Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=O)[CH:4]=1)#[N:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH2:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:36][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:24])([CH3:34])[CH3:35])=[CH:29][CH:28]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: COc1ccc(C(C)(C)N)cc1
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Preparation 16a, but using 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)] and 1-(4-methoxyphenyl)-1-methylethylamine as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained in a yield of 93%.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][C:11]1[N:10]([CH2:23][O:24][CH3:25])[CH:9]=[N:8][CH:12]=1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)NCCc1cn(C(=O)OC(C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCn1cncc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
1-t-Butoxycarbonyl-4-[2-(t-butoxycarbonylamino)ethyl]imidazole (78.1 g) is dissolved in acetonitrile (500 ml), and thereto is added methoxymethyl chloride (22.2 g). The mixture is stirred at room temperature overnight, and poured into aqueous 10% sodium carbonate solution, and extracted with ethyl acetate. The extract is washed, dried and evaporated to give 5-[2-(t-butoxycarbonylamino)ethyl]1-methoxymethylimidazole (54.4 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[F:9][C:10](I)([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]>CS(C)=O.[Cu]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:10]([F:27])([F:9])[C:11]([F:25])([F:26])[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: Fc1cccc(I)c1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: Fc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1

Procedure:
1-Fluoro-3-(perfluorohexyl) benzene was prepared by heating 6.02 g 1-fluoro-3-iodobenzene and 13.3 g perfluorohexyl iodide with excess copper in dimethyl sulfoxide (DMSO) at approximately 125° C. for 24 hours. The product, 1 -fluoro-3-perfluorohexyl benzene, was obtained in good yield (10.0 g, 89%).
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[C:4](=[O:6])[CH2:5][NH:1][C:2]2=[O:7])=[CH:12][CH:11]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2C(=O)CNC2=O)cc1

Procedure:
Using imidazolidine-2,4-dione (1.00 g) and 4-methoxybenzyl chloride (1.63 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (1.68 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][Si:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.2 %

Procedure:
To a solution of ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol (9 g, 68.6 mmol) in anhydrous dichloromethane (40 mL) were added triethylamine (11.2 mL), tert-butylchlorodiphenylsilane (19.8 g, 372 mmol), and N,N-dimethylaminopyridine (DMAP, 418 mg, 3.4 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. It was then diluted with additional dichloromethane and the reaction mixture was washed with water, brine, dried over sodium sulfate, filtered and evaporated to give the title compound (27 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>ClCCl>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:10]2[C:11](=[O:15])[C:12]([CH3:14])([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:31])[CH3:30])=[CH:7][CH:6]=3)[C:9]2=[S:28])=[CH:17][C:18]=1[C:24]([F:26])([F:27])[F:25])#[N:21]
Reactant: CC(=O)Cl
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 4-[3-(4-aminophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (2d) [RD9] (0.008 g, 0.02 mmol), acetyl chloride (0.004 g, 0.03 mmol) and triethylamine (0.003 g, 0.03 mmol) in dichloromethane (1 ml) was stirred at 0° C. for 2 hours. The mixture was concentrated and chromatographed (dichloromethane:acetone, 90:10) to yield N-{4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]phenyl}acetamide, 48a, [RD151] (0.007 g, 0.016 mmol, 80%), the structure of which is illustrated in Formula 3, as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5](OS(C)(=O)=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(OS(C)(=O)=O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 33.1 %

Procedure:
Methanesulfonyloxy-(4-trifluoromethyl-phenyl)-acetic acid ethyl ester (I102) (594 mg, 1.82 mmol), aniline (0.25 mL, 2.73 mmol), and DIPEA (0.48 mL, 2.73 mmol) are dissolved in acetonitrile (4 mL). The reaction is heated under microwave irradiation at 100° C. for 1 hour and 30 minutes. Aniline (0.17 mL, 1.820 mmol) is added again and the reaction is heated under microwave irradiation at 100° C. for 3 hours. Acetonitrile is removed under vacuum and the residue is purified by flash chromatography (Petroleum ether/DCM=75/25) to afford intermediate I151 as a yellow oil (195 mg, 60% yield).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:12]1([C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: COC(=O)CCCCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.4 %

