Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:12].N1C=CC=CC=1.Cl[S:20]([C:23]1[N:31]=[C:30]2[N:25]([C:26]([O:33][CH2:34][CH3:35])=[N:27][C:28]([F:32])=[CH:29]2)[N:24]=1)(=[O:22])=[O:21]>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH:12][S:20]([C:23]1[N:31]=[C:30]2[N:25]([C:26]([O:33][CH2:34][CH3:35])=[N:27][C:28]([F:32])=[CH:29]2)[N:24]=1)(=[O:21])=[O:22]
Reactant: CCOc1nc(F)cc2nc(S(=O)(=O)Cl)nn12
Reactant: COC(=O)c1cccc(Cl)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1nc(F)cc2nc(S(=O)(=O)Nc3c(Cl)cccc3C(=O)OC)nn12
Temperature: 10 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
The same product was obtained in a similar fashion using the N-(2-chloro-6-methoxycarbonylphenyl)-S,S-tetramethylenesulfilimine product mixture of Example 4 as the catalyst. A 9 mL portion of that product was diluted with 75 mL of dichloromethane, the solution was cooled to 10° C., and 9.3 g (50 mmol) of methyl 3-chloroanthranilate and then 4.8 g (60 mmol) of pyridine were added with cooling and stirring. 2-Chlorosulfonyl-7-fluoro-5-ethoxy[1,2,4]triazolo[1,5-c]pyrimidine (15.5 g of 91 percent pure, 50 mmol) was added with cooling to 0-2° C. The reaction was complete in 6 hours and a 90 percent yield of 98 percent purity title compound was obtained on recovery.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13](=[O:15])[CH3:14])[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:23][Mg+].[Br-].O>C1COCC1>[OH:15][C:13]([CH3:23])([CH3:14])[CH:11]([N:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[C:2]1[CH3:1])[CH3:12]
Reactant: C[Mg+]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(C)(C)O
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
To a solution of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H pyrrolo[2,3-b]pyridine-3-carboxylate (0.6 g, 2 mmol) in THF (10 mL) were added CH3MgBr (2 mL, 6 mmol) at −78° C. The mixture was stirred at −78° C. for 3 hr. Water (4 mL) was added and the mixture was extracted by ethyl acetate (30 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The crude product was concentrated and purified by pre-TLC (eluted: petroleum ether/ethyl acetate=4/1) to give tert-butyl 1-(3-hydroxy-3-methylbutan-2yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300 mg, 49%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]#[C:22][C:23]3([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH2:22][C:23]3([OH:28])[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:15][CH:16]=2)[C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccc(C#CC3(O)CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(CCC3(O)CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-(1-hydroxycyclopentyl)ethyl)-3-methylnaphthalen-2-yl)acetic acid (91) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.58 (s, 1H), 7.51 (m, 2H), 7.29 (m, 2H), 7.07 (s, 1H), 5.05 (s, 1H), 2.70 (m, 2H), 2.62 (s, 3H), 1.75 (m, 4H), 1.61 (m, 6H), 0.94 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 4.0 min run): tR (min)=3.69.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.CCOC(C)=O>C(O)C.[Pd]>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]2[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccc2sc3ccccc3c12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Methyl-2-nitrodibenzothiophene (Method 11; 0.855 g, 3.52 mmol) was stirred in ethanol (50 ml) and EtOAc (50 ml) under an argon atmosphere. 10% Palladium on carbon (0.09 g) was added to the solution and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 h. The mixture was filtered through diatomaceous earth and washed with EtOAc before the filtrate was evaporated in vacuo. The crude product was purified by flash chromatography eluting with 50% DCM/iso-hexane-DCM. Evaporation of the appropriate fractions left the product as a colourless solid. NMR: 8.39 (m, 1H), 7.92 (m, 1H), 7.50 (m,1H), 7.42 (m, 2H), 6.92 (d, 1H), 4.98 (brs, 2H), 2.60 (s, 3H); m/z 215.
