Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[OH:3][CH:1]1[CH2:2][CH2:12][C:11]2[C:5](=[CH:6][C:8]([CH3:7])=[CH:9][CH:10]=2)[O:4]1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Product: Cc1ccc2c(c1)OC(O)CC2
Temperature: 5 °C

Procedure:
The resulting oil was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1), and a fraction containing a desired compound was concentrated to obtain 4.64 g (24.1 mmol) of 2-ethoxy-7-methylchroman as pale-yellow oil. To 4.59 g (23.9 mmol) of the resulting 2-ethoxy-7-methylchroman were added 75 ml of acetonitrile, 25 ml of water and 5.3 ml (60.0 mmol) of a 35% hydrochloric acid aqueous solution, and the reaction was conducted at 60° C. for 1 hour with stirring. After the completion of the reaction, the reaction solution was extracted by adding thereto 50 ml of water and 200 ml of diethyl ether to obtain an organic layer. Further, the aqueous layer was re-extracted by adding thereto 100 ml of diethyl ether, and the thus obtained ether layer was combined with the organic layer obtained earlier. The organic layer was washed twice with 100 ml of a saturated aqueous solution of sodium bicarbonate and then with 100 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Magnesium sulfate was then removed by filtration, and the filtrate was vacuum-concentrated to obtain 3.90 g of oil. This oil was homogenized by adding thereto 0.5 ml of ethyl acetate and 10 ml of hexane at 60° C., and cooled to 5° C. for crystallization to precipitate crystals. Further, the mother liquor was vacuum-concentrated, and then purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/1), and a fraction containing a desired compound was concentrated. This concentrated solution was homogenized by adding thereto 15 ml of hexane, and cooled to 5° C. for crystallization to precipitate crystals. These crystals were collected by filtration, and vacuum-dried at room temperature for 7 hours to obtain 2.68 g (16.3 mmol) of 2-hydroxy-7-methylchroman.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: N#Cc1ccc(Cl)nc1
Product: CN(CCNc1ccc(C#N)cn1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine and 2-chloro-5-cyano-pyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]-methyl{2- [(5-cyano(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[NH:12][C:11]1=S)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH2:34]>C(O)C>[Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]=[C:11]1[NH:34][NH:33][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=S
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NNC1=Nc2cc([N+](=O)[O-])ccc2OC1(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Yield: 76.3 %

Procedure:
2,2-Bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (4.6 g) and ethyl hydrazinecarboxylate (2.88 g, 3.0 eq.) were suspended in ethanol (50 ml). The reaction mixture was refluxed for three days. The mixture was then evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=0-80%) to give ethyl 2-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazin-3-yl)hydrazine-1-carboxylate (4 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
4-Hydroxyindole (831 mg, 6.24 mmol) was dissolved in DMF (8.0 mL), and the solution was added with imidazole (510 mg, 7.49 mmol) and tert-butyldimethylsilyl chloride (1.03 g, 6.86 mmol), followed by stirring at room temperature for 5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=85/15) to obtain 4-(tert-butyldimethylsilyloxy)indole (1.53 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@H:13]2[O:17][CH2:18][C:19]([O:22][CH3:23])([O:20][CH3:21])[C@@H:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:13]2[O:17][CH2:18][C:19]([O:22][CH3:23])([O:20][CH3:21])[C@@H:12]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OCc3ccccc3)[C@@H]21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(OC)CO[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@H]2OS(C)(=O)=O
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
To a stirred solution of compound 12d (500 mg, 1.55 mmol) in CH2Cl2 (20 mL) was added triethyl amine (332 μL, 2.32 mmol) and mesyl chloride (266 mg, 2.32 mmol). After stirring for 30 minutes the reaction was washed with saturated NaHCO3 (1×20 mL), 2M HCl (1×20 m), dried MgSO4 and concentrated to give the title compound (655 mg, 99%) as a yellow oil. MS M+H 402.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.ClC1C=CN=CC=1.[NH2:18][C:19]1[C:24]2[O:25][C:26]3[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][C:27]=3[S:28](=[O:31])(=[O:30])[CH2:29][C:23]=2[CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[O:30]=[S:28]1(=[O:31])[C:27]2[CH:32]=[C:33]([C:36]([OH:38])=[O:37])[CH:34]=[CH:35][C:26]=2[O:25][C:24]2[C:19]([N:18]3[CH:3]=[CH:7][CH:6]=[CH:5]3)=[CH:20][CH:21]=[CH:22][C:23]=2[CH2:29]1
Reactant: Nc1cccc2c1Oc1ccc(C(=O)O)cc1S(=O)(=O)C2
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)Cc1cccc(-n3cccc3)c1O2
Reaction time: 1 h
Yield: 73.7 %

