Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=[CH:10][CH3:11].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:8]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:15]=1)[CH:9]=[CH:10][CH3:11]
Reactant: CC=CCCl
Reactant: CC(C)c1cc(N)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCNc1ccc(Cl)c(C(C)C)c1
Reaction time: 1 h

Procedure:
2.8 g of anhydrous potassium carbonate and 2.0 g of -chloro-2-butene were added to 3.2 g of 4-chloro-3-isopropylaniline in 15 ml of N,N-dimethylformamide, followed by stirring at 70°-90° C. for 1 hour. After potassium carbonate was removed by filtration, 100 ml of water were added, and extraction was then carried out with toluene. After drying over anhydrous sodium sulfate, the reaction solution was concentrated by means of an evaporator, and silica gel chromatography was then done to obtain 1.5 g of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:6])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]([OH:13])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1cccc(O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-Hydroxy-phenyl)-propionic acid ethyl ester (19.0 g) in acetic acid (150 mL) was added nitric acid (11.3 g) at room temperature. The reaction mixture was stirred for 1 h at room temperature and added water. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as yellow solid. (6.08 g, 26.0%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:40]=[CH:41][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:50][CH:51]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-2-methylbenzamide (800 mg, 1.629 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (740 mg, 2.443 mmol), sodium carbonate (621 mg, 5.86 mmol) in 20 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (188 mg, 0.16 mmol) was added to the mixture and heated to 100° C. overnight. The reaction was cooled to room temperature and diluted with water, compound was extracted in 10% MeOH in DCM, dried over Na2SO4, concentrated and crude was purified by silica gel (100-200) chromatography to obtain the title compound (700 mg, 73.0%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])=[CH:7][C:6]=1[C:17]([F:20])([F:19])[F:18])(=[O:4])=[O:3].C(O)(=[O:23])C>[Fe]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:23])[CH3:13])=[CH:7][C:6]=1[C:17]([F:20])([F:19])[F:18])(=[O:4])=[O:3]
Reactant: CC(=Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: CC(=O)Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of freshly prepared 1-methanesulfonyl-4-(2-nitro-propenyl)-2-trifluoromethyl-benzene (59b) (14 g, 45 mmol) in acetic acid (100 ml) is added slowly to a stirred slurry of Iron powder (27.6 g, 495 mmol) in acetic acid (100 ml) at 60° C. The reaction is then stirred at 100° C. for 2 hours then allowed to cool and poured onto ice-water (300 ml). After filtration through celite, washing with dichloromethane (500 ml), the organic extract is separated and washed with water (3×300 ml) followed by brine (500 ml). The organic extract is dried (MgSO4) and concentrated to give a red oil. Chromatography on silica, eluting with ethyl acetate-hexane, affords the titled compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)(=[O:15])=[O:14].[CH3:25][O-:26].[Na+]>CN1CCCC1=O.CO>[CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20]([O:26][CH3:25])=[CH:21][CH:22]=1)(=[O:15])=[O:14]
Reactant: C[O-]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nn3)cccc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)nn1

Procedure:
5-Dimethylamino-N-(6-chloro-3-pyridazinyl)-1-naphthalenesulphonamide (0.36 g), was suspended in N-methylpyrrolidone (1 ml) and freshly prepared 1M sodium methoxide in methanol (3 ml) was added. The reaction mixture was heated to reflux for 4 hours, cooled and evaporated to dryness. The residue was purified by flash chromatography on silica gel (5 g) eluting with a methanol/dichloromethane gradient to give 5-dimethylamino-N-(6-methoxy-3-pyridazinyl)-1-naphthalenesulphonamide (0.14 g), m.p. 125°-127° C.; mass spectrum (+ve CI): 359 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]=[CH:9][C:8]=1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[F:29])(=O)=O.[CH3:32][Si:33]([CH3:41])([CH3:40])[O:34][C:35]([CH3:39])([C:37]#[CH:38])[CH3:36]>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.[Cu](I)I.C(N(CC)CC)C>[C:14](=[O:15])([O:13][C:11]1[CH:12]=[CH:7][C:8]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[F:29])=[C:9]([C:38]#[C:37][C:35]([CH3:39])([O:34][Si:33]([CH3:41])([CH3:40])[CH3:32])[CH3:36])[CH:10]=1)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2OS(=O)(=O)C(F)(F)F)c1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)O[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, to a mixture of 4-((tert-butoxycarbonyl)oxy)-2′-fluoro-5′-methoxybiphenyl-2-yl trifluoromethanesulfonate (408 mg), tetrakis(triphenylphosphine)palladium (308 mg), copper iodide (32 mg) and triethylamine (10 mL) was added trimethyl((2-methylbut-3-yn-2-yl)oxy)silane (1.7 mL). The mixture was stirred at 80° C. for 15 hr, and tetrakis(triphenylphosphine)palladium (308 mg) was added. The mixture was stirred at 80° C. for 20 hr, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (232 mg) as a yellow oil.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].[Br:6][CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>O.C(O)(=O)C>[OH:4][N:1]=[C:9]([C:8]([CH2:7][Br:6])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)CBr
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CBr
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrate (12.4 g.) in water (150 ml.) was dropwise added with stirring at 5° to 7° C. to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10° C. Water (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (500 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (32.6 g.).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]1[O:14][CH:13]1[CH2:15][OH:16]>C(O)(C)C>[OH:14][CH:13]([CH2:15][OH:16])[CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: OCC1CO1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CC(C)O
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)CO

