Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]([NH:5][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[CH:6]([CH3:8])[CH3:7])=[O:9]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NCCCS(=O)(=O)O)C(C)C
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of L-valine methylester in THF (25 mL) was slowly added 1,3-propanesultone (2.49 g, 19.9 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×30 mL). It was dried in the vacuum oven (50° C.) affording the title compound (2.52 g, 50%). 1H NMR (D2O, 500 MHz) δ ppm 3.92 (m, 1H), 3.75 (s, 3H), 3.13 (t, 2H, J=6.8 Hz), 2.88 (t, 2H, J=6.8 Hz), 2.24 (m, 1H), 2.06 (m, 2H)), 0.96 (d, 3H, J=6.8 Hz), 0.88 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 169.35, 65.85, 55.61, 48.14, 45.59, 29.48, 21.32, 18.25, 16.57. [α]D=+9.6° (c=0.0014 in water), ES-MS 254 (M+1).
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[CH3:22][NH:23][CH3:24]>[Cu]Br>[CH3:22][N:23]([CH3:24])[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(I)nn1
Agent: [Cu]Br
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N(C)C)nn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
3-Iodo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (500 mg, 1.3 mmol) was dissolved in an ethanolic solution of dimethylamine (7.5 mL of a 33% solution, excess). After addition of copper(I) bromide (219 mg, 1.5 mmol) the mixture was stirred for 72 h at room temperature followed by heating to 50° C. for 3 h. Then the solvent was evaporated and the residue was stirred with ethyl acetate and saturated aqueous Seignette salt solution. The organic phase was dried with sodium sulfate and evaporated. Chromatography (SiO2, heptane/ethyl acetate=100:0 to 10:90) afforded the title compound as a light yellow oil (30 mg, 8%). MS: m/e=311.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cnc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.40 g, 1.14 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.303 g, 1.37 mmol) according to the general procedure VI. Obtained as a white solid (0.050 g, 10%). MS (ISP) 409.2 [(M+H)+]; mp 264° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: Cc1ccccc1C1CCNCC1
Agent: Cl
Product: Cc1ccccc1C1CCN(C(=O)c2cnc3c(Br)cnn3c2NCc2ccccc2)CC1
Yield: 85.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 22, step 3 instead of 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid and 4-(2-methylphenyl)piperidine hydrochloride (0.15 g, 0.69 mmol), the title compound (0.25 g, 85%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9](OC)[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16].CO[Na].[Cl-].[NH4+]>CO>[N:14]([C:17](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:3]=1[O:2][CH3:1])[C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: COc1ccc(C=O)c(OC)c1C
Agent: CO[Na]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(=Cc1cccc(C)c1OC)N=[N+]=[N-]
Yield: 88.5 %

Procedure:
To the mixture of 2.46 g of 2-methoxy-3-methylanisaldehyde (16 mmol) and 4.72 g of methyl azidoacetate (41 mmol) in 20 mL of MeOH is added 7.6 mL of 5.4M MeONa over 30 minute at −10 degrees. After addition the mixture was stirred for additional hour at the same temperature and then transferred in cold room (4 degrees) and stirred overnight. On the morning reaction mixture was poured in 0.5 L mixture of ice and conc. ammonium chloride solution, stirred for 10 minutes and filtered off. The solid was washed with plenty of ice cold water and then moved at ambient temperature. After air drying for 1 hr the solid was dissolved in 50 mL of DCM, dried over magnesium sulfate and passed through short silica gel plug. Evaporation of solvent produced 3.5 g of methyl 2-azido-3-(2-methoxy-3-methylphenyl)acrylate, that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[IH:10].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[I:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(Cl)n1
Reactant: I
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1nccc(I)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
4-Chloro-2-methylthiopyrimidine (5 g, 31.15 mmol) was added dropwise to a cooled 57% aqueous hydriodic acid solution (0° C.). Stirring was continued at 0° C. for 30 minutes, before warming to ambient temperature and stirring for 24 hours. Aqueous sodium bicarbonate was then carefully added and the resultant suspension basified to pH 9 by addition of sodium carbonate. The mixture was extracted with ethyl acetate and the extracts dried over magnesium sulfate and concentrated by reduced pressure. The resultant solid was dissolved in boiling isohexane and cooled by refridgeration overnight. The resultant solid was filtered and dried to afford the title compound as colourless needles (5.4 g, 69%); NMR Spectrum: (CDCl3) 2.55 (s, 3H), 7.40 (d, 1H), 7.98 (d, 1H); Mass Spectrum: M+H+ 253.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.S(Cl)(Cl)=O.[CH3:19]O>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:19])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1ccc2c(=O)[nH]cnc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(=O)[nH]cnc2c1
Temperature: 80 °C
Yield: 70 %