Procedure:
2,5-Dimethoxy tetrahydrofuran (0.053 g, 0.40 mmol) and 4-chloropyridine hydrochloride (0.0047 g, 0.03 mmol) were added to a solution of the methyl ester of Example 10k (0.1 g, 0.31 mmol) in dry dioxan (15 mL). The reaction mixture was refluxed with stirring for 1 h, concentrated and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to obtain a product which was subsequently hydrolysed as described in the synthesis of Example 1i to obtain the title compound. Yield: 73.7%; 1H NMR (DMSO-d6): δ 5.40 (s, 2H, CH2), 6.40 (s, 2H, pyrrolyl), 6.80 (d, 1H, Ar), 7.10 (s, 2H, pyrrolyl) 7.50-7.70 (m, 3H, Ar), 8.05 (d, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (EI+) 355 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Li][CH2:10]CCC.CI>O1CCCC1>[CH3:10][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccsc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1sccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.32 g (41.5 mmol) of 3-thiophenecarboxylic acid in 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 57.1 ml (91.4 mmol) of 1.6 M n-BuLi in hexanes. The cloudy suspension was stirred at -78° C. under a blanket of argon for 40 minutes, and was then transfered via canulla onto a solution of 59.05 g (25.9 ml, 416 mmol) of methyl iodide dissolved in 20 ml of anhydrous tetrahydrofuran (chilled to -78° C.). The resulting clear, colorless solution was allowed to warm to room temperature and stirred for 20 hours. A white solid was formed. The reaction mixture was concentrated in vacuo, partitioned between 75 ml of sat. NH4Cl solution and 150 ml of ethyl ether, and the layers separated. The aqueous phase was washed with 100 ml of ethyl ether and layered with 100 ml of ethyl ether and acidified with 1N sulfuric acid solution until all of the yellow emulsion dissapated. All organic phases were combined, washed with brine solution, dried over MgSO4, filtered and concentrated in vacuo to yield an off-white solid. Purification by flash chromatography (silica gel, 75% ethyl acetate in hexane) yielded the title compound as an off white solid.
Reaction SMILES: O=C1NC[C@@H](C2C=CC([Cl:22])=C([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)C=2)C1.Cl.Cl.[NH2:25][CH2:26][C@@H:27]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34](Br)[CH:33]=1)[CH2:28][C:29]([OH:31])=[O:30]>>[ClH:22].[NH2:25][CH2:26][C@@H:27]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:33]=1)[CH2:28][C:29]([OH:31])=[O:30]
Reactant: O=C1C[C@H](c2ccc(Cl)c(-c3ccc(C(=O)O)cc3)c2)CN1
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)c(Br)c1
Agent: Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1

Procedure:
(4R)-4-(3-Bromo-4-chlorophenyl)pyrrolidin-2-one (0.5 g, 0.55 mmol) and 4-methoxycarbonylphenyl boronic acid (0.144 g, 0.55 mmol) were mixed in DMF (2 mL). The mixture was degassed by alternately applying a vacuum and flushing with nitrogen gas. Palladium acetate (0.025 g, 0.11 mmol) and tetrabutylammonium bromide (0.053 g, 0.165 mmol) were added followed by potassium phosphate (0.35 g, 1.65 mmol). The mixture was stirred overnight at 90° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with 10% aqueous HCl solution then brine, and concentrated in vacuo to provide 4-[5-((3R)-5-oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid. 4-[5-((3R)-5-Oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid was then treated with HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride to provide the title compound (24). MS (ESI) m/z 334.07 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(OC(C)C)(C)C>>[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CC(C)OC(C)C
Product: COC(=O)CCCc1ccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)cc1