Reaction SMILES: [Cl:1]/[C:2](/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[CH:3]\[CH2:4]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6](/[C:2](/[Cl:1])=[CH:3]/[CH2:4][Cl:15])=[CH:7][CH:8]=1
Reactant: OC/C=C(\Cl)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: ClC/C=C(\Cl)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (Z)-3-chloro-3-(4-chloro-phenyl)-prop-2-en-1-ol (101 mg) in toluene (3 ml) was added thionyl chloride (0.11 ml) and one drop of dimethylformamide. After 1 h, the solution was concentrated in vacuo to afford 120 mg of the desired allylic chloride (100%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:23]([C:26]1[O:30][C:29]([C:31]2[C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:32]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCOCC1.N1C=CC=CC=1>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([O:38][C:36]([C:35]3[C:31]([C:29]4[O:30][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)=[N:32][N:33]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:34]=3)=[O:37])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(OC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1

Procedure:
Add a solution of 0.64 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride dropwise to a warm solution of 0.60 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid in 10 ml of dioxane and 0.48 ml of pyridine at 40° C. Stir the resulting reaction mixture at from 45° to 50° C for 6 hours. Draw off the formed precipitate and recrystallize it from dimethylformamide to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid anhydride [m.p. 262° to 264° C].
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[N:20][CH:21]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-{[4-(2-{[5-(4-Fluorophenyl)pyridin-2-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester obtained in Example 100-2 was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1 to 2:1) to give the title compound (201 mg) as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N:1]1[C:21]([NH2:22])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=[N:2]1
Reactant: COc1ccc(CC#N)cc1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3ccc(F)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-fluoro-benzene (0.300 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.309 g, 1.2 eq) in ethanol (5 ml) kept under nitrogen, a solution of sodium methoxide (0.142 g, 1.5 eq) in ethanol (5 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (20 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (˜0.500 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 20% ethylacetate in hexane, to afford the title compound as a white solid (0.190 g, 34% yield). M.p. 136.3-141.2° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:21](=[O:22])[CH2:20][CH2:19][C:18]3=[O:23])[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:21](=[O:22])[CH2:20][CH2:19][C:18]3=[O:23])[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Product: Nc1cccnc1Nc1cccc(N2C(=O)CCC2=O)c1
Yield: 92.1 %

Procedure:
The solution of 3-nitro-2-(3-succinimidophenylamino)pyridine (3.47 g) was hydrogenated with palladium on carbon (0.5 g) at 3 atm for 5 hours. The mixture was filtrated and evaporated to give 3-amino-2-(3-succinimidophenylamino)pyridine (2.89 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:15]=3[CH:16]=O)[S:10][C:5]=2[C:4](=[O:26])[NH:3]1.[C:28]1([CH2:34][CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.C1COCC1>[CH3:27][C:2]1([CH3:1])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[C:15]=3[CH2:16][NH:36][CH2:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:10][C:5]=2[C:4](=[O:26])[NH:3]1
Reactant: NCCc1ccccc1
Reactant: CC1(C)NC(=O)c2sc(-c3cnn(COCC[Si](C)(C)C)c3C=O)cc2N1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)NC(=O)c2sc(-c3cnn(COCC[Si](C)(C)C)c3CNCCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of 4-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-6-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbaldehyde (122 mg, 0.30 mmol), 2-phenylethanamine (0.151 mL, 1.20 mmol) and THF (5 mL) was stirred at room temperature overnight. Then, sodium borohydride (0.023 g, 0.60 mmol) and MeOH (2 mL) were added. After 30 min, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH) to afford 2,2-dimethyl-6-(5-{[(2-phenylethyl)amino]methyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (140 mg). 2,2-Dimethyl -6-(5-{[(2-phenylethyl)amino]methyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (140 mg) was dissolved with N,N,N,N-tetrabutylammonium fluoride (1.0 M in THF, 3.0 mL, 3.00 mmol) and the mixture was stirred at 60° C. overnight. The mixture was filtered, and the filtrate was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH) to afford the title compound (27.5 mg, 24%) as a colorless oil:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)\[CH3:9])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: CC(=O)c1cccc(O)c1
