Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.FC(F)(F)C([O:17][C:18](=O)[C:19](F)(F)F)=O.ClC(OCC(C)C)=O.[NH2:34][C@@H:35](C(O)=O)CC1N=CNC=1>>[C:35]([CH2:19][C:18]([NH:2][C@@H:3]([CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)[C:10]([OH:12])=[O:11])=[O:17])#[N:34]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Product: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
An optical purity of >99.8% was determined for a sample obtained according to the procedure above. The determination was carried out by hydrolysing the amide bond (6 N hydrochloric acid, 110° C., 24 h), followed by derivatizing the liberated histidine with trifluoroacetic anhydride and isobutyl chloroformate. A D-histidine content of <0.1% was detected by means of gas chromatography on a chiral stationary phase.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:10]1[C:11]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCn1ncc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1ncc2ncnc(Cl)c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol (2.91 g) and POCl3 (30 mL) was stirred at 100° C. overnight. The mixture was concentrated under reduced pressure. The residue was neutralized with saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (2.14 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:7][C:6]1[CH:28]=[CH:29][C:3]([CH2:2][O:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:4][CH:5]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)(=[O:10])=[O:11])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CO)cc1)Cc1ccccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirring solution of N-(4-hydroxymethyl-benzyl)-2-nitro-N-pyridin-2-ylmethyl-benzenesulfonamide (Bridger, et al., U.S. Ser. No. 09/111,895) (0.2096 g, 0.51 mmol) in CH2Cl2 (5 mL) at 0° C. under Ar, was added Et3N (0.14 mL, 1.02 mmol) and MsCl (0.05 mL, 0.66 mmol). The mixture was stirred at 0° C. for 2 hours, then stirred at room temperature for 3 hours. Additional Et3N (0.30 mL, 2.16 mmol) and MsCl (0.10 mL, 1.32 mmol) were added, and stirred for 18 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 0.2383 g (95%) of methanesulfonic acid 4-{[(2-nitro-benzenesulfonyl)-pyridin-2-ylmethyl-amino]-methyl}-benzyl ester as a yellow oil. 1H NMR (CDCl3) δ 3.14 (s, 3H), 4.51 (s, 2H), 4.60 (s, 4H), 7.02-7.24 (m, 6H), 7.54-7.57 (m, 2H), 7.66 (d, 2H, J=3.0 Hz), 7.94 (d, 1H, J=9.0 Hz), 8.41-8.43 (m, 1H).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][CH:11]1[C:34]([OH:36])=O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1.[F:70][C:71]1[CH:72]=[C:73]([CH:76]=[CH:77][CH:78]=1)[NH:74][CH3:75]>C1COCC1>[F:70][C:71]1[CH:72]=[C:73]([N:74]([CH3:75])[C:34]([CH:11]2[C@H:10]([OH:9])[C@H:14]([OH:15])[C@@H:13]([CH2:24][OH:25])[O:12]2)=[O:36])[CH:76]=[CH:77][CH:78]=1
Reactant: CNc1cccc(F)c1
Reactant: O=C(OC[C@H]1OC(C(=O)O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: C1CCOC1
Product: CN(C(=O)C1O[C@H](CO)[C@@H](O)[C@H]1O)c1cccc(F)c1
Reaction time: 16 h
Yield: 42.5 %

Procedure:
(3R,4R,5R)-3,4-Bis(benzoyloxy)-5-(benzoyloxymethyl)tetrahydrofuran-2-carboxylic acid (3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid, 2 g, 4 mmol) was dissolved in anhydrous THF (40 mL) under argon atmosphere. To this, triphenylphosphine (2.1 g, 8 mmol) was added and the mixture was stirred until it was dissolved completely. To this clear solution, 2,2′-dipyridyldisulfide (1.8 g, 8 mmol) was added and the mixture was stirred at room temperature for 2 hours, after which, 3-fluoro-N-methylaniline (0.7 g, 5.6 mmol) was added and stirring was continued at room temperature for 16 hours. The solvent was evaporated to dryness, the residue was dissolved in chloroform (150 ml), the solution washed twice with 0.1M NaOH solution (100 mL), twice with 0.2 M HCl solution (100 mL), once with saturated NaHCO3 solution (100 mL), and then dried over Na2SO4. The solution was evaporated to dryness and the residue was re-dissolved in methanolic ammonia (7M solution, 250 mL). The solution was stirred for 16 hours at room temperature and evaporated to dryness. The crude product was purified by silica gel chromatography using a mixture of chloroform-methanol (3:1) and evaporation of the appropriate fractions yielded the title compound as a colorless oil (0.5 g, 1.7 mmol, 42%): MS (ES) m/z 308 [M+Na]+, 284 [M−H]−.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:7]([NH2:10])[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([NH:10][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:8]=[CH2:9]
Reactant: CCCC(=O)Cl
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNC(=O)CCC
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
Butyroyl chloride (194.7 g, 1.83 mol) in 1 L of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (208.7 g, 3.65 mol) in 50 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtrate was concentrated under vacuum to yield 236.4 g of N-allyl butyramide as a colorless viscous liquid.