Procedure:
2,2,6,6-Tetramethyl-4-piperidinol 15.7 g and glycidol 7.8 g were dissolved in 50 ml of isopropanol and refluxed for five hours. Isopropanol was distilled off and the residue was recrystallized from n-hexane. A white powder, 21.3 g m.p. 97° to 99° C., was obtained.
Reaction SMILES: [Mg].II.[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]Br.Cl[P:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C([Li])CCC.C(OCC)C>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][P:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1Br
Agent: II
Agent: [Li]CCCC
Agent: [Mg]
Solvent: CCOCC
Product: Brc1ccccc1CP(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Under nitrogen, magnesium (1.87 g) was placed in a 3-neck 250 ml round bottom flask along with about 60 ml of diethyl ether and a few crystals of iodine and a few drops of n-butyl lithium (2M). 1-bromo-2-(bromomethyl)benzene (17.5 g) was added to an addition funnel along with 20 ml of diethyl ether. This solution was added dropwise to the mixture. The reaction was refluxed for an additional ½ hour after dropwise addition was completed. Chlorodiphenylphosphine (11.3 ml) in 20 ml of diethyl ether was then added dropwise with vigorous stirring to the Grignard solution at a rate to maintain a reflux. When the addition was complete, the reaction was refluxed for an additional hour and then cooled to room temperature and quenched with aqueous hydrochloric acid (dropwise addition) under nitrogen. The layers were separated and the organic layer was washed with water. The mixture was then filtered, separated, and dried. The solvent was then removed to obtain 24.8 g of (2-bromobenzyl)diphenyl-phosphine.
Reaction SMILES: [N:1]([CH:4]1[C:10](=O)[N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1)=[N+]=[N-]>C(O)C.C1COCC1.[Pd]>[NH2:1][C:4]1[N:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[N:9]([CH2:12][C:13]([F:16])([F:14])[F:15])[CH:10]=1
Reactant: [N-]=[N+]=NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1=CN(CC(F)(F)F)c2ccccc2C(c2ccccc2)=N1
Yield: 75.6 %

Procedure:
To a stirring solution of 3-Azido-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine (83.4 mmol ,30 g) in 300 mL ethanol and 150 mL THF was added 10% Pd/C (10 wt %, 3.0 g). Hydrogen gas was bubbled through the solution for 8 h. The reaction was filtered and evaporated under reduced pressure. The residue was crystallized from ethyl ether to give 20.0 g of white crystals. Another 4 g was recovered from evaporation and recrystallization of the filtrates. Combined yield, 86.7%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:15](Cl)(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:8]([S:15]([NH:19][C:20]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NS(=O)(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
0.082 mL of triethylamine, 39 mg of benzylsulfonyl chloride and 2.0 mL of methylene chloride were added to 1.0 mL of methylene chloride solution containing 50 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 2 hours. 380 mg of aminomethylated polystyrene was added to she reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzylsulfonamido)-4-phenethylbenzoate.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([CH2:11][N:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[C:15](=O)[CH:14]([CH3:23])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CO>[C:5]1([CH2:11][N:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:14]([CH3:23])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC(C)C1=O
Reactant: Nc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(Cc2ccccc2)CC(C)C1Nc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.5 %

Procedure:
Sodium cyanoborohydride (0.69 g, 11 mmole) and 26 g of 30A molecular sieves were slowly added at room temperature to a stirred solution of 1-phenylmethyl-3-methyl-5-methoxycarbonyl-4-piperidone (5.04 g, 18.3 mmole) from Example 3 in 200 ml of methanol, 10.22 g (110 mmole) of aniline and 9.48 ml of 3.86N hydrochloric acid (36.6 mmole) in methanol. The reaction mixture was stirred at room temperature for 3 days, after which time the molecular sieves were filtered off and the solution was made acidic with 10 ml of 20% hydrochloric acid. The methanol was evaporated under vacuum and the residue was diluted with 100 ml of water then extracted with ether. The aqueous layer was then made alkaline with dilute aqueous sodium hydroxide and extracted with 3×100 ml of ether. The combined organic layers were concentrated under vacuum to yield 3.87 g (60%) of crude 1-phenylmethyl-3-methyl-5-methoxycarbonyl-4 -(N-phenylamino)piperidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[NH4+:23].[OH-]>O1CCOCC1.O>[NH2:23][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(NS(=O)(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Temperature: 95 °C

