Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1.C(#N)C.[C:28]([C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][C:42](Cl)=[O:43])=[CH:38][CH:37]=1)([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[CH:46][C:36]([C:28]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:29])[CH3:30])=[CH:37][CH:38]=3)[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Reactant: Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1ccc(OCC(=O)Nc2ccc(Cl)c(Nc3cc(=O)n(-c4c(Cl)cc(Cl)cc4Cl)[nH]3)c2)cc1
Yield: 854.2 %

Procedure:
Forty point four grams of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-aminoanilino)-5-pyrazolone were dissolved into 250 ml of acetonitrile, and to the solution were added 9.4 grams of pyridine. To this mixture, while being refluxed by heating, were dropwise added 28.3 g of 4-t-octylphenoxyacetyl chloride, and the reflux was further continued for another hour. The acetonitrile was distilled off from the reaction liquid under reduced pressure, then 500 ml of water and ethyl acetate were added to the liquid, and then the reaction product was extracted by ethyl acetate. The residuum that has been obtained by distilling off the ethyl acetate phase under reduced pressure was recrystallized from 300 ml of ethanol, whereby 55 g of objective 1-(2,4,6-trichlorophenyl)-3-[2-chloro-5-(4-t-octylphenoxyacetamido)anilino]-5-pyrazolone were obtained. Melting point: 126° to 128° C. The structure was confirmed through the procedures of NMR, IR and MASS.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[S:11][CH2:12][C:13]([CH3:21])=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:24])=[N-]>CCOCC>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[S:11][CH2:12][C:13]([CH3:21])=[C:14]2[C:18]([O:20][CH3:24])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C1=C(C)CSC2C(NC(=O)OC(C)(C)C)C(=O)N12

Procedure:
7-tert.-Butoxycarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-end can be prepared by esterifying 7-tert.-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (16.7 g) (described in Example 1) with a solution of diazomethane in ether, according to the method of R. B. Morin, et al., J. Amer. Soc., 91(6), 1401 (1969). 7-tert.-Butoxycarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (13.6 g) is obtained in the form of white crystals (m.p.=148° C.).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]1COCC1>>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:28](=[O:34])[O:27][CH2:25][CH3:36])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: C1CCOC1
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CCOC(=O)NC1(c2ccc(C(C)C)cc2OC)C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.80 g, 2.58 mmol) in anhydrous THF (20 ml) was added triphosgene (0.84 g, 2.84 mmol) and stirred for 15 min. The reaction mixture was concentrated and was dissolved in ethanol (20 ml) was stirred for 2 hrs at room temperature to afford the title compound (0.95 g, 96%).
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.F[B-](F)(F)F.[H+].N([O-])=[O:21].[Na+]>O>[Cl:11][C:10]1[C:2]([OH:21])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=N[O-]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COc1cc(O)c(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (25 g; 0.12 mol) in 125 ml of water was added tetrafluoroboric acid (40.5 ml of 48% aqueous solution). The white cake was then cooled to 0° C. and NaNO2 (9.41 g in 75 mL of H2O) was added drop wise and the whole stirred at that temperature for 30 minutes. The white precipitate was collected by filtration. The diazonium salt was suspended in glacial AcOH (1250 mL) and the resulting suspension was stirred at 100° C. for 1 hour (it became a brown solution). It was allowed to stand at RT for two more hours. The solvent was removed under reduced pressure and the brown oily residue suspended in brine (1250 ml) and extracted with EtOAC (3×400 ml). The combined organic layers were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give brown oil. Purification by preparative reversed-phase HPLC (Et2O/EtOH 0/100 to 40/60) afforded 3.0 g (13%) of a red solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:10][C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: COCCOc1ccc(C(=O)O)cc1
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCOc1ccc(C(=O)Oc2cc(F)c(F)c(F)c2)cc1
Reaction time: 8 h