Procedure:
Heat 200.8 mg (0.596 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 149.8 mg (0.775 mmol) of 4-(4-aminophenyl)butanoic acid methyl ester to 150° C. for 1.5 h. After cooling, concentrate under reduced pressure, add dichloromethane to the residue and purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 20:1). The product thus obtained is stirred with diisopropyl ether and the solid obtained is filtered off with suction and washed with a little diisopropyl ether. 236.7 mg (80.4% of theory) of the target product are obtained as a pale pink solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:2]3[N:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Clc1nc(NCCCN2CCOCC2)c2cc[nH]c2n1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: c1cc2c(NCCCN3CCOCC3)nc(Nc3ccc4cn[nH]c4c3)nc2[nH]1
Temperature: 116 °C
Yield: 18.5 %

Procedure:
A mixture of 2-chloro-N-(3-morpholinopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (65 mg, 0.22 mmol), 6-aminoindazole (80 mg, 0.60 mmol) and trimethylsilyl chloride (0.100 mL, 0.72 mmol) in nBuOH (3 mL) was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (16 mg). MS 393.5 (M+H); UV 217.9, 239.1, 309.1 nm.
Reaction SMILES: C([NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.Cl>CO>[NH2:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1NC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1N
Temperature: 55 °C

Procedure:
A mixture of methyl 2-(acetylamino)-3-nitro-4-(trifluoromethyl)benzoate (1.00 g, 3.27 mmol) and 10% hydrochloric acid in methanol solution (10 ml) was heated at 55° C. for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 30% ethyl acetate/n-hexane to give 780 mg (0.030 mol 90%) of the title compound as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@H:6]([NH:20][C:21]([NH2:23])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCO>[CH2:31]([O:30][C:28]([C:27]1[N:23]=[C:21]([NH:20][C@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[O:22][CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(N)=O
Solvent: CCO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)Nc1nc(C(=O)OCC)co1
Temperature: 25 °C

Procedure:
To a suspension of (R)-4-biphenyl-4-yl-3-ureido-butyric acid ethyl ester (169 mg, 0.518 mmol) in EtOH (5 ml) at ice bath is added ethyl bromopyruvate (0.098 ml, 0.777 mmol). The reaction is warmed up slowly to room temperature and stirred at reflux overnight. The reaction is concentrated and the residue is taken up in EtOAc and H2O. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-((R)-1-biphenyl-4-ylmethyl-2-ethoxycarbonyl-ethylamino)-oxazole-4-carboxylic acid ethyl ester. HPLC retention time=1.42 minutes (condition B); MS (m+1)=423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:19][C:20]([F:33])([F:32])[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:29]([CH:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:20]([F:33])([F:19])[F:32])[CH2:28][CH2:27]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)C2CCN(C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a stirred solution of 3-methoxy phenylethylamine (9.3 g, 61.6 mmol) and triethylamine (8.1 g, 11.2 ml, 80.1 mmol) in CH2Cl2 (50 ml) at 0° C. under an atmosphere of N2 was added 1-trifluoroacetyl-piperidine-4-carbonyl chloride (15.0 g, 61.6 mmol) as a solution in CH2Cl2 (50 ml) in a dropwise manner. The reaction was allowed to warm to RT overnight. The reaction was quenched with water (50 ml), the layers were separated, and the organic layer was washed with water (1×50 ml). The combined aqueous layers were back extracted with CH2Cl2 (1×75 ml). The combined organic layers were washed with brine (1×75 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with Et2O and filtered to give the desired product (18.8 g, 52.3 mmol, 85% yield).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]([F:31])([F:30])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:38]([O:42][C:43](=[O:46])[CH2:44]Br)([CH3:41])([CH3:40])[CH3:39]>CC(C)=O>[C:38]([O:42][C:43](=[O:46])[CH2:44][N:3]([CH2:1][CH3:2])[S:4]([C:7]([F:30])([F:31])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC(=O)OC(C)(C)C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
20 g (37.94 mmol) of N-ethylperfluorooctylsulfonamide and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is added in drops at 60° C. It is stirred for 3 hours at 60° C. The salts are filtered out, and the filtrate is evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (mobile solvent: hexane/dichloromethane/acetone=10/10/1). After the product-containing fractions are concentrated by evaporation, the residue is recrystallized from methanol/ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2([S:19][CH2:20][CH3:21])[CH2:18][CH2:17]2)([OH:15])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2([S:19]([CH2:20][CH3:21])=[O:30])[CH2:17][CH2:18]2)([OH:15])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC1(C(O)(Cc2nc[nH]n2)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CCS(=O)C1(C(O)(Cc2nc[nH]n2)c2ccc(Cl)cc2)CC1
Yield: 57 %

