Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(OS(C)(=O)=O)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a suspension of 2-(2,4-dichlorophenyl)-3-hydroxy-1-(triazol-1-yl)butan-2-ol (1.0 g; 3.3 mmol) obtained in Reference Example 3 in benzene (10 ml) was added triethylamine (1.0 g; 9.9 mmol) and methanesulfonyl chloride (0.76 g; 6.6 mmol) at 25 to 40° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo to give 2-(2,4-dichlorophenyl)-3-mesyloxy-1-(triazol-1-yl)butan-2-ol (1.26 g, 100 %) as crystals m.p., 147-149° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[CH:17]=3)=[N:12][N:13]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32].CN(C=O)C.C(#N)C>C(Cl)Cl.C1COCC1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[O:10][C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[CH:17]=3)=[N:12][N:13]=2)[C:30](=[O:33])[CH:31]=[CH2:32])=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(=O)N(c1ccc(F)cc1)c1nnc(/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.07 mL) was added to a suspension of (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}amine synthesized in Example 162 (100 mg) in methylene chloride (3 mL) and THF (2 mL) at room temperature. Acrylic acid chloride (0.03 mL) was added to the reaction solution at 0° C., and the reaction solution was stirred at room temperature for two hours. TEA (0.08 mL) and acrylic acid chloride (0.04 mL) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for two hours. Further, DMF (0.5 mL), acetonitrile (0.5 mL), DMAP (2 mg), TEA (0.08 mL) and acrylic acid chloride (0.04 mL) were added and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and a saturated sodium bicarbonate solution were added to the residue, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 22 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[Br:6][C:7]1[N:8]=[C:9](S(C)(=O)=O)[C:10]2[N:11]([C:13]([I:16])=[CH:14][N:15]=2)[CH:12]=1>CN(C)C=O>[Br:6][C:7]1[N:8]=[C:9]([NH:4][CH2:3][CH2:2][CH2:1][NH2:5])[C:10]2[N:11]([C:13]([I:16])=[CH:14][N:15]=2)[CH:12]=1
Reactant: NCCCN
Reactant: CS(=O)(=O)c1nc(Br)cn2c(I)cnc12
Solvent: CN(C)C=O
Product: NCCCNc1nc(Br)cn2c(I)cnc12
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 1.26 mL propane-1,3-diamine in 8 mL 2.0 g N,N-dimethylformamide was added a solution of (4.98 mmol) 6-bromo-3-iodo-8-(methylsulfonyl)imidazo[1,2-a]pyrazine which was prepared according to intermediate example 60c in 20 mL N,N-dimethylformamide at 40° C. during 1.5 hours. The mixture was stirred at 40° C. for additional 1.5 hours. The solvent was removed and the residue was purified by chromatography to give 1.52 g (77%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:10])[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1cnc(C)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a 0° C. solution of 1-ethyl-4-methyl-1H-imidazole-5-carbaldehyde (806 mg, 5.8 mmol) in anhydrous methanol (55 mL) was added sodium borohydride (500 mg, 13.2 mmol). The reaction mixture was stirred at room temperature overnight. Water (30 mL) was added. The mixture was evaporated. The resultant residue was treated with EtOAc (50 mL). The solution was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (1-ethyl-4-methyl-1H-imidazol-5-yl)methanol (754 mg, 93% yield). The product was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[I-].[Na+].C(=O)(O)[O-].[Na+].[C:12]([C@@H:15]1[CH2:19][C@H:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][NH:16]1)(=[O:14])[NH2:13]>CN(C)C=O>[C:12]([C@@H:15]1[CH2:19][C@H:18]([S:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:17][N:16]1[CH2:2][CH2:3][F:4])(=[O:14])[NH2:13]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: FCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(CCF)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.4 ml of 1-bromo-2-fluoroethane, 3.83 g of sodium iodide and 0.38 g of sodium bicarbonate were added to a solution of 1.2 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 12 ml of dry dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 20 minutes and then at 40° C. for 20 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was subjected to column chromatography through silica gel (Katayama Chemicals Industries Co., silica gel 60K070). 838 mg of the title compound, melting of 122°-123° C., were obtained as a powder from those fractions eluted with ethyl acetate.
