Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=2)=[CH:4][C:3]=1I.C1(P(C2CCCCC2)C2CCCCC2)C(C2C=CC=CC=2)=CC=CC=1.C(NC(C)C)(C)C.[CH2:50]([N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[CH3:59])[CH2:51][C:52]#[CH:53]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.CN(C)C=O.CC#N>[CH3:59][C@@H:55]1[CH2:56][CH2:57][CH2:58][N:54]1[CH2:50][CH2:51][C:52]1[O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=3)=[CH:4][C:3]=2[CH:53]=1
Reactant: C#CCCN1CCC[C@H]1C
Reactant: CC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Temperature: 45 °C
Yield: 30 %

Procedure:
The product from Example 136B (1.15 g, 3.40 mmol), palladium (II) acetate (38 mg, 0.17 mmol), biphen-2-yl-dicyclohexylphosphine (119 mg, 0.34 mmol), diisopropylamine (4.8 mL, 34 mmol), and copper(I) iodide (76 mg, 0.40 mmol) were suspended in a 0.09 M MeCN solution of (R)-1-but-3-ynyl-2-methylpyrrolidine (45 mL, 4.0 mmol). N,N-dimethylformamide (10 mL) was added, and the mixture was heated at 45° C. overnight, cooled to room temperature, partitioned between CH2Cl2 (100 mL) and 5% aqueous ammonia (100 mL), worked up as usual but with 5% aqueous ammonia, filtered, and concentrated. The residue was dissolved into CH2Cl2 and washed consecutively with water and brine, dried (Na2SO4), concentrated, and chromatographed through silica with a gradient of 0 to 4% MeOH/CH2Cl2. The appropriate fractions were combined and rechromatographed with 50% CH2Cl2/hexanes followed by a gradient of 0 to 4% MeOH/CH2Cl2 to provide the title compound as a dark brown gum (30% yield). MS (APCI) m/z 348 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.17 (d, 3H), 1.38-1.52 (m, 1H), 1.73-1.86 (m, 2H), 1.94-2.07 (m, 1H), 2.23-2.34 (m, 1H), 2.40-2.58 (m, 2H), 2.67 (s, 3H), 2.95-3.14 (m, 2H), 3.19-3.32 (m, 2H), 6.62 (s, 1H), 7.49-7.52 (m, 2H), 7.57 (dd, 1H), 7.78 (dd, 1H), 7.88 (ddd, 1H), 7.96 (ddd, 1H), 8.22 (dd, 1H).]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:4]([F:20])[CH:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O.O>CN(C)C(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:29][C:30]([F:33])([F:32])[F:31])[S:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-methanesulfonamide (4.21 g, 11.8 mmol) in N,N-dimethylacetamide (40 mL) was added sodium hydride (60% in mineral oil) (611 mg, 15.3 mmol) and the reaction was stirred at ambient temperature for 30 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (2.0 mL, 14.1 mmol) was then slowly added (exothermic) and the reaction was stirred at ambient temperature for 2.5 hours. Water was added and the reaction was diluted with EtOAc, washed with water (×2), brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-100% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (4.62 g, 89% yield). LCMS (m/z) ES+ 457 [M+18]+.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2C)[S:4]1(=[O:6])=[O:5].[Cl:16]C1C=CC=C2C=1C(=O)NS2(=O)=O.C=O>>[OH:1][CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:16])[S:4]1(=[O:6])=[O:5]
Reactant: Cc1cccc2c1C(=O)N(CO)S2(=O)=O
Reactant: O=C1NS(=O)(=O)c2cccc(Cl)c21
Agent: C=O
Product: O=C1c2c(Cl)cccc2S(=O)(=O)N1CO

Procedure:
2-Hydroxymethyl-4-chlorosaccharin was prepared in the same manner as 2-hydroxymethyl-4-methylsaccharin, in Example 1, from 4-chlorosaccharin (1.00 g; 4.60 mmol) and formalin (37%; 3.22 ml; excess). All attempts to crystallize the viscous oily product resulted in decomposition to the starting material, and the product was thus used in the next step without characterization.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([O:19][CH2:20][CH3:21])[CH:10]=[C:11]([C:14](OCC)=[O:15])[CH:12]=2)[N:7]=[C:6]([CH3:22])[CH:5]=1)[CH3:2].CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOC(C)=O.[OH-].[K+]>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([O:19][CH2:20][CH3:21])[CH:10]=[C:11]([CH:14]=[O:15])[CH:12]=2)[N:7]=[C:6]([CH3:22])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c2nc(C)cc(OCC)c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C)nc2c(OCC)cc(C=O)cc12
Temperature: 25 °C
Yield: 38.6 %