Procedure:
5 g (0.0155 mol) of 1-(4-chlorophenyl)-1-[1-(ethylthio)-1-cyclopropyl]-2-(1,2,4-triazol-yl)-1-ethanol (see Example 1) are stirred with 3.3 g of m-chloroperbenzoic acid (80-90% strength) in 40 ml of methylene chloride overnight at room temperature and then for one hour under reflux. Thereafter, the mixture is washed with twice 20 ml of 5% strength aqueous sodium hydroxide solution and twice with water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is recrystallized from glycol monomethyl ether acetate. 3 g (57% of theory) of 1-(4-chlorophenyl)-1-[1-(ethylsulphinyl)-1-cyclopropyl]-2-(1,2,4-triazol-yl)1-ethanol of boiling point 185° C. are obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.[NH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH2:51])=[O:50].Cl.NCC(N)=O>>[C:49]([C:48]([NH:47][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:44]([CH3:46])[CH3:45])=[C:32]([CH3:43])[CH:33]=1)=[O:42])([CH3:53])[CH3:52])(=[O:50])[NH2:51]
Reactant: CC(C)(N)C(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: Cc1cc(CCCC(=O)NC(C)(C)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:52][CH2:53][C@H:54]([NH2:65])[C:55]1[NH:59][C:58]2[CH:60]=[CH:61][C:62]([Cl:64])=[CH:63][C:57]=2[N:56]=1)[CH:50]=[CH2:51].ClCl>O1CCCC1.ClCCl.C(O)C>[CH2:49]([O:52][CH2:53][C@H:54]([NH:65][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:55]1[NH:59][C:58]2[CH:60]=[CH:61][C:62]([Cl:64])=[CH:63][C:57]=2[N:56]=1)[CH:50]=[CH2:51]
Reactant: C=CCOC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-2-allyloxy-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 63%; Rf value: 0.60 (silica gel: dichloromethane/ethanol=9:1); C25H25ClN4O3 (464.951); mass spectrum: (M+H)+=465/467 (chlorine isotope) and (M−H)−=463/465 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH2:9]1[CH2:15][S:12](=O)(=[O:13])[O:11][CH2:10]1>C(OCC)(=O)C>[S:12](=[CH:15][CH2:9][CH2:10][N:3]1[CH:4]=[C:5]([CH3:8])[N:6]=[CH:7][CH:2]1[CH3:1])(=[O:13])=[O:11]
Reactant: O=S1(=O)CCCO1
Reactant: Cc1cnc(C)cn1
Solvent: CCOC(C)=O
Product: CC1=CN(CCC=S(=O)=O)C(C)C=N1
Temperature: 40 °C

Procedure:
6.0 g of 2,5-dimethylpyrazine (701) and 7.0 g of 1,3-propane sultone were dissolved in 10 ml of ethyl acetate and heated at 40° C. for 2 days. The resultant solid was then filtered and washed with ethyl acetate giving 7.9 g of product (700). It was recrystallized from propanol/water, m.p. 258°-9°. UV H2O max: 204 (3.94), 290 (3.85). 13C NMR: 159.25, S (C5); 152.47, D (C3); 146.91, S (C2); 136.88, D (C6); 57.84, T (NCH2); 47.94, T (CH2SO3-); 25.42, T (CH2); 21.49, Q, 17.16, Q (ArCH3). 1H NMR: 9.15, S (H3); 8.83, S (H6); 4.77, T (NCH2); 3.09, T (CH2SO3-), 2.90, S, 2.75, S (ArCH3); 2.40, M=5 (--CH2 --).