Procedure:
A mixture of 4-oxo-3,4-dihydroquinazoline-7-carboxylic acid (2.5 g, 13.15 mmol) in 80 mL of methanol was added thionyl chloride (2.5 mL) at 5° C. and then refluxed at 80° C. over night. The reaction mixture was concentrated under vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with 10% aqueous NaHCO3, water, brine and dried. The solvent was removed to give methyl 4-oxo-3,4-dihydroquinazoline7-carboxylate in 70% yield as solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([NH:11][CH2:12][CH3:13])[C:6]([O:8]CC)=O)(=[O:3])[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C-]#N.[Na+]>>[C:1]([NH:4][CH:5]([NH:11][CH2:12][CH3:13])[C:6]([NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCNC(NC(C)=O)C(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Product: CCNC(NC(C)=O)C(=O)NCc1ccccc1

Procedure:
Using ethyl 2-acetamido-2-(ethylamino)acetate (0.90 g, 4.79 mmol), benzylamine (0.62 g, 5.75 mmol), and NaCN (0.03 g, 0.51 mmol) gave an oily residue which was purified by flash column chromatography on SiO2 gel (3% MeOH/CHCl3) to give the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[N:4][C:5](Br)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate A) (1 g, 3.51 mmol), 4-fluorophenylboronic acid (0.736 g, 5.26 mmol) and 1,1′Bis(diphenylphosphoshio)ferrocene palladium dichloride (0.286 g, 0.351 mmol) and 1.0M Cs2CO3 (3.3 ml) in THF (10 ml) was heated to reflux for 10 hours. After cooling to RT, the mixture was partitioned between DCM (100 ml) and 1 M NaOH (2×100 ml). The aqueous phase was acidified with 5M HCl and the resulting milky solution was extracted into DCM (2×100 ml). The organic portion was separated, dried (MgSO4) and concentrated in vacuo to afford the product as a crude oil. The crude material was purified by flash chromatography on silica cartridge eluting with a gradient of DCM: MeOH from 0% to 10% MeOH to afford the title product as a pale yellow solid;
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:12](OCC1C=CC=CC=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:12][NH:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(NC1CCc2ccccc2C1)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CCc2ccccc2C1
Yield: 112.3 %

Procedure:
7.43 g (26.4 mmol) of phenylmethyl 1,2,3,4-tetrahydronaphthalene-2-carbamate were added in portions to a suspension of 4.5 g (26.4 mmol) of lithium aluminium hydride in 200 ml of tetrahydrofuran, and the mixture was heated to reflux for 3 h 30, allowed to cool, and hydrolysed with an excess of aqueous 1N sodium hydroxide solution, the mixture was filtered and concentrated, and the residue was distilled at about 80 Pa between 140 and 240° C. 4.78 g of impure oil were obtained, which was utilised in its impure state in the following step.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.N.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1
Reactant: COc1ccc(-c2nc(C)cc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: COc1ccc(-c2nc(C)cc(Cl)n2)cc1
Reaction time: 0.5 h

Procedure:
6.5 g of 4-hydroxy-2-(4-methoxyphenyl)-6-methylpyrimidine prepared in reference example 1 (3) was added to 30 ml of phosphorus oxychloride, and the mixture was refluxed with stirring for 30 minutes. The reaction mixture was cooled and poured into diluted ammonia solution and the precipitated crystals were filtered off. The crystals were dissolved in chloroform. After the chloroform layer was washed twice with water, it was dried with anhydrous magnesium sulfate and was evaporated in vacuo. The residue was crystallized with n-hexane and filtered off. Whereby 5.1 g of crystals was obtained. Melting point is 80° to 81° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:23][CH2:24][N:25]([CH2:33][CH2:34]Cl)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[CH3:31][C:28]([O:27][C:26]([N:25]1[CH2:33][CH2:34][C:5]2([C:6](=[O:11])[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]2=3)[CH2:23][CH2:24]1)=[O:32])([CH3:29])[CH3:30]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1ccc(F)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.3 %

