Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21](O)=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].C1N=C[N:32](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-].O>CS(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([NH2:32])=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-6-nitroquinazoline-8-carboxylic acid (40 mg, 0.09 mmol) in 1 mL of anhydrous DMSO, CDI (22 mg, 0.14 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 50° C. for 3 h. After cooling down to rt, NH4Cl (11 mg, 0.14 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at it overnight. The reaction mixture was poured into water. The yellow precipitate was collected as the desired product by filtration, followed by washed with water in 96% yield. 1HNMR (in DMSO): 4.90 (d, J=5.5 Hz, 2H), 7.66-7.72 (m, 2H), 7.93 (s, 1H), 8.19 (d, J=3.3 Hz, 1H), 8.72 (s, 1H), 9.17 (d, J=2.6 Hz, 1H), 9.53 (d, J=2.6 Hz, 1H), 9.87 (t, J=5.8 Hz, 1H), 10.22 (d, J=3.3 Hz, 1H). Mass: M+H+: 426.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]([NH:26][CH:27]([C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])([CH3:25])[CH3:24].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[N:26]([CH:23]([CH3:25])[CH3:24])[CH:27]([C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)NC(C)c1nc(-c2ccccc2)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N(C(C)C)C(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
Into a solution of 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid (0.18 g, 0.6 mmol) in DMF (7 mL) was added isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.11 g, 0.5 mmol), 1-hydroxybenzotriazole (0.22 g, 1.6 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.12 g, 0.6 mmol). The resulting mixture was stirred under an Argon atmosphere at rt overnight. The reaction mixture was extracted with EtOAc and the combined organic extracts were washed sequentially with saturated aqueous NaHCO3 solution, 1N HCl, saturated aqueous NaHCO3 solution, and brine. The organic phase was then dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: EtOAc) to afford the product (2-(4-hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester (0.13 g, 50%). MS (ES+): 521.5 (100%).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH:2]=[CH2:3].SC1N=CNN=1.[CH2:16]([N:19]([CH2:23][CH:24]=[CH2:25])[C:20](Cl)=[O:21])[CH:17]=[CH2:18].C(N(CC)CC)C>O1CCCC1>[CH2:16]([N:19]([CH2:23][CH:24]=[CH2:25])[C:20]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH:2]=[CH2:3])=[N:6]1)=[O:21])[CH:17]=[CH2:18]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: C=CCSc1nc[nH]n1
Agent: Sc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCSc1ncn(C(=O)N(CC=C)CC=C)n1

Procedure:
A mixture of 7.1 g. 3-allylthio-1,2,4-triazole, (m.p. 27° - 30° C., prepared from 3-mercapto-1,2,4-triazole in an analogous manner to that described in Example 1), 8.0 g. diallylcarbamoyl chloride, 7.5 ml. dry triethylamine and 100 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 48 hours. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-allylthio-1,2,4-triazole, b.p. 120° - 122° C./0.1 mm. (95.2% 1-isomer by GLC assay).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][N:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.P(Cl)(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:28][CH2:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][N:9]=2)[CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1

Procedure:
[2-(5-Phenyl-thiazol-2-ylamino)-pyridin-4-yl]-methanol 8-7 (0.500 g, 1.77 mmol) was stirred in anh CH2Cl2 (5 mL) under N2. N,N-Dimethylformamide (0.137 mL, 1.76 mmol, 1 equiv) was added followed by the addition of phosphorous oxychloride (0.165 mL, 1.76 mmol). After 1.5 h the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ11.49 (bs, 1H), 8.34 (d, 1H, J=5.2 Hz), 7.81 (s, 1H), 7.60 (d, 2H, J=7.7 Hz), 7.39 (t, 2H, J=7.6 Hz), 7.26 (t, 1H, 7.0 Hz), 7.13 (s, 1H), 6.99 (d, 1H, J=5.3 Hz), 4.77 (s, 2H).
Reaction SMILES: Br[CH:2]([CH2:10][CH2:11][CH2:12][Cl:13])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:14][C:15]([NH2:17])=[S:16]>CC(C)=O>[NH2:17][C:15]1[S:16][C:2]([CH2:10][CH2:11][CH2:12][Cl:13])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(Br)CCCCl
Solvent: CC(C)=O
Product: CCOC(=O)c1nc(N)sc1CCCCl
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of ethyl 3-bromo-6-chloro-2-oxohexanoate (23A) (0.845 g, 3.11 mmol) in acetone (6 mL) was added thiourea (0.284 g, 3.73 mmol) and refluxed overnight. The reaction mixture was concentrated under reduced pressure. EtOAc and hexanes in a ratio of 1:9 was added and stirred for 1 hour. Added acetone to dissolve material and concentrated under reduced pressure to give 0.718 g (93%) of the desired product ethyl 2-amino-5-(3-chloropropyl)thiazole-4-carboxylate (23B): LC/MS (APCI): m/z 249.5 (M+H).
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCSC3)c1ccc(F)cc1
Yield: 67 %