Reaction SMILES: [NH2:1][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(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C(OCC)(=O)C>O1CCCC1>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (3.5 g, 23.6 mmol, prepared according to U.S. Pat. No. 6,114,371) in 20 ml of tetrahydrofuran was added with triethylamine (1.3 ml, 9 mmol). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was stirred for 20 minutes at room temperature and added with ethyl acetate (20 ml) until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g, 88.9%) as a white solid.
Reaction SMILES: [C:1]1(C)C=C[CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([CH2:34][CH:35]=[CH2:36])=[O:33])=[CH:27][CH:26]=3)=[CH:23][N:24]=2)=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:37]([SiH:41](C)[CH3:42])CCC>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.O>[CH2:8]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH2:34][CH2:35][CH:36]([SiH:41]([CH3:42])[CH3:37])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:33])=[CH:29][CH:30]=3)=[CH:23][N:24]=2)=[CH:18][CH:19]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC[SiH](C)C
Reactant: C=CCC(=O)Oc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)s2)cc1
Reactant: Cc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OC(=O)CCC(CCCC)[SiH](C)C)cc3)s2)cc1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
2 ml of toluene was added to 0.81 g (1.99 mM) of 2-(4-hexylphenyl)-5-(4-allylcarbonyloxyphenyl)-1,3-thiazole, followed by stirring at room temperature. To the mixture, an appropriate amount chloroplatinic acid, three drops of isopropyl alcohol and 0.24 g (2.06 mM) of butyldimethylsilane were successively added and heated to 80° C., followed by stirring for 7 hours. After the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate. The magnesium sulfate in the resultant organic layer was filtered off, followed by distilling-off of the solvent, purification by silica gel column chromatography (eluent: toluene) and recrystallization from a mixture solvent (methanol/toluene) to obtain 0.25 g of 2-(4-hexylphenyl)-5-[4-(3-butyldimethylsilylpropylcarbonyloxy)phenyl]-1,3-thiazole (Yield: 24.3%). ##STR83##
Reaction SMILES: OO.[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4].C([O-])([O-])=[O:38].[K+].[K+].CS(C)=O>O>[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:38])[NH2:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 197.2 %

Procedure:
Add 30% aq. H2O2 (239 uL) to a suspension of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester (111 mg, 0.239 mmol), K2CO3 (16 mg, 0.120 mmol) and DMSO (3 ml) stirring in an ice/water bath. After 1.5 hours, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give [5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4 methyl-pentyl)-carbamic acid tert-butyl ester (114 mg) as a white foam. Use this material without further purification.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:14]([Zn]CC)[CH3:15].O.Cl.O1CCO[CH2:23][CH2:22]1>>[CH2:14]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:22][CH3:23])[CH:5]=[CH:4][N:3]=1)[CH3:15]
Reactant: CCOC(=O)c1c(Cl)ccnc1Br
Reactant: C1COCCO1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: O
Product: CCOC(=O)c1c(CC)ccnc1CC
Temperature: 70 °C
Yield: 46 %

Procedure:
Ethyl 2-bromo-4-chloropyridine-3-carboxylate (2.0 g, 7.6 mmol) was dissolved in anhydrous dioxane (55 mL). A solution of diethyl zinc (6.9 mL, 7.6 mmol, 1.1 M in toluene) was added dropwise, and then was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (83 mg, 113 μmol). The mixture was heated at 70° C. for 6 hours, and water followed by 1 N HCl was added. The mixture was extracted 3 times with ethyl acetate, and the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-20% hexane/ethyl acetate to afford ethyl 2,4-diethylpyridine-3-carboxylate (720 mg, 46% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]1[CH3:27])=[O:20])[CH3:17].[CH3:28]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]2([O:26][CH3:28])[CH2:24][CH2:25][N:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH:22]2[CH3:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(=O)C1C
Reactant: CI
Reactant: Brc1cccc(OCc2ccccc2)c1
Product: CCOC(=O)N1CCC(OC)(c2cccc(OCc3ccccc3)c2)C1C
Yield: 65 %

Procedure:
Using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials, 3-benzyloxybromobenzene was reacted with 1-ethoxycarbonyl-2-methylpyrrolidin-3-one (J. Med. Pharm. Chem., 1962, 5, 755) and the resultant product was reacted with methyl iodide to give (2RS,3SR)-3-(3-benzyloxyphenyl)-1-ethoxycarbonyl-3-methoxy-2-methylpyrrolidine in 65% yield as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Cl:21][CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C>[Cl-:21].[C:18]([C:3]1[N:4]=[C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[S:6][C:2]=1[NH:1][C:27]([C:26]1[CH:30]=[CH:31][C:23]([CH2:22][N+:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:24][CH:25]=1)=[O:28])(=[O:19])[NH2:20]