Procedure:
A solution of 3,4,5-trifluorophenol (0.38 g, 2.55×10−3 mol) in dichloromethane (10 cm3) was added to a solution of N,N-dicyclohexylcarbodiimide (0.63 g, 3.06×10−3 mol), 4-(2-methoxyethoxy)benzoic acid (0.50 g, 2.55×10−3 mol), 4-(dimethylamino)pyridine (0.03 g 2.55×10−4mol) in dichloromethane (5 cm3), at 0° C. and then left to stirred overnight, filtered to remove precipitated material (DCU) and the filtrate evaporated down under reduced pressure. The crude product was purified by column chromatography on silica gel using a 1:1 dichloromethane-petroleum ether (40°-60° C.) mixture as eluent, followed by recrystalisation from ethanol. Yield 0.32 g (38%), GC purity (99.76%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][CH:34]([CH2:39][CH3:40])[CH2:35][C:36](O)=[O:37].O.ON1C2C=CC=CC=2N=N1.N=C=N>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][CH:34]([CH3:33])[CH2:39][CH3:40])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Reactant: CCC(C)CC(=O)O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(C)CC(=O)N1CCN(c2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
React 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (0.20 g, 0.46 mmol) with 3-methyl-pentanoic acid (0.059 g, 0.51 mmol), 1-hydroxybenzotriazole hydrate (0.06 g, 0.46 mmol) and polymer supported carbodiimide (0.83 g, 1.0 mmol), suspended in a mixture CH2Cl2/DMF (18/1, mL). Stir the mixture at room temperature overnight and then filter and wash the resin with CH2Cl2. Concentrate and purify the residue with a SCX cartridge eluting with NH4OH/CH3OH 2N to yield 135 mg (55%) of the title compound as a pale pink solid. MS(ES+): m/z=532 [M+H].
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6](OCC)=[O:7].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([N:26]=[C:27]=[O:28])=[C:18]([F:29])[CH:17]=1.[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O.C1(C)C=CC=CC=1>[NH2:30][N:3]1[C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:6](=[O:7])[N:26]([C:19]2[CH:20]=[C:21]([O:22][CH:23]([CH3:24])[CH3:25])[C:16]([Cl:15])=[CH:17][C:18]=2[F:29])[C:27]1=[O:28]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Reaction time: 0.25 h

Procedure:
A suspension of sodium hydride (1.0 g, 60% in oil ) in N,N-dimethylformamide (30 ml) was stirred at 0° C. under nitrogen while a solution of ethyl 3-amino-4,4,4-trifluorocrotonate (4.5 g) in N,N-dimethylformamide (20 ml) was added dropwise. After stirring for 15 minutes, a solution of 4-chloro-2-fluoro-5-isopropyloxyphenylisocyanate (5.6 g) in toluene (25 ml) was added slowly at -35° C. The solution was stirred at room temperature for 2 hours and treated with a solution of 2,4-dinitrophenoxyamine (5.8 g) in N,N-dimethylformamide (20 ml). Stirring was continued for 3 days. The solution was processed and gave a solid which was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:5, containing 0.1% of triethylamine. 1-Amino-3-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione was obtained as a white solid (5.3 g).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[CH:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1)=[O:2]
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC=O)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
Formic acid (0.35 mL, 9.1 mmol) was added to acetic anhydride (0.69 mL, 7.3 mmol) at 0° C. The mixture was warmed to 60° C. for 2 hours, then cooled to 0° C. To the anhydride mixture was added a solution of methyl 2-(4-aminophenyl)acetate (0.95 g, 5.7 mmol) in tetrahydrofuran (14 mL). The mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and diluted with ether. The ether layer was separated, dried over sodium sulfate, and concentrated. The residue was filtered through silica (1% methanol/dichloromethane eluent) to give methyl 2-(4-formamidophenyl)acetate (0.8 g, 4.14 mmol, 56% yield). The product was dissolved in tetrahydrofuran (14 mL) and cooled to 0° C. Borane methyl sulfide complex (0.393 mL, 4.14 mmol) was added. After 15 minutes, the mixture was warmed to room temperature for 30 minutes. The mixture was cooled to 0° C. again, and 5 mL of methanol was added. The mixture was concentrated and the residue was purified by silica chromatography (10% ethyl acetate/hexane eluent) to give methyl 2-(4-(methylamino)phenyl)acetate: 1H NMR (300 MHz, CDCl3) δ ppm 2.82 (s, 3 H), 3.51 (s, 2 H), 3.67 (s, 3 H), 6.51-6.61 (m, 2 H), 6.99-7.15 (m, 2 H): MS (ESI+) m/z 179.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][CH:14]([NH:19][CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH2:24]=O>C(O)=O>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][CH:14]([N:19]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH3:24])[CH2:13]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Brc1csc2ncnc(N3C4CCC3CC(NC3CCC3)C4)c12
Reactant: C=O
Solvent: O=CO
Product: CN(C1CCC1)C1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Yield: 81 %