Procedure:
To a solution of ethyl 4,8-diethoxy-2-methylquinoline-6-carboxylate (60 mg, 0.20 mmol) in THF (2 mL) was added DIBAL (0.79 mL, 1M in toluene) at −78° C. The reaction mixture was allowed to warm up to room temperature and was stirred for 10 additional minutes before it was diluted with EtOAc (20 mL) and 5% KOH (20 mL). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was redissolved in DCM (3 mL) and Dess-Martin periodinane (110 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and was then diluted with EtOAc and washed with 10% KOH. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of 20-35% EtOAc/hexanes (with 1% TEA) to give the title intermediate (20 mg).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](C)C(O)=O)C=CC=CC=1.[C:23]([N:26]1[N:30]=[C:29]([NH2:31])[S:28][C:27]1([CH2:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:25])[CH3:24].N1C=CC=CC=1>S(Cl)(Cl)=O>[C:23]([N:26]1[C:27]([CH2:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:42])=[O:43])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:28][C:29]([NH:31][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])=[N:30]1)(=[O:25])[CH3:24]
Reactant: C[C@@H](C(=O)Cl)c1ccccc1
Reactant: CC(=O)N1N=C(N)SC1(CCNS(C)(=O)=O)c1ccccc1
Agent: C[C@@H](C(=O)O)c1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(=O)N1N=C(NC(=O)C(C)c2ccccc2)SC1(CCNS(C)(=O)=O)c1ccccc1
Yield: 12 %

Procedure:
Next, (R)-(−)-2-phenylpropionyl chloride prepared from (R)-(−)-2-phenylpropionic acid (4.65 g, 3.10 mmol) and thionyl chloride (30 mL), and N-[2-(3-acetyl-5-amino-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methane-sulfonamide obtained above were treated in pyridine (5.0 mL, 61.8 mmol) in the same manner as that in Step 1 of Example 20, and the resultant was purified by silica gel column chromatography (chloroform/n-hexane/ethyl acetate/methanol=20/3/2/1) to give one diastereomer of N-[4-acetyl-5-(2-methanesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (0.75 g, 12%) as a fraction eluted first, and another diastereomer of N-[4-acetyl-5-(2-methane-sulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (0.82 g, 13%) as a fraction eluted later.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(N(CC)CC)C.Cl[C:22](=O)[CH:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[CH3:1][N:2]1[C:3]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[N:13]=[C:22]1[CH:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: CNc1ccc2ncccc2c1N
Reactant: COC(=O)CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(C)c1nc2c3cccnc3ccc2n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
To a solution of N6-methylquinoline-5,6-diamine (914 mg, 5.28 mmol) in DCM (30 mL) was added triethylamine (1.07 g, 10.57 mmol). A solution of methyl 4-chloro-3-methyl-4-oxobutanoate (1.3 g, 7.90 mmol) in DCM (10 mL) was added dropwise to the above solution over 5 min. The resulting mixture was stirred at room temperature for 20 min. The mixture was concentrated to dryness. To the residue was added acetic acid (10 mL). The solution was stirred at 60° C. for 2 h. The solvent was removed under reduce pressure and to the residue was added saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with DCM (3×40 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (DCM/MeOH v/v 30:1) to give the title compound as a yellow solid (560 mg 33% yield). ESI MS: m/z 284.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.94-8.88 (m, 2H), 7.95 (d, J=9.2 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (dd, J=4.4, 8.4 Hz, 1H), 3.94 (s, 3H), 3.70-3.63 (m, 4H), 3.28 (d, J=8.4 Hz, 0.5H), 3.23 (d, J=8.4 Hz, 0.5H), 2.86 (d, J=6.0 Hz, 0.5H), 2.82 (d, J=6.0 Hz, 0.5H), 1.47 (d, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCCCCCCCCCCCC
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A solution of 6-bromo-2-pyridinecarboxaldehyde (12.3 g), 1-hexadecyne (16.1 g), triethylamine (20.0 g), bis(triphenylphosphine)palladium(II)chloride (0.92 g), and copper(I)iodide (0.13 g) in dry tetrahydrofuran (55 ml) was heated at 50° C. for 29 hrs, under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated and the residue was taken up in ethyl acetate (100 ml). The mixture was washed with 1:1 -water:saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was flash chromatographed on silica gel, eluting with 1% ethyl acetate:hexanes. The appropriate fractions were collected and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give 11.5 g (53.5%) of product, mp 38.5°-40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH3:8])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][N:19]=1)CCC>C1COCC1.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>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1-c1nccs1
Temperature: 90 °C
Yield: 40 %