Reactant: c1ccncc1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(C[n+]2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.18 g, 0.62 mmol) and a catalytic amount of DMAP in pyridine (5 mL) was added 4-chloromethylbenzoyl chloride (0.13 g, 0.68 mmol) at 0° C. under N2-atmosphere. The mixture was stirred for 16 hrs at rt under nitrogen atmosphere. The solvent was evaporated, and the residue was triturated with water. The resulting solids were collected by filtration and washed with MeOH to give 0.030 g (10% yield) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C(=O)C>[C:7]1([N:6]2[C:2]([NH:1][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:34])=[CH:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (498 mg) synthesized according to the method described in WO2004/98589 in N,N-dimethylacetamide (10 mL) were added N-ethyldiisopropylamine (417 mg) and benzoyl chloride (453 mg) at room temperature. After stirring at the same temperature for 18 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→3:1) to give the title compound as colorless crystals (yield 550 mg, yield 76%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)CO.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCCCCCCCC>[Cu]I.C(OCC)(=O)C>[CH3:18][C:16]1[CH:17]=[C:12]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[C:14]([CH3:19])[CH:15]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Cc1cc(C)cc(Sc2ccccc2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
CuI (0.05 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added to a screw-capped test tube with a Teflon-lined septum. The tube was evacuated and backfilled with argon (3 cycles). Solvent (1.0 mL), ethylene glycol (111 μL, 2.0 mmol; for entries 2, 4, 6, 8, 10), 5-iodo-m-xylene (144 μL, 1.0 mmol) and thiophenol (103 μL, 1.0 mmol) were added by syringes at room temperature. The tube was heated to 80° C. and stirred for 20 hours. The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added. The aliquot was analyzed by GC or GC-MS. See FIG. 9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([OH:20])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)O.C(N(C(C)C)C(C)C)C.[NH2:43][CH:44]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=1)[C:45]#[N:46]>CC#N>[C:45]([CH:44]([NH:43][C:18]([C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])=[O:20])[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=1)#[N:46]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CC(N)c1cccc(O)c1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CC(NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid (0.095 g, 0.3 mmol) is dissolved in CH3CN. O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU, 90.2 mg, 0.3 mmol), N-Ethyldiisopropylamine (DIPEA, 0.208 ml, 1.21 mmol) are added. The amino-(3-hydroxy-phenyl)-acetonitrile in CH3CN (1.5 ml) is added. The mixture is stirred at RT for 16 hours. The solution is filtered and concentrated. The residue is dissolved in CH2Cl2 (15 mL) and extracted with NH4Cl (2×10 ml). The H2O layers are extracted with CH2Cl2 (2×15 ml). The collected CH2Cl2 layers are dried over MgSO4 and evaporated. The solid is purified by preparative HPLC.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:17])[CH2:12][CH2:11]1>CN(C)C=O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:17])[CH2:12][CH2:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(N1CCC(O)CC1)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyldimethylsilyl chloride (30.14 g, 0.20 mol) was added to a stirred solution of (4-hydroxy-piperidin-1-yl)-imidazol-1-yl-methanone (39.05 g, 0.20 mol) in dimethylformamide (200 mL). After stirring for 3 days at room temperature, the solvent was removed by evaporation in vacuo. The residue was redissolved in dichloromethane, extracted twice with water, dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[S:24][C:25]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[F:32][C:30]1[CH:29]=[CH:28][C:26]2[N:27]=[C:23]([N:7]3[CH2:8][CH:4]4[CH:5]([CH2:1][N:2]([C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[C:17]5[S:18][CH:19]=[CH:20][CH:21]=5)=[O:10])[CH2:3]4)[CH2:6]3)[S:24][C:25]=2[CH:31]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nc4ccc(F)cc4s3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-6-fluoro-benzothiazole. MS (ESI) mass calcd. for C24H20FN3OS2, 449.57; m/z found, 450.0 [M+H]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:27]([Mg]Br)=[CH2:28].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14](=[O:15])[CH:27]=[CH2:28])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (10.2 g) in tetrahydrofuran (100 mL) was added dropwise vinylmagnesium bromide (1.0M tetrahydrofuran solution, 73 mL) under ice-cooling. The reaction mixture was stirred overnight at room temperature, 1M hydrochloric acid (80 mL) was added and the mixture was further stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (4.25 g, yield 46%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 92-93° C. MS: 349 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11]>O1CCOCC1>[CH2:10]([O:12][C:13](=[O:14])[NH:15][C:16](=[S:17])[NH:9][C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[C:5]([CH3:8])[N:4]=1)[CH3:11]
Reactant: Cc1cnc(C)c(N)n1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1nc(C)cnc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of 3,6-dimethyl-pyrazin-2-ylamine (5 g, 40.65 mmol) in dioxane (150 ml) was added ethoxycarbonyl isothiocyanate (4.75 ml, 40.65 mmol) at 25° C., and the reaction mixture was stirred for 18 hours at 25° C. Volatiles were removed in vacuo. The resultant residue was dissolved in ethyl acetate, washed with water twice, and brine, dried over anhydrous sodium sulfate, filtered, and evaporated affording ethyl-N-[(3,6-dimethylpyrazin-2-yl)carbamothioyl]carbamate (10 g, 96.73%) as a light yellow solid. MS: m/z=255 (M+H+)