Reaction SMILES: [Cu+2:1].[Cu+2].[Cu+2].[Cu+2].[Zn+2:5].[Zn+2].[Zn+2].[Zn+2].[Sn].Cl.[Tc:11]([O-])(=O)(=O)=O>>[Tc:11].[Cu+2:1].[Cu+2:1].[Cu+2:1].[Cu+2:1].[Zn+2:5].[Zn+2:5].[Zn+2:5].[Zn+2:5]
Reactant: O=[Tc](=O)(=O)[O-]
Agent: [Cu+2]
Agent: Cl
Agent: [Sn]
Product: [Tc]

Procedure:
99MTc-labeled orgotein obtained by adding to 1-10 mg. dry samples of orgotein, 2 tin shot pellets (shiny), 1.0 ml. 0.02N HCl and 0.5 ml. pertechnetate (5-20 mCi) followed by 10 minutes incubation at room temperature and thereafter, when neutralization prior to injection was desired, followed by 1 ml. of 0.02N Na3CO3, was employed in the experiments.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][N:17]([CH2:19][CH2:20][OH:21])[CH2:16][N:15]([CH3:22])[C:14]1=[S:23].C(OCC)C>C1(C)C=CC=CC=1>[C:1]([O:21][CH2:20][CH2:19][N:17]1[CH2:18][N:13]([C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[CH3:5])[C:14](=[S:23])[N:15]([CH3:22])[CH2:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(N2CN(CCO)CN(C)C2=S)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)OCCN1CN(C)C(=S)N(c2ccc(C)cc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
Acetyl chloride (0.168 g, 1.5 mmole) was added dropwise with stirring to a cooled solution of 1-(2,4-dimethylphenyl)-5-(2-hydroxyethyl)-3-methyl-tetrahydro-s-triazin-2[1H]-thione (0.60 g, 1 mmole) in dry toluene (30 ml). After 10 minutes the solution was allowed to warm to room temperature and stirring was continued for a further 3 hours. The solution was filtered and the solvent removed under vacuum. The product was chromatographed on a column of silica eluting with dichloromethane containing 2% methanol to yield an oil. Trituration with diethyl ether gave 5-(2-acetoxyethyl)-1-(2,4-dimethylphenyl)-3-methyl-tetrahydro-s-triazin-2[1H]-thione (0.24 g, 35%), m.p. 80°-83° C.
Reaction SMILES: [Li]CCCC.N12CCN(CC1)CC2.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=1.CON(C)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[Cl:14][C:15]1[C:20]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Clc1cccc(Cl)n1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(Cl)nc1Cl
Reaction time: 1 h
Yield: 14.4 %

Procedure:
n-BuLi (1.6 M in hexane, 13.94 mL, 22.298 mmol) was added dropwise to a cooled (−78° C.) solution of 1,4-diazabicyclo[2.2.2]octane (2.501 g, 22.298 mmol) in dry THF (40 mL) and stirred for 1 h. 2,6-Dichloropyridine (3.684 g, 20.272 mmol) was added portionwise to the reaction mixture while the color of the reaction mixture turned to pale pink. Stirring was continued for 1 h at −78° C. N-methoxy-N-methylbenzamide (3.0 g, 22.298 mmol) in dry THF (10 mL) was added to the reaction mixture dropwise (color changes to orange then slowly to yellow) and stirring was continued for 1 h. After completion of the reaction, the reaction mixture was concentrated and diluted with diethyl ether. The organic layer was washed with water, followed by brine and dried over Na2SO4. Concentration of the organic layer furnished the crude product as a pale yellow oil. The crude compound was purified by column chromatography (3% EtOAc in hexane) to yield the title compound as a colorless solid (0.736 g, 16.1%). [1H-NMR (CDCl3, 300 MHz) δ 7.84-7.76 (m, 2H), 7.74-7.63 (m, 2H), 7.58-7.48 (m, 2H), 7.422 (d, 1H); HPLCA Rt=4.851 min. (94%); LCMS RtA=0.471 min; [M+H]+=251.9]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:52])[C@@H:33]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH2:11]1.C(N(CC)CC)C.[C:60]1([CH2:66][S:67](Cl)(=[O:69])=[O:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:66]([S:67]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:52])[C@H:33]([CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:47][C:48]([O:50][CH3:51])=[O:49])[O:12][CH2:11]1)(=[O:69])=[O:68])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CCc2ccccc2N)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CCc2ccccc2NS(=O)(=O)Cc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To tert-Butyl(2R,5R)-5-[2-(2-aminophenyl)ethyl]-2-{2-[2-({(2S)-2-[(methoxycarbonyl)amino]-3,3-diphenylpropanoyl}amino)phenyl]ethyl}morpholine-4-carboxylate (1.0 equiv) in CH2Cl2 (0.1 M) were added triethylamine (3 