Procedure:
Monomethyl adipate (3.20 g) is dissolved in chloroform (70 ml), and thereto are added morpholine (2.61 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.75 g) and triethylamine (3.04 g) under ice-cooling. The mixture is then stirred at room temperature for 19 hours. Ice-water is added to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure to give methyl 6-morpholin-4-yl-6-oxohexanoate (4.63 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CCC(=O)O)cc1
Product: Cc1ccc(CCC(=O)Cl)cc1
Temperature: 25 °C

Procedure:
3-(4-Methylphenyl)propanoic acid (0.055 moles, 9 g) is dissolved in thionyl chloride (1.008 moles, 120 g). The mixture is stirred for 30' at r.t., then refluxed for 1 h 30', evaporated under vacuum to an oil and taken up with toluene and hexane, each time evaporating to dryness. Yield: 12.4 g
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].O.[C:8]([NH:11][C@@H:12]1[C@@H:17]([CH2:18][CH:19]([OH:22])CO)[CH2:16][C:15]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])=[CH:14][C@H:13]1[O:32][CH:33]([CH3:35])[CH3:34])(=[O:10])[CH3:9]>CO>[C:8]([NH:11][C@@H:12]1[C@@H:17]([CH2:18][CH:19]=[O:22])[CH2:16][C:15]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])=[CH:14][C@H:13]1[O:32][CH:33]([CH3:35])[CH3:34])(=[O:10])[CH3:9]
Reactant: CC(=O)N[C@@H]1[C@@H](CC(O)CO)CC(C(=O)OCC[Si](C)(C)C)=C[C@H]1OC(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(=O)N[C@@H]1[C@@H](CC=O)CC(C(=O)OCC[Si](C)(C)C)=C[C@H]1OC(C)C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Sodium periodate (54 mg, 0.252 mmol) and water (1.5 mL) were added to a room temperature solution of Example 10B (70 mg, 0.168 mmol) in methanol (15 mL). After stirring for 3 hours, the reaction mixture was filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using ethyl acetate to afford 57 mg (92%) of the desired product.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([C:10]([CH3:23])([CH3:22])[CH:11]([CH:17]([O:20][CH3:21])[O:18][CH3:19])[CH2:12][C:13]([O:15]C)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+]>O>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([C:10]([CH3:22])([CH3:23])[CH:11]([CH:17]([O:18][CH3:19])[O:20][CH3:21])[CH2:12][C:13]([OH:15])=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(OC)C(CC(=O)O)C(C)(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
1 g of the product of Step A was added to a mixture of 20 ml of ethanol and 20 ml of aqueous 2 N sodium hydroxide solution and the mixture was refluxed for 17 hours and was cooled and poured into water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness to obtain 4-p-tolylsulfonyl-4-methyl-3-dimethoxymethyl-pentanoic acid.
Reaction SMILES: O=[C:2]1[C:10]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][C:5]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=[CH:6][CH:7]=2.C[Si]([N:28]=[C:29]=[N:30][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([C:5]2[CH:4]=[C:3]3[C:8](=[CH:7][CH:6]=2)[CH2:9][C:10]2([CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:2]3=[N:30][C:29]#[N:28])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCOCC2)C3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cccc(C#N)c3)ccc2CC12CCOCC2
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 3-(1-oxo-1,2′,3,3′,5′,6′-hexahydrospiro[indene-2,4′-pyran]-6-yl)benzonitrile (42 mg, 0.139 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.28 mL, 0.28 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.1 mL, 0.427 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (20 g), and stirred for 20 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 44 mg of N-(5-(3-cyanophenyl)-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-3(1H)-ylidene)cyanamide as light brown solid which was used for next step without further purification. MS ESI+ve m/z 328 (M+H)+.
Reaction SMILES: O.[ClH:2].[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH2:20]CC)=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[C:23](OC(NC1CCN(C2C=CC(C(NCCCC)=O)=CC=2)CC1)=O)(C)(C)[CH3:24]>>[ClH:2].[ClH:2].[NH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:18]([CH2:19][CH3:20])[CH2:23][CH3:24])=[O:17])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1
Reactant: CCCCNC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Reactant: CCCCNC(=O)c1ccc(N2CCC(N)CC2)cc1
Agent: Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccc(N2CCC(N)CC2)cc1