Procedure:
To a solution of (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole from EXAMPLE 1 (80 mg, 0.32 mmol) in 1,4-dioxane (15 ml) at 25° C. was added 4-chloro-1-(4-fluorophenyl)butan-1-one (96 mg, 0.48 mmol), K2CO3 (100 mg, 0.72 mmol), and KI (32 mg, 0.19 mmol), respectively. The mixture was stirred at ambient temperature for 16 hours before H2O (10 mL) was added and then extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give the title compound of EXAMPLE 4 as an oil (88 mg, 67%). 1H NMR(CDCl3, 300 MHz): δ 8.01 (m, 2H), 7.15 (m, 2H), 6.96 (d, 1H, J=6.6 Hz), 6.92 (d, 1H, J=6.6 Hz), 3.82 (m, 2H), 3.25 (m, 2H), 3.19-2.60 (m, 8H), 2.42 (m, 2H), 1.95 (m, 5H). LRMS (ES)+: 411 (M+H)+.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33]([O:35][CH2:36][C:37](O)=[O:38])[CH3:34].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:33]([O:35][CH2:36][C:37]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:38])[CH3:34]
Reactant: CCOCC(=O)O
Reactant: O=C(CCc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOCC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 35.5 %

Procedure:
To a solution of 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (889 mg) and ethoxyacetic acid (250 mg) in pyridine (25 ml) is added N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1527 mg) under ice-cooling, and the mixture is stirred at room temperature for 19 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is stirred. The organic layer is collected, washed with water, dried, and evaporated to remove the solvent. The residue is dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml), and thereto is added triethylamine (202 mg). The mixture is stirred at 50° C. for 40 minutes, and evaporated to remove the solvent. The residue is dissolved in ethyl acetate, and the mixture is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 2'-(6-O-ethoxyacetyl-β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (377 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([OH:15])[CH:6]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([O:15][CH2:29][C@@H:30]2[CH2:32][O:31]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OC(C)=O)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(OC(C)=O)cc1OC[C@@H]1CO1
Yield: 34.9 %

Procedure:
A solution of 4-(acetylamino)-3-hydroxyphenyl acetate (669 mg, 3.2 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (748 mg, 2.9 mol) and caesium carbonate (1.05 g, 3.2 mmol) in 1-methyl-pyrrolidinone (10 mL) was stirred over night at room temperature, and then partitioned between water and ethyl acetate. The organic phase was washed twice with water and concentrated to an yellow oil, which was suspended in methanol/diethyl ether, ½. The precipitated beige solid was filtered off and dried to give the titled compound (296 mg, 38%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:12]1([CH2:11][C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:41]#[C:40][C:39]([OH:38])([CH3:43])[CH3:42])=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC(C)(C)O)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (120 mg, 0.257 mmol), N,N-diisopropylethylamine (0.5 mL, 2.87 mmol), and 3-hydroxy-3-methylbutyne (90 mg, 1.07 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.0157 mmol) and copper(I) iodide (5.5 mg, 0.0288 mmol). The mixture was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (25 mL) and a 0.2M aqueous hydrochloric acid solution (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL), and each aqueous phase was back-extracted with a small volume of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with increasing concentrations of ethyl acetate/hexanes) afforded the 3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 77%) as a yellow foam: (ES)+-HRMS m/e calcd for C25H31N3O4S (M+H)+ 470.2108, found 470.2113.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:3].O.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])O.[Na+]>C(O)C>[CH2:2]([N:4]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCNCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC(=O)O)c1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
(a-1) To a stirred solution of 1.4 parts of ethyl glycine hydrochloride in 10 parts of water was added a solution of 1.7 parts of 4-fluoro-3-nitrobenzaldehyde in 8 parts of ethanol. Then there were added 1.76 parts of sodium hydrogen carbonate and stirring at room temperature was continued for 48 hours. The precipitated product was filtered off, washed successively with water, ethanol and 2,2'-oxybispropane, and dried, yielding 2 parts (79%) of ethyl N-(4-formyl-2-nitrophenyl)-glycine; mp. 90° C. (int. 29).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14](O)([CH3:16])[CH3:15])[N:13]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([CH3:16])=[CH2:15])[N:13]=1
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(C)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Yield: 78 %