Procedure:
To a suspension of 4-chloro-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide (0.22 g) in dioxane (2 mL) was added NH4OH (3 mL). The reaction mixture was heated to 95° C. for 8 h. The mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The extract was dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 hexane/EtOAc) afforded 4-amino-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(N(CC)CC)C.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:34].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
40 mg (0.11 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzo-thiophene-2-carboxamide hydrochloride are dissolved in 2 ml of DMF, 6.5 mg (0.05 mmol) of N,N-dimethyl-4-aminopyridine, 59.6 μl (0.43 mmol) of triethylamine and 16.61 (0.21 mmol) of methanesulfonyl chloride are added and the mixture is stirred at room temperature for 16 h. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 1N aqueous hydrochloric acid and acetonitrile, then reconcentrated and dried under high vacuum. 15 mg (33.8% of theory) of the title compound are obtained.
Reaction SMILES: Cl[Si](Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:17]=[C:18]([NH:20][C:21](=O)[CH3:22])[CH:19]=1)=[O:13]>C(#N)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:17]=[C:18]([N:20]2[C:21]([CH3:22])=[N:8][N:7]=[N:6]2)[CH:19]=1)=[O:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(NC(C)=O)cc(-c2ccc(C)cc2)c1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of tetrachlorosilane (10.07 mmol, 2 mL), NaN3 (30.21 mmol, 1.96 g) and 5-acetylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (3.36 mmol, 950.9 mg) in 10 ml of dry acetonitrile was stirred at room temperature for 16 hours. The reaction mixture were poured into ice-cold aqueous Na2CO3 solution and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl ester was used for next step directly (880 mg, 85% yield).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]OS(C)(=O)=O)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>ClCCCl>[Cl:15][C:6]1[C:7]2[CH2:8][CH2:9][N:23]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: CS(=O)(=O)OCCc1c(Cl)ncnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: ClCCCl
Product: COc1ccc(CN2CCc3c(Cl)ncnc32)cc1
Yield: 71 %

Procedure:
A solution of methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-ethyl ester (0.50 g, 1.84 mmol) and 4-methoxybenzylamine (0.60 g, 4.37 mmol) in DCE (30 mL) and TEA (4 mL) was refluxed overnight. After cooling, the solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to give 4-Chloro-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.36 g, 71%). 1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 7.26 (dd, J=2.8 Hz, J=1.6 Hz, 2H), 6.88 (d, J=4.4 Hz, 2H), 5.33 (s, 1H), 4.62 (d, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.73 (t, J=7.2 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H). MS (APCI+) [M+H]+276.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])=[N:3]1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][N:2]1[C:6]([O:7][CH:8]([F:9])[F:10])=[C:5]([Cl:19])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])=[N:3]1
Reactant: Cn1nc(-c2ccc(Cl)cc2F)cc1OC(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccc(Cl)cc2F)c(Cl)c1OC(F)F
Yield: 98.1 %

Procedure:
A solution of 16.2 grams (0.059 mole) of 1-methyl-5-difluoromethoxy-3-(2-fluoro-4-chlorophenyl)pyrazole and 8.5 grams (0.064 mole) of N-chlorosuc-cinimide in about 500 mL of N,N-dimethylformamide was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into about 1600 mL of water and then extracted with two portions of diethyl ether. The combined extracts were washed with one portion of aqueous 10% lithium chloride and two portions of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 18.0 grams of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chlorophenyl)pyrazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.C([C@@:35]1([C:44]([OH:46])=[O:45])[CH2:39][CH2:38][CH2:37][N:36]1[C:40](=[O:43])[CH2:41]Br)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:41][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:44]([OH:46])=[O:45])=[O:43])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: O=C(CBr)N1CCC[C@@]1(Cc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.24 g, 0.0011 mole) in chloroform (10 ml) was added triethylamine (0.34 ml, 0.002 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (0.29 ml, 0.0023 mole) was added to the above solution dropwise, followed by benzyl bromoacetyl-L-proline (0.25 g, 0.0011 mole). The ice bath was removed and the mixture stirred at room temperature for 4 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil was vacuum dried to get 0.23 g (57%) of title compound, TLC: silica gel, CH2Cl2 :MeOH:HOAc shows one main spot at Rf =0.23.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH:29]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:32][CH:31]=1)[OH:30])[CH3:8]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Ethyl isobutyrate (2.5 mL, 18.42 mmol) was dissolved in THF (8 mL), and the solution was cooled to −78° C. LDA (9.2 mL, 18.42 mmol) was added thereto, and the mixture was stirred at the corresponding temperature for 2 hours. After 4-benzyloxy-benzaldehyde (1.7 g, 8.01 mmol) obtained in Step A was added thereto at −78° C., the mixture was heated to room temperature, and then stirred for 2 days. The reactant was added with water, and then extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (1.77 g, 67%).