Procedure:
A solution of 5-bromo-2-iodotoluene (0.15 g, 1.18 mmol) and 2-tributylstannylthiazole (0.45 g, 1.18 mmol) in THF (4 mL) in a sealed tube was degassed with a balloon of argon for 5 min. Bis(triphenylphosphine)palladium(II) chloride (1.18 mmol) was added, the reaction was capped and heated at 90° C. for 6 h. Silica gel chromatography eluting with 100% hexanes yielded 0.12 g of desired product: 1H NMR (500 MHZ, CDCl3) δ 7.95 (d, J=3.0 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=2.8 Hz, 2H), 2.60 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.C1C=C(O[C:30](OC2N=CC=CC=2)=[S:31])N=CC=1>>[N:1]([C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1)=[C:30]=[S:31]
Reactant: CNc1nccc(-c2ccccc2Oc2ccc(N)cc2)n1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Product: CNc1nccc(-c2ccccc2Oc2ccc(N=C=S)cc2)n1
Reaction time: 8 h

Procedure:
To a slurry of 4-(2-(4-aminophenoxy)phenyl)-N-methylpyrimidin-2-amine (0.300 g, 1.03 mmol) in MC was added di-2-pyridyl thionocarbonate (0.227 g, 0.977 mmol). The orange reaction was allowed to stir overnight, and was then diluted with MC and washed 4×H2O. The organic layer was dried over anhyd. Na2SO4, filtered, and concentrated in vacuo to give 4-(2-(4-isothiocyanatophenoxy)phenyl)-N-methylpyrimidin-2-amine as an off-white solid. This material was used without further purification. MS m/z=335 [M+H]+. Calc'd for C18H14N4OS: 334.4.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I>[CH:1]1([C:4]#[C:5][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(I)cc1
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#CC2CC2)cc1
Reaction time: 4 h
Yield: 66.9 %

Procedure:
Cyclopropylethyne (15 g, 0.22 mol) was slowly added to a mixture of 4-iodoanisole (30. g, 0.13 mol), copper (I) iodide (1.2 g, 0.0063 mol), and triethylamine (30. g, 0.30 mol) in tetrahydrofuran (THF, 400 mL). After being stirred for 4 hours, the resulting precipitate was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by column chromatography to afford 1-cyclopropylethynyl-4-methoxy-benzene as a yellow oil (15 g, 0.087 mol, 67%). 1H NMR (CDCl3): δ 7.31 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 1.43 (m, 1H), 0.85 (m, 2H), 0.78 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>CCOCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:21]([CH3:20])(=[O:23])=[O:22])[CH3:2]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccccc1NS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a cooled, stirred solution of 2-amino-benzoic acid ethyl ester (10.0 g, 60.5 mmol) in ether (50 mL) at 5° C. was added triethylamine (8.44 mL, 60.5 mmol). methanesulfonyl chloride (4.68 mL, 60.5 mmol) in ethyl acetate (50 mL) was added dropwise to the mixture, was stirred for 1 hour at 5° C. then at room temperature for 18 hours. Water (100 mL) was added to the stirring mixture and was extracted with ethyl acetate (3×50 mL). The combined organic was washed with water (2×50 mL) and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was stirred with warm methanol (30 mL) for 30 minutes and cooled to room temperature. The crystalline material was filtered and rinsed with a minimum of methanol. 2-Methanesulfonylamino-benzoic acid ethyl ester was isolated as a white solid (7.0 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.52 (br s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 3.06 (s, 3H), 1.42 (t, J=7.0 Hz, 3H). MS=266 (M+Na)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10](I)[C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17]>>[F:33][C:19]1[CH:20]=[C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:31]=[CH:32][C:18]=1[C:16]1[O:14][C:11]2=[N:12][CH:13]=[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[C:10]2[CH:17]=1
Reactant: Oc1ncc(Cc2ccccc2)cc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)cnc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3 and general procedure G from 5-benzyl-3-iodopyridin-2-ol (0.400 g, 1.29 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.381 g, 1.54 mmol): light yellow solid. MS (ESI) m/z: Calculated: 430.2; Observed: 431.1 (M++1).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc2cc(C(O)=CC(C)=O)cc(F)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2cc(CCC(C)=O)cc(F)c2c1
Yield: 49.3 %