Procedure:
To a 25 mL round bottom flask attached with Vigreux column was added 2-[2-(2,6-Dichloro-phenyl)-1-(3′-methanesulfonyl-biphenyl-4-yl)-1H-imidazol-4-yl]-propan-2-ol (383 mg, 764 μmol), anhydrous toluene (8 mL) and acetic acid (3.5 mL). The reaction solution was allowed to stir at reflux for 1.5 hr. The cooled reaction solution was concentrated in vacuo, and the residue was taken into EtOAc (200 mL) and washed with aq NaHCO3 (100 mL×2) and aq. NaCl (100 mL). The organic phase was partitioned, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed through a 25 g SiO2 column using a mobile gradient of 100% Hx to 80% EtOAc to provide 288 mg (78% yield) of title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.15 (br s, 1H), 8.08-7.97 (m, 2H), 7.92 (d, 1H), 7.89 (d, 2H), 7.75 (t, 1H), 7.64-7.57 (m, 3H), 7.43 (d, 2H), 5.77 (br s, 1H), 5.10 (br s, 1H), 3.29 (s, 3H), 2.11 (s, 3H); MS (ES): 483.1, 485.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:30]3[CH2:31][CH2:32][N:27]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:28][CH2:29]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)cc1OC
Yield: 142.9 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (20 mg, 0.08 mmol) and 1-benylpiperazine (13.4, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (48 mg, 0.23mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 20 hr and followed the same processes as in Example 1 to obtain 24.1 mg (74.6%) of the target compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=3)(=[O:25])=[O:24])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1ccc(-c2csc(NCc3cccs3)n2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(-c2csc(N(Cc3cccs3)S(=O)(=O)c3ccc(C(=O)O)cc3)n2)cc1
Temperature: 100 °C

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amine (50 mg, 0.16 mmol), 4-(chlorosulfonyl)benzoic acid (53 mg, 0.24 mmol), triethylamine (45 μL, 0.32 mmol), and DMAP (2 mg, 0.016 mmol) were combined in DCM (2 mL). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature, saturated NaHCO3 (aq) solution (5 mL) was added. The mixture was extracted with DCM (2×4 mL). The combined organic layer was dried over Na2SO4 and concentrated. Purification of the crude product was carried out using silica gel chromatography eluting with DCM/MeOH 9:1, yielding 4-{[4-(4-isopropyl-phenyl)thiazol-2-yl]-thiophen-2-ylmethyl-sulfamoyl}-benzoic acid. LCMS m/z: 500 (M+1)+.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=3)=[CH:16][N:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:33]>O1CCCC1>[ClH:33].[ClH:33].[NH2:8][C@H:12]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)=[CH:16][N:17]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](c2ncc(-c3cccc(Br)n3)s2)COC1(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H](CO)c1ncc(-c2cccc(Br)n2)s1
Temperature: 90 °C