eq) and phenylmethanesulfonyl chloride (1.5 eq). The reaction was stirred at room temperature for 18 h and ethyl acetate and saturated sodium bicarbonate were added. Aqueous layer was extracted twice with ethyl acetate and combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified using automated silica-gel flash chromatography using a solvent gradient of 20% to 100% of ethyl acetate and hexanes to afford tert-butyl (2R,5R)-5-(2-{2-[(benzylsulfonyl)amino]phenyl}ethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate which was treated with TFA by following procedure described in step 12 of Example 1 to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH:40]1[C:45](=[O:49])[NH:46][O:47][CH3:48])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:30])([F:29])[F:31])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][CH:40]1[C:45](=[O:49])[NH:46][O:47][CH3:48])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CONC(=O)C1CNCCN1C(=O)OC(C)(C)C
Product: CONC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([S:13]([NH:16][C:17](=[O:30])[NH:18][C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=3)(=[O:15])=[O:14])=[CH:10][C:11]=1[CH3:12])(=O)C.[Li+].[OH-]>>[OH:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([S:13]([NH:16][C:17](=[O:30])[NH:18][C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=3)(=[O:15])=[O:14])=[CH:10][C:11]=1[CH3:12]
Reactant: COc1ccc2nc(NC(=O)NS(=O)(=O)c3cc(C)c(CCOC(C)=O)s3)sc2n1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc2nc(NC(=O)NS(=O)(=O)c3cc(C)c(CCO)s3)sc2n1

Procedure:
2-[5-({[(5-Methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)carbamoyl]amino}sulfonyl)-3-methyl-2-thienyl]ethyl acetate (235 mg, 0.5 mmol, 1 equiv.) was saponified by addition of 1N LiOH (1 mL, 1 mmol, 2 equiv.) for 60 min. The solution was purified by chromatography on a HPLC 75×30 mm RP18 5 μm column, with A=0.1% HCOOH and B=MeCN and with a gradient of 20% to 70% B in 10 min. The corresponding fractions were lyophilized to give 5-(2-hydroxyethyl)-N-[(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)carbamoyl]-4-methylthiophene-2-sulfonamide, 47 mg, m/e 427.0 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1)[CH2:5][CH2:6][S:7]([CH3:10])(=O)=O.[CH2:25]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([S:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C@H:32]1[CH2:44][NH2:45])=[O:30])[CH:26]=[CH2:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:25]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([S:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][C@H:32]1[CH2:44][NH:45][S:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12](=[O:23])[NH:11][C@H:4]([C:3]([O:2][CH3:1])=[O:24])[CH2:5][CH2:6][S:7][CH3:10])[CH:14]=1)(=[O:21])=[O:20])=[O:30])[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CN
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNS(=O)(=O)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 15(a) (1.53 g. 4.18 mmol) in CH2Cl2 (20 mL) was added to a stirred solution of (2S,4S)-2-aminomethyl-4-BOCsulfanyl-pyrollidine-1-carboxylic acid allyl ester (15(b)) (prepared as described in International Patent Application WO 92/17480. see pages 39-41) (1.32 g. 4.18 mmol) and (iPr)2NEt (1.5 mL. 9.0 mmol) in CH2Cl2 (30 mL) at 0° C. under argon. The resulting solution was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then washed with water (100 mL), dried over MgSO4, filtered and concentrated to a viscous white gum. This was then purified by flash chromatography on 9385 SiO2. eluting with a gradient of 35-50% EtOAc/i-Hexane to give (2S,4S)-4-BOCsulfanyl-2-{[3-([1S]-1-methoxycarbonyl-3-methylsulfanyl-propylcarbamoyl)-benzenesulfonylamino]-methyl }-pyrrolidine-1-carboxylic acid allyl ester (15(c)) as a colourless foam: 2.19 g (81.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:32])[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=2)=[O:17])[C:11](=[O:33])[CH:10]=1.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:32])[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:30][CH:31]=2)=[O:17])[C:11](=[O:33])[CH:10]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