Procedure:
By carrying out the operation as described in preparation 11b but using the product from the preceding stage instead of the product from preparation 11a, the title compound is obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.N[CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[Cl:8][CH:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH3:19])=[C:11]([CH3:20])[N:10]1[CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: NCCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C)N(CCCCO)C(Cl)C([N+](=O)[O-])=C1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Under a nitrogen atmosphere, triethylamine (14.19 mL, 101.8 mmol, 1.5 eq) was added in a single portion to a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (15.0 g, 67.86 mmol, 1.0 eq) and N,N-dimethylformamide (DMF) (200 mL). The reaction mixture was stirred for 10 minutes, 4-amino-1-butanol (8.76 mL, 95 mmol, 1.4 eq) in DMF (20 mL) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to provide crude product as an oil. The oil was partitioned between ethyl acetate (300 mL) and water (50 mL). The aqueous layer was back-extracted with ethyl acetate (2×50 mL). The combined organic phases were separated, washed with water (3×30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an orange solid. This material was recrystallized from ethyl acetate/hexanes to provide 12.2 g of 4-(2-chloro-5,6-dimethyl-3-nitropyridin-1-yl)butan-1-ol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.O([Si:30]([CH3:33])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:31][Si:30]([CH3:33])([CH3:32])[O:13][C:11]([C:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)=[CH2:12]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1ccnc2ncccc12
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=C(O[Si](C)(C)C)c1ccnc2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1,8]Naphthyridin-4-yl-ethanone from Preparation 18 (250 mg, 1.45 mmol), 2,6-lutidine (0.254 ml, 2.18 mmol) in DCM (3.6 ml) was treated with trimethylsilyl triflate (0.276 ml, 1.53 mmol) and allowed to stir at RT overnight. Mixture diluted with DCM and washed with satd. NaHCO3. Organics dried over Na2SO4 and concentrated, furnished 350 mg 4-(1-trimethylsilanyloxy-vinyl)-[1,8]-naphthyridine as an oil. MS (ESI+) for m/z 245 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH2:16])/[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:25][C:24]([NH:16]/[C:5](/[CH2:6][C:7]1[C:8]([F:15])=[CH:9][C:10]([F:14])=[C:11]([F:13])[CH:12]=1)=[CH:4]\[C:3]([O:2][CH3:1])=[O:17])=[O:26]
Reactant: COC(=O)/C=C(\N)Cc1cc(F)c(F)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)/C=C(/Cc1cc(F)c(F)cc1F)NC(C)=O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of (Z)-methyl-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate (4.90 g, 20 mmol) of Example 2, pyridine (4.8 ml) and acetic anhydride (4.80 g, mmol) in THF (30 ml) was heated to reflux for 16 h. The reaction mixture was stirred at room temperature, quenched with 1N HCl, and extracted with ethyl acetate (3×20 ml). The combined organic phase was washed with saturated sodium bicarbonate, then brine, then dried over sodium sulfate. Concentration was followed by purification by flash chromatography to afford 4.03 g of product (70.3%). 1H NMR (300 MHz, CDCl3) 11.14 (s, 1H) 7.10-7.00 (m, 1H), 6.96-6.87 (m, 1H), 4.81 (s, 1H), 4.14 (s, 2H), 3.70 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Cl.O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[NH2:15][NH2:16]>CO>[NH2:5][C@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[CH:3]=[N:15][NH2:16]
Reactant: NN
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Solvent: CO
Product: NN=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of glucosamine hydrochloride, 5 ml of methanol and 5 ml of hydrazine hydrate was stirred overnight and then evaporated to dryness giving 2-amino-2-deoxy-D-glucose hydrazone.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](F)=[O:7])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[Si](Cl)(Cl)(Cl)[Cl:20]>>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:20])=[O:7])#[N:2]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: N#Cc1c(F)c(F)cc(C(=O)F)c1F
Agent: [Al+3]
Agent: [Cl-]
Product: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
76.6 g of 3-cyano-2,4,5-trifluoro-benzoyl fluoride are introduced at 60-65° C. together with 1 g of anhydrous aluminium chloride and then 25 g of silicon tetrachloride are added dropwise in the course of the evolution of gas. After the evolution of gas at 65° C. has ended, the mixture is distilled in vacuo. 73.2 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride pass over in the boiling range from 120-122° C./14 mbar.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=O)[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>O1CCOCC1>[Cl:16][C:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2cccc(F)c21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(Cl)c2c(F)cccc21
Yield: 93.3 %