Procedure:
8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine (200 mg, 0.5 mmol) in formalin solution (5 mL) and formic acid (5 mL) was heated to 80° C. for 1 h. The reaction was then concentrated in vacuum to a gum, diluted with ethyl acetate (50 mL) and 10% potassium carbonate solution (10 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give a colourless gum. The gum was chromatographed on a 25 g silica column in a gradient of 2-15% methanol in dichloromethane. The slower running peak was collected to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-N-methyl-8-azabicyclo[3.2.1]octan-3-amine (165 mg, 0.405 mmol, 81%). 1H NMR (CDCl3) δ: 1.35 (2H, t, J=12 Hz), 1.5-1.7 (4H, m), 1.8-2.0 (6H, m), 2.1 (3H, s), 2.5 (2H, br m), 3.1 (2H, br m), 4.7 (2H, br m), 7.3 (1H, s), 8.4 (1H, s).
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:31][OH:32]>C(O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:31][OH:32])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)Cc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a stirring suspension consisting of 1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-phenyl-ethanone (compound A, 955 g) in ethanol (8 L) is added pyridine (4 L) and hydroxylamine hydrochloride (610 g). The resulting mixture is heated at 100° C. for two hours and subsequently stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to afford a residue that is dissolved in ethyl acetate. The solution is washed with 5% aqueous citric acid and brine. The organic layer is separated, is dried over anhydrous Na2SO4, and is concentrated under reduced pressure. The concentrate is triturated with pentane. The triturated solids are collected by filtration to afford the solid product (480 g.) The filtrate is concentrated under reduced pressure and that concentrate is triturated with pentane. The solids are collected by filtration to provide another crop of solid product (320 g), which afforded a total of 800 g of Compound B.
Reaction SMILES: [CH3:1][CH:2]([SiH:10]([Cl:12])[Cl:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]=[CH:6][CH2:5]1.C[SiH:14]([Cl:16])[Cl:15].[CH:17](O)(C)C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([SiH:10]([Cl:12])[Cl:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH3:17])[SiH:14]([Cl:16])[Cl:15]
Reactant: CC(CC1CC=CCC1)[SiH](Cl)Cl
Reactant: C[SiH](Cl)Cl
Reactant: CC(C)O
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CC(CC1CCCCC1(C)[SiH](Cl)Cl)[SiH](Cl)Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 111.6 g (0.50 mol) of 4-(2-methyldichlorosilylethyl)-1-cyclohexene and 0.1 g of a 20 wt % isopropanol solution of chloroplatinic acid, which were heated at 80° C. After the internal temperature became constant, 63.3 g (0.55 mol) of methyldichlorosilane was added dropwise over 5 hours. After the completion of addition, the reaction solution was stirred for 8 hours at 80° C. The reaction solution was distilled, collecting 136.0 g of (2-methyldichlorosilylethyl)methyldichlorosilylcyclohexane as a fraction having a boiling point of 122-124° C./0.1 mmHg (yield 80.4%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.C[O-].[K+].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=[O:28])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CO.C(OCC)(=O)C>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](=[O:28])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1C=O
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1CC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.7 %

Procedure:
After dissolving 1.34 g of o-anisaldehyde in 10 ml of methanol, 1.83 g of p-toluenesulfonyl hydrazide was added, the mixture was stirred for 2 hours at room temperature and then 725 mg of potassium methoxide and a solution of 1.00 g of 1-benzylpiperidine-4-carboxaldehyde in methanol (3 ml) was added, and the mixture was shielded from light and stirred overnight at 55° C. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: toluene/ethyl acetate) to obtain the title compound (249 mg, 16% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[C:4]([CH2:13]Br)[N:3]=1.[NH2:15][C@@H:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH2:17][OH:18].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH2:13][N:15]([C@@H:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:17][OH:18])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Br)nc1CBr
Reactant: N[C@H](CO)Cc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Br)nc2CN1[C@H](CO)Cc1cccc(F)c1
Temperature: 67 °C
Reaction time: 8 h

