.3 mmol) prepared in Example 10 was dissolved in 50 mL of 1,4-dioxane, and 5.8 g of selenium dioxide (52 mmol) was added thereto. The mixture was refluxed under heating and stirring for 18 hours, and cooled to room temperature. Then, the mixture was concentrated under reduced pressure, and dissolved in ethyl acetate to be washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent:ethyl acetate/hexane=1/4) to obtain 3.2 g of 3-chloro-5-vinyl-2,3′-bipyridine-6′-carbaldehyde (yield 75%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[N:20]1([C:26](=[O:28])[CH3:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:26]([N:20]1[CH2:25][CH2:24][N:23]([S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:22][CH2:21]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCN(C(C)=O)CC3)s2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (100 mg; 0.3 mmol; 1 eq) is dissolved in anhydrous DCM (5 ml). The reaction is put under nitrogen. 1-Piperazin-1-yl-ethanone (76.1 mg; 0.59 mmol; 2 eq), diisopropylethylamine (0.3 ml; 1.78 mmol; 6 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. The solvents are evaporated and the crude product is purified by preparative HPLC. Compound (2) is isolated as a pale yellow powder (35 mg; 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6](C(C3C=CC=CC=3)=O)[CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(c1ccccc1)N1CCCOc2cc(Cl)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)OCCCN2
Yield: 47 %

Procedure:
(3-Chloro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-phenyl-methanone from Example E25.2 (783 mg, 2.7 mmol) was dissolved in dioxan (10 ml) and 6M HCl aqueous solution (50 ml) was added. The mixture was heated at reflux for 20 h then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in diethyl ether and water, basified with NaHCO3 and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo to yield the title compound (280 mg, 47%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCN2CCCCC2)c1
Yield: 94.8 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and piperidine (1.33 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (480 mg, 94.7%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 194.6° C. MS m/z (relative intensity, 70 eV) 301 (M+, 1), 99 (8), 98 (bp), 96 (4), 55 (5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11](Br)[CH3:12].[Mg].O1CCCC1.[OH-].[Na+]>O1CCCC1.O.C(OCC)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2([NH2:10])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCBr
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Mg]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(Cc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluorophenyl acetonitrile (2.7 g) in tetrahydrofuran (40 mL) was added tetraisopropoxy titanium (6.5 mL), whereafter a solution of 1.0M magnesium ethylbromide-tetrahydrofuran (40 mL) was added dropwise over 30 minutes, and stirred for 1 hour. After adding a trifluoroborane-diethyl ether complex (50.1 mL) over 20 minutes, the solution was further stirred for 1 hour. The reaction solution was cooled with ice water, an aqueous solution of 5N sodium hydroxide (20 mL) was added, and stirred at room temperature for 20 minutes. After diluting with water and diethyl ether, and filtration using Celite was carried out. The organic layer was separated, washed with saturated sodium chloride water, and then dried with anhydrous sodium sulfate. After the solvent was evaporated at reduced pressure, filtration was carried out using a small amount of NH-silica gel, and washing was carried out with ethyl acetate. The residue that was obtained upon removing the solvent by evaporation was purified by NAM silica gel column chromatography (dichloromethane/methanol), and the title compound (0.75 g) was obtained as a yellow oily substance.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[CH2:17][NH2:18].[BH4-].[Na+]>CCCCCC>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OC(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(Cc1ccc(OC(C)C)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
1-(4-Isopropoxyphenyl)propan-2-one (1.92 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.71 g) were condensed and subsequently reduced with sodium borohydride (2.00 g) by an analogous procedure to that described in Example 1. Chromatography of the crude product on silica gel using 1% methanol-dichloromethane as eluent gave N-[2-(4-isopropoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, mp 58°-61° C. (hexane) as a 42:58 mixture of diastereoisomers.