Procedure:
To a solution of (S)-4-[5-(6-bromopyridin-2-yl)thiazol-2-yl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (5.00 g, 11.4 mmol) obtained in Step 2 in tetrahydrofuran (30 ml) was added 4N hydrogen chloride-ethyl acetate solution (30 ml) and heated to reflux at 90° C. for 2 hours. After the reaction solution was cooled, it was concentrated and washed with ethyl ether and dried, and the title compound (3.57 g) was obtained.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.ClCCl>N1C=CC=CC=1>[C:34]([NH:33][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:6]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Yield: 73.5 %

Procedure:
To a solution of hydrocortisone (3.62 g, 0.01 mole) and N,N-(N'-methyl-3'-azapentamethylene)succinamic acid (2.00 g, 0.01 mole) in 15 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.00 g, 0.01 mole). After stirring the reaction mixture 10 minutes, 25 ml dichloromethane was added to it to keep the suspension, which had resulted, sufficiently fluid for stirring. After stirring overnight, the reaction was filtered. The residue was washed twice with CH2Cl2 and air dried to give 1.65 g (84% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to give a light brown foam which was in turn triturated 2 hours with 10 ml CH2Cl2 to give a suspension which was filtered. The residue was dried in the vacuum oven 3 hours at 40° C. after a preliminary NMR showed contamination of the product with CH2Cl2. The resulting finely crystalline, off-white powder was the desired product: 2.70 g, 51% yield; mp 159°-163° C.; NMR (DMSO-d6) δ5.53 (s, 1, O=C-CH=C-), 5.32 (m, 1, C-OH), 4.91 (ABq, 2, JAB=17 Hz, ΔνAB =18 Hz, O=C-CH2 -O), 4.29 (m, 2, CH-OH), 3.41 (m, 8, -N(CH2CH2)N-), 2.59 (s, 3, N-CH3), 1.37 (s, 3, C-CH3), 0.78 (s, 3, C-CH3), 2.7-0.8 (m, 21, CH, CH2); IR (KBr) 3400 cm-1 (s) (OH), 1730 cm-1 and 1710 cm-1 (s) (C-C=O and O-C=O) and 1640 and 1615 cm-1 (s) (O=C-CH=C, N-C=O); [α]24D=+122° (C=0.5, dioxane); TLC (silica gel, MeOH) Rf 0.27.
Reaction SMILES: [CH2:1]([C:3]([OH:9])([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C:3]([O:9][Si:18]([CH3:21])([CH3:20])[CH3:17])([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(CC)(CC)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-ethyl-3-hydroxy-5-hexyne (12.6 g) (WO 93/19044), triethylamine (67 ml) and DMAP (0.47 g) in dichloromethane (150 ml) was added, with stirring at 0° C., trimethylchlorosilane (38 ml), during 10 min. Stirring was continued at 0° C. for 15 min. and at 25° C. for 45 min. The reaction mixture was worked up, and the crude product was purified by distillation in vacuo to give the title compound as an oil, b.p. 83-85° C./25 mm Hg.
Reaction SMILES: [F:1][C:2]([F:20])([S:13]([CH2:16][CH2:17][CH2:18][OH:19])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-].[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(C1C=C(O)C(=CC=1)O)(C)(C)C.ClCCl>[C:31]([O:19][CH2:18][CH2:17][CH2:16][S:13]([C:2]([F:1])([F:20])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])(=[O:15])=[O:14])(=[O:34])[CH:32]=[CH2:33]
Reactant: O=S(=O)(CCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=O)Cl
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCCS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A solution of 3-(perfluorobutylsulfonyl)propanol (54.4 g, 159 mmol), triethylamine (33 ml, 238 mmol), 4-t-butylcatechol (0.14 g) and dichloromethane (520 ml) was cooled to 0° C. in a state of being equipped with a calcium chloride, and then acryloyl chloride (15.5 ml, 191 mmol) was slowly added dropwise over 40 minutes. After stirring at room temperature for one hour and washing the mixture with 15% citric acid (600 ml) water and saturated saline, the mixture was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a crude acrylate ester. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) and the transparent liquid was vacuum-dried after concentration to obtain 60.0 g of 3-(perfluorobutylsulfonyl)propyl acrylate. Yield was 95.3%.