Procedure:
To a stirred solution of 5-fluoro-1,3-dihydro-2H-indol-2-one (1.80 g, 11.9 mmol) in tetrahydrofuran (30 mL) was added dropwise a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (35.7 mL, 35.7 mmol) at −78° C. for 15 min and the mixture was stirred for 1.5 h at the same temperature. To the mixture was added dropwise a solution of tert-butyl bis(2-chloroethyl)carbamate (2.88 g, 11.9 mmol) in tetrahydrofuran (10 mL) at −78° C., then this resulting mixture was slowly warmed up to room temperature and stirred for 19 h at the same temperature. The reaction mixture was quenched by the addition of ammonium chloride aqueous solution, and concentrated to give a brown residue. The crude material was partitioned between ethyl acetate and water, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/acetone (3/1) to afford 356 mg (15%) of the title compound as a slight brown syrup:
Reaction SMILES: Cl.[O:2]1CCOCC1.C([C:12](=[O:25])[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1)(C)(C)C>O1CCOCC1>[CH2:23]([O:22][C:20]([CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][C:12]([OH:25])=[O:2])[CH2:19][CH2:18]1)=[O:21])[CH3:24]
Reactant: C1COCCO1
Reactant: CCOC(=O)C1CCN(CC(=O)C(C)(C)C)CC1
Agent: Cl
Product: CCOC(=O)C1CCN(CC(=O)O)CC1
Temperature: 60 °C

Procedure:
At room temperature, 3.0 ml of 4 M hydrogen chloride/1,4-dioxane was added to 8 ml of 1,4-dioxane solution containing 543 mg of ethyl 1-(2-tert-butyl-2-oxoethyl)piperidine-4-carboxylate, and stirred at 60° C. for 8Hours. The thus formed solid was collected by filtration to obtain 300 mg of [4-(ethoxycarbonyl)piperidin-1-yl]acetic acid as a white solid. EP: 216.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]=[C:6]1[CH2:13]O.C(N(CC)CC)C.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:13][C:6]1[N:5]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]=1
Reactant: O=[N+]([O-])c1cn(Cc2c(Cl)cccc2Cl)c(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cn(Cc2c(Cl)cccc2Cl)c(CCl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
210 mg (0.70 mmol) of the compound from Example 37A were dissolved in 10 ml of dichloromethane, and 145 μl (1.04 mmol) of triethylamine and 61 μl (0.83 mmol) of thionyl chloride were added at 0° C. The mixture was stirred at RT for 24 h. A further 200 μl (2.72 mmol) of thionyl chloride were then added, and the mixture was stirred under reflux for 15 min. Under reduced pressure, the reaction mixture was then freed from all volatile components. This gave, in a purity of 88%, 200 mg (80% of theory) of the target compound, which was reacted further without any further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[Cl:15][CH:16]([Cl:20])[C:17]([OH:19])=[O:18]>>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:16]([Cl:20])([Cl:15])[C:17]([OH:19])=[O:18]
Reactant: BrCCCCCCCCCCCCBr
Reactant: O=C(O)C(Cl)Cl
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCBr

Procedure:
Analogously to example 1 from 50.0 g (152 mmol) 1, 12-dibromododecane and 39.3 g (305 mmol) dichloroacetic acid. Yield 11.9 g (21%), melting point 59-60° C.
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:2]([C:25]([OH:27])=[O:26])[C@@H:3]([CH3:24])[O:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:46]>CO.C1C=CC=CC=1>[NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:2]([C:25]([O:27][CH3:46])=[O:26])[C@@H:3]([CH3:24])[O:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H](OC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of Fmoc-L-Thr(Trt)-OH (2.33 g, 4.00 mmol) in methanol (4.0 mL) and benzene (16 mL) was added TMS-diazomethane (2.40 mL, 4.80 mmol). After 1 hour, the mixture was concentrated in vacuo to afford Fmoc-L-Thr(Trt)-OMe which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1F)[C:5]([OH:7])=[O:6].[CH2:16]([N:18](CC)CC)C.CN.Cl>O.CN>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[NH:18][CH3:16])[C:5]([OH:7])=[O:6]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Agent: CN
Agent: Cl
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
A suspension of 5 g (21.05 mmol) of 3-chloro-2,4-difluoro-5-nitro-benzoic acid (known from WO 03/077914) in 50 mL of H2O is cooled to a temperature of 0° C. Then 5.86 ml (42.10 mmol) of triethylamine were added dropwise followed by the dropwise addition of 1.82 ml (21.05 mmol) of methylamine (40% in H2O). After 30 min of stirring at 0° C., 0.18 ml (2.11 mmol) of methylamine (40% in H2O) is added and the mixture is stirred again during 30 min at a temperature of 0° C. The pH of the mixture is adjusted to 1-0.5 by the addition of concentrated HCl at a temperature of 0° C. The product is extracted with tert-butyl methyl ether (2 times) and the organic phase is washed once with brine, dried on Na2SO4, filtrated and the solvent is evaporated. 5.35 g (21.52 mmol, 102%) of a crude yellow solid were obtained and used directly in the next step without purification. LC/MS: 247/249 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1.C(Cl)Cl.S(Cl)(Cl)(=O)=[O:27].C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:21])=[O:27])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred mixture of 7.7 g of 1-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-piperidone, 80 ml of methylene chloride, 3 g of silica gel, and 2.2 g of water was added 3.44 g of sulfuryl chloride at 15° to 25° C., and the mixture was stirred at 15° to 25° C. for 2 hours. The reaction mixture was poured into a cold aqueous sodium hydrogen carbonate solution. The methylene chloride solution was washed with a saturated aqueous sodium chloride solution, dried, and concentrated. The residue was purified by silica gel column chromatography (solvent; ethyl acetate:ethanol=10:1) and recrystallization from ethyl acetate to give 7.69 g of 1-(4-chlorophenyl)-6-(4-methylsulfinylphenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:18]([C:25]([F:28])([F:27])[F:26])=[N:17]2)=[CH:12][CH:11]=1>CN(C=O)C>[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[C:18]([C:25]([F:28])([F:26])[F:27])=[N:17]3)=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1nn(-c2ccc(Cn3ccnc3)cc2)c2c1CCCC2
Reaction time: 1 h
Yield: 88 %

Procedure:
Sodium hydride (60% in mineral oil, 14.0 mg; 0.35 mmol) was added in one portion to a room temperature stirring solution of imidazole (11.5 mg; 0.17 mmol) in anhydrous DMF (1 mL). After stirring at this temperature for 1 hour, a solution of 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (61.2 mg; 0.19 mmol) in anhydrous DMF (0.4 mL) was added in one portion and the resulting mixture stirred at room temperature for a further 16 hours. The reaction was quenched with aqueous hydrochloric acid (0.2 M; 0.2 mL), and purified by SCX column chromatography, giving the title compound as a yellow oil (51.8 mg; 89%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N:9]([S:18]([CH3:17])(=[O:20])=[O:19])[S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(Cl)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)ccc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a dry flask, 6-chloro-2-methylpyridin-3-amine (160 mg, 1.12 mmol) and triethylamine (470 μl, 3.37 mmol) were taken up in dichloromethane (5.6 ml) under argon. The solution was cooled to 0° C. and stirred for 20 minutes. Methanesulfonyl chloride (131 μl, 1.68 mmol) was added dropwise over 15 minutes. The mixture was allowed to warm to room temperature and stirred as such for 16 hours. The reaction was quenched with aqueous sodium bicarbonate and washed three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[CH:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([CH:29]([OH:32])[CH2:30][NH2:31])[CH:23]=1>>[CH3:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:16][CH2:17][CH:18]([NH:31][CH2:30][CH:29]([C:24]3[CH:25]=[C:26]([OH:28])[CH:27]=[CH:22][CH:23]=3)[OH:32])[CH2:19][CH2:20]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: NCC(O)c1cccc(O)c1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(NCC(O)c3cccc(O)c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(1,1-dimethyl-propyl)-benzenesulfonyl-piperidin-4-one and norphenylephrine according to the reductive amination procedure of Intermediate 21 as an off-white solid; 1H NMR (DMSO) δ 0.60 (t, J=7.32 Hz, 3H), 1.28 (s, 6H), 1.60-1.68 (m, 2H), 1.77-1.91 (m, 2H), 2.27-2.45 (m, 4H), 2.51-2.56 (m, 2H), 2.56-2.59 (m, 2H), 3.42-3.47 (m, 2H), 4.42-4.44 (m, 2H), 5.18 (bs, 1H), 6.57-6.60 (m, 1H), 6.67-6.71 (m, 2H), 7.05 (t, J=7.74 Hz, 1H), 7.58 (d, J=8.61 Hz, 2H), 7.65 (d, J=8.58 Hz, 2H) 9.25 (s, 1H); MS (ES) m/z 446.9 (MH+); HRMS for C24H34N2O4S: 447.2323