Procedure:
Ethyl 6-bromo-2-(bromomethyl)nicotinate (0.17 g, 0.53 mmol), (2S)-2-amino-3-(3-fluorophenyl)propan-1-ol (0.11 g, 0.64 mmol), N,N-diisopropylethylamine (0.2 g, 2 mmol) and 1,4-dioxane (5 mL) were mixed in one 20 mL microwave tube, and the mixture was stirred at 67° C. for overnight. LC-MS showed most starting material was converted to Br-replacement product. Then the temperature was raised to 125° C. for 45 mins, cooled to room temperature, then worked up with EtOAc and aqueous NaHCO3 solution, extracted twice with EtOAc and dried over sodium sulfate, and concentrated under reduced pressure. Purification by combi-flash chromatography gave the desired product. LC-MS found: 365.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:29])[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[CH:9]=1)=[O:7].[CH3:31][I:32]>CC(C)=O>[I-:32].[CH3:31][N+:24]1([CH2:23][CH:22]([N:11]2[C:10]3[CH:9]=[C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH:2]([CH3:30])[CH3:1])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: CI
Solvent: CC(C)=O
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)C[N+]1(C)CCCC1)c1ccccc1S2
Product: [I-]
Reaction time: 0.17 h

Procedure:
A solution of N-(3-methylbutyl)-10-[1-(1-pyrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (1.5 g), and methyl iodide (0.94 cc) in acetone (50 cc) is stirred for 4 days at a temperature in the region of 20° C. The light yellow solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C., and the light cream-colored meringue-like residue is suspended with stirring for 10 minutes in diethyl ether (100 cc), drained, washed with diethyl ether (2×10 cc) and dried at 40° C. under reduced pressure (5 mm Hg, 0.7 kPa). 1-Methyl-1-{2-[2-(3-methylbutyl)carbamoyl-10-phenothiazinyl]propyl}-pyrrolidinium iodide, L series (1.55 g) is thereby obtained in the form of a light beige powder, m.p. about 125°-130° C., the NMR spectrum of which is identical to that of the product of Example 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][CH2:15][OH:16])[N:12]=[C:11]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][NH:26][CH3:27]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][CH2:15][OH:16])[N:12]=[C:11]([C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:26]([CH3:27])[CH3:25])[CH:18]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=Cc1cccc(-c2nc(-c3ccc(Cl)c(Cl)c3)n(CCO)n2)c1
Reactant: CNC
Product: CN(C)Cc1cccc(-c2nc(-c3ccc(Cl)c(Cl)c3)n(CCO)n2)c1
Product: Cl

Procedure:
Using 3-[5-(3,4-dichloro-phenyl)-1-(2-hydroxy-ethyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde and dimethylamine the title compound was prepared as a pale yellow amorphous foam (98.4% yield) after evaporation of all solvents under reduced pressure followed by drying under high vacuum (0.05 mmHg) at 50° C. for 2 h, MS: m/e=391.2 (M+H+).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH:32]3[CH2:33][O:30][CH2:31]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C1COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCNC3COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a stirred of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine (84 mg, 0.2 mmol, prepared in analogy to Example 9-3), oxetan-3-one (15 mg, 0.21 mmol) and ethyldiisopropylamine (43 μL, 0.25 mmol) in dichloromethane (10 mL) was added molecular sieves (4 Å, 84 mg) followed by sodium triacetoxyborohydride (63.6 mg, 0.3 mmol). After being stirred at room temperature overnight, another batch of sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 26 mg of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamine as a white solid. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.6 Hz, 1 H), 7.34 (s, 1 H), 7.68 (t, J=14.8 Hz, 1 H), 7.58-7.51 (m, 2 H), 7.45 (d, 1 H), 5.99 (s, 1 H), 5.24 (s, 2 H), 4.85 (t, J=3.3 Hz, 2 H), 4.85 (t, J=13.6 Hz, 2 H), 4.55 (m, 4 H), 4.06-4.00 (m, 1 H), 3.67 (s, 2 H), 3.50 (t, J=13.2 Hz, 2 H), 2.74 (t, J=13.6 Hz, 2 H), 2.45 (s, 3 H), 1.98-1.91 (m, 2 H).