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)-4-hydroxy-but-3-en-2-one (3 g) was hydrogenated at atmospheric pressure and room temperature in glacial acetic acid (150 ml) using 10% palladium on carbon (0.5 g) catalyst. When hydrogen uptake had ceased the catalyst was removed by filtration and the filtrate concentrated. The residue was taken up in ether and the resulting solution washed with sodium bicarbonate solution, then water, dried (MgSO4) and concentrated in vacuo to give a low melting solid which was recrystallised from ether to give colourless crystals (1.40 g) m.p. 69°-70° C. 'H Nmr (CDCl3)δ: 6.81-7.71 (m, 5H), 3.89 (s, 3H), 2.88-2.99 (m, 4H), 2.12 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[S:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:20][C:5]1[S:6][C:7]([S:8][CH2:9][CH2:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]([CH2:2][Cl:1])[N:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(=O)(CCSc1scnc1CCl)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(CCSc1sc(Cl)nc1CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 4-chloromethyl-5-(2-phenylsulfonylethyl)thio-1,3-thiazole (400 mg, 1.2 mmol) in N,N-dimethylformamide (3 mL) was added N-chlorosuccinimide (160 mg, 1.2 mmol), and the mixture was stirred at room temperature for 16 h. The resulting mixture was poured into water and extracted with ethyl acetate. The organic solution was washed with water, dried over sodium sulfate, and concentrated; The residue was chromatographed (silica gel, 20% ethyl acetate-hexane), affording 260 mg of the title compound. 1H NMR (CDCl3) δ 3.09 (2H), 3.36 (2H), 4.60 (2H), 7.5-7.9 (5H).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH2:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH:13][C:24]([CH3:25])=[O:26])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of THF is dissolved 2.03 g (6.5 m mols) of Z-Phe-NH-NH2, and under cooling, 1.4 ml of acetic anhydride and 0.9 ml of TEA are added dropwise. The mixture is stirred at room temperature for 2 hours. The crystals are collected by filtration, washed with diethyl ether and recrystallized from AcOEt. 1.9 g (83%); m.p. 205°-206° C.; [α]D23 -16.4° (c=0.5, DMF); Rf1 =0.60.
Reaction SMILES: [Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:21][C@@H:22]([CH3:36])[CH2:23][C@H:24]([CH3:35])[O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([O:25][C@@H:24]([CH3:35])[CH2:23][C@@H:22]([Cl:21])[CH3:36])=[CH:34][CH:33]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(C(=O)O)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(C(=O)Oc2ccc(-c3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1

Procedure:
0.30 g of (S,S)-4-[4'-(3"-chloro-1"-methylbutoxy)phenyl]phenol, 0.24q of (S,S)-4-(3'-chloro-1'-methylbutoxy)benzoic acid, 0.22 g of dicyclocarbodiimide, 0.04 g of 4-pyrrolidinopyridine and 6 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (4:1) as a developing solvent to thereby give 0.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][NH:10][C:4]=2[C:3]=1[I:11].[H-].[Na+].S(OC)(O[CH3:18])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][N:10]([CH3:18])[C:4]=2[C:3]=1[I:11]
Reactant: COS(=O)(=O)OC
Reactant: Clc1ncc2cc[nH]c2c1I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cnc(Cl)c(I)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 6-chloro-7-iodo-1H-pyrrolo[3,2-c]pyridine (600 mg, 2.15 mmol) in N,N-dimethylformamide (8 mL) was added 60% sodium hydride (130 mg, 3.25 mmol) under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., and then thereto was added dropwise dimethyl sulfate (250 μL, 2.64 mmol). Then, the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and then the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→75:25) to give 6-chloro-7-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine (540 mg, 86%) as a colorless powder.
Reaction SMILES: O[CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.CC1C=CC(S([Cl:26])(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:26][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: ClCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h
Yield: 16.2 %

Procedure:
8.48 g of 5-(4-hydroxy-1-butynyl)-2,2'-bithiophene was dissolved in 100 ml of pyridine. 16 g of p-tosyl chloride was added in under nitrogen gas atmosphere. After stirred overnight, the pyridine was evaporated under reduced pressure. The reside was extracted with ethyl acetate (100 ml) twice, filtered, washed with water (100 ml) twice, HCl solution twice (5%, 100 ml) and water (100 ml) twice again. The organic layer dried over anhydrous magnesium sulfate was filtered and the solvent thereof was evaporated. The residual solid was further purified by rapid silica gel column chromatography. From the eluate of ethyl acetate/n-hexane (1/6). 6.25 g of 5-(4-tosyloxy-1-butynyl)-2,2,'-bithiophene and 1.48 g of 5-(4-chloro-1-butynyl)-2,2'-bithiophene were respectively obtained and the yield thereof was 44% and 16%.