96 mg (0.18 mmol) of tert-butyl 4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 2.10C) were hydrolysed with TFA according to General Method 2. Yield: 69 mg (82% of theory)
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10](=O)[CH3:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br.[CH2:14]([S:20][C:21](=[NH:23])[NH2:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:14]([S:20][C:21]1[N:23]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:9]=[C:10]([CH3:11])[N:22]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)C#CCN1CCOCC1
Reactant: CCCCCCSC(=N)N
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCSc1nc(C)cc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Morpholin-4-yl-pent-3-yn-2-one (1 g, 6 mmol) and 2-hexyl-isothiourea hydrobromide (1.06 g, 7 mmol) were dissolved under nitrogen in DMF (10 mL), then N,N-diisopropyl ethylamine (4.1 mL, 24 mmol) was added and stirring at the room temperature continued for 18 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:17][CH2:16]2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (4 g, 17.4 mmol) in DMF (80 mL), cooled at 0° C. with an ice bath, was added 60% NaH in mineral oil (0.918 g, 38.3 mmol) and the reaction mixture was stirred at 0° C. for 15 min. Then, a solution of 1,2-dibromoethane (3.27 g, 17.4 mmol) in DMF (16 mL) was added at 0° C. After the addition, the mixture was stirred at room temperature for 1 h. Two other portions of 60% NaH in mineral oil (2×0.2 g) were added sequentially, until conversion was complete. Then, the reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (3×125 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (4.764 g, 99%) as a brown oil, which was used with no further purification. MS: 256.0 and 258.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30]O)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58]>CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][Br:58])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A 100 mL round bottomed flask was charged with 3-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (1.0 g, 2.29 mmol), anhydrous THF (25 mL), and then triphenylphosphine (1.20 g, 4.57 mmol) and CBr4 (1.52 g, 4.57 mmol). The yellow mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 h and was poured into EtOAc (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified using radial chromatography (EtOAc:hexanes 15:85 to 25:75) to give a colorless oil (0.95 g, 83%). MS (ES) m/e 501 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[Br-].[O:14]1[CH2:19][CH2:18]C[O:16][CH:15]1[CH:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:21].[Li]CCCC>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:21][CH2:20][CH:15]2[O:14][CH2:19][CH2:18][O:16]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C1OCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=CCC2OCCO2)cc1
Yield: 50.3 %

Procedure:
The olefin was prepared from 4.3 g (26.2 mmol) of the aldehyde 167, 13.94 g of [1-(1,3-dioxan-2-yl)ethyl]triphenylphosphoniumbromide and 12.6 mL (32.0 mmol) of n-BuLi in 75 mL of THF as described for the synthesis of 156 in Example 8. Flash chromatography (elution with 10% ethyl acetate in hexane) gave 3.27 g of the olefin 168. 1H NMR consistent with the product.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18]([O:20]CC)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:23].C1COCC1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([OH:20])=[O:19])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:23]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a mixture of ethyl 4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (108.9 mg, 0.342 mmol) in a mixture of MeOH (2 mL)/THF (2 mL) at r.t. under N2 was added sodium hydroxide (1.0 mL, 1.0 mmol) (1 M aq.). The mixture was stirred at 100° C. for 1.5 hours. The mixture was cooled to r.t., added with 1.5 ml 1N HCl, and then added 10 ml H2O. The white precipitates were filtered and washed with 3×2 ml H2O and dried (73 mg). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, 2H), 7.25 (t overlapping with dd, 2H), 7.24 (dd, 1H), 7.02 (t, J=8.39, 1H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=291.01, HPLC Rt=1.478 min.