Procedure:
1.1 g of 4-fluoro-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (EP291851 A2 19881123), 2 g of thionyl chloride and a catalytic amount of DMF in 6 ml of dioxane are heated under reflux for 18 hours. Then additional 2 g of thionyl chloride are added and the mixture is heated for 8 hours. The mixture is concentrated and 1.12 g of a crude solid is obtained.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[OH:20].FC(F)(F)[C:23](O)=[O:24]>>[F:11][C:12]1[C:13]([OH:20])=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][C:17]=1[CH:23]=[O:24]
Reactant: COc1cccc(F)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)c(F)c1O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a heated solution (80° C.) of hexamethylenetetramine (2.8 g, 20 mmol) in trifluoroacetic acid (10 mL) was added dropwise over a 50 minutes period 2-fluoro-6-methoxyphenol (1.42 g, 10 mmol) in trifluoroacetic acid (10 mL). The mixture was heated for an additional 1 hour, concentrated and water (50 ml) was added. The solution was stirred for 10 minutes and solid potassium carbonate was added until the solution was neutral. The solid that formed was collected to afford 1.1 g of 2-fluoro-3-hydroxy-4-methoxybenzaldehyde (65%). 1H NMR (500 MHz; DMSO-d6): δ 3.90 (s, 3 H); 6.98 (d, J=8.5 Hz, 1 H); 7.31 (t, J=8.5 Hz, 1 H); 9.66 (br, 1 H); 10.02 (s, 1 H).
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])=[C:36]([F:42])[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])=[C:36]([F:42])[CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(F)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

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 g), 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (0.67 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.15 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, 64%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][C@@H:54]2[CH2:56][O:55]2)[CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:48]4[CH:49]=[CH:50][CH:51]=[C:46]([OH:45])[CH:47]=4)=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1cccc(OC[C@@H]2CO2)c1)(c1ccccc1)c1ccccc1
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(O)c3)cc2)CC1

Procedure:
4-[4-(2-Amino-ethyl)-phenylamino]-piperidine-1-carboxylic acid 4-fluoro-benzylamide (0.66 g, 1.6 mmol) was reacted tert-butyl{3-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane according to Procedure G to yield the title compound (0.284 g, 0.4 mmol).
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[C:18](=[O:24])=[N:19]S(Cl)(=O)=O>C(#N)C>[C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[N:10]([C:18]([NH2:19])=[O:24])[C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2cnccc2C1C(=O)c1cccs1
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccncc21

Procedure:
The title compound was prepared from 3-(2-thenoyl)-6-azaoxindole (Example 38) according to the procedure of Example 2C, using 3-(2-thenoyl)-6-azaoxindole (3.09 g, 12.6 mmol), N-chlorosulfonyl isocyanate (1.2 mL, 13.8 mmol) and acetonitrile (60 mL). Reaction time: 31/2 hours.