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: C/C(=N\OCc1ccc([N+](=O)[O-])cc1)c1cccc(O)c1
Yield: 81.6 %

Procedure:
3′-Hydroxyacetophenone (24) (150 mg, 1.10 mmol) was condensed with compound 19 (248 mg, 1.21 mmol) according to the general procedure II-A defined above. After being heated for 3 h the reaction mixture was cooled and the solvent removed under reduced pressure. The resulting solid was filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30260 (257 mg, 82%) as a white solid, m.p. 123.6-125.3° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].CN(C=O)C.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CCOC(C)=O>[Si:27]([O:1][CH2:2][CH:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)C(CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-butyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (21a) (4.4 g, 17.5 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by DMF (35 mL) and cooled to 0° C. via an ice bath. Next, TBDMSCl (2.90 g, 19.3 mmol, 1.1 equiv.) and imidazole (2.40 g, 35.1 mmol, 2.0 equiv.) were added to the reaction flask. The solution was stirred at 0° C. for 1 h and then allowed to warm to rt, stirring an additional 2 h. The reaction solution was transferred to a 500 mL separatory funnel with EtOAc (150 mL). The mixture was washed with 1% HCl (3×40 mL), sat. NaHCO3 (1×40 mL), and sat. NaCl (2×40 mL). The organic layer was separated and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 5.9 g (93%) of 22a as an oil which crystallized to a white solid upon standing. Rf=0.54 (50% EtOAc/hexanes); mp=71-72° C.; IR (film) 3437, 3324, 2953, 2929, 2884, 2856, 1715, 1666, 1496, 1471, 1365, 1253, 1171, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (br d, J=8.5 Hz, 1H, carbamate-NH), 4.73 (br s, 1H, Boc-NH—CH), 3.83 (m, 1H, CH—CH2), 3.77 (m, 1H, CH—CH2), 3.73 (s, 3H, N—OCH3), 3.19 (s, 3H, N—CH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.84 (s, 9H, Si-t-butyl-CH3), 0.00 (s, 6H, Si—(CH3)2); 13C NMR (125 MHz, CDCl3) δ 170.9, 155.5, 79.7, 63.6, 61.6, 52.6, 32.3, 28.5, 25.9, 18.4, −5.4; LRMS (ESI-MS m/z): Mass calcd for C16H34N2O5Si [M]+, 362.54. Found 363.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].N1C=CC=CC=1.P(Br)(Br)[Br:23]>C(OCC)C>[Br:23][CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC#CCC#CCC#CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC#CCC#CCC#CCBr

Procedure:
6 g of 1-hydroxy-2,5,8-tetradecatriyne prepared above, dissolved in 30 cm3 of ethyl ether, are introduced into a round-bottomed flask equipped with an argon inlet. 0.05 cm3 of pyridine is added and 1 cm3 of phosphorus tribromide is added dropwise, and the mixture is then brought to reflux for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccccc1Cl
Product: O=C(NCc1ccccc1Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 2-chloro benzylamine (45 mg, 0.32 mmol). The title compound was obtained as a solid (29 mg, 22% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.36 (1H, m), 8.98 (2H, m), 8.53 (1H, s), 7.45 (1H, m), 7.33 (3H, m), 4.46 (2H, m). MS m/z: 471.97, 473.95 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:24]1[CH:25]=[C:26]([C:41]([O:43]C)=[O:42])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[Cl:23])=[CH:7][CH:6]=1.[OH-].[Na+]>CCOCC.CCOC(C)=O>[NH2:1][CH2:2][CH:3]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=[O:42])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[Cl:23])=[CH:9][CH:10]=1
Reactant: COCCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a solution of methyl 4-(2-amino-1-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-benzyl}ethyl)-2′-(3-methoxypropyl)biphenyl-2-carboxylate (1.0 eq.; EXAMPLE 22) in THF/MeOH (1/1; 0.09M) was added aqueous sodium hydroxide (1N; 3 eq.). The mixture was stirred in a microwave (Smith Creator; Personal Chemistry),) at 120° C. for 80 min. The resulting mixture was cooled to room temperature quenched with excess acetic acid and concentrated. The residue was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH(NH3; 2M) 5% afforded the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.50 (br s, 0.5H), 7.44 (br s, 0.5H), 7.25-7.11 (m, 6H), 7.11-7.03 (m, 4H), 6.87-6.81 (m, 2H), 4.36-4.27 (m, 4H), 3.30-3.21 (m, 8H), 3.01-2.91 (m, 2H), 2.65-2.53 (m, 2H), 2.30 (s, 3H), 1.77-1.64 (m, 2H) (mixture of rotamers). LRMS ESI [M+H]; 622.2
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH:26]([CH2:28]O)[CH2:25][C:24]3=[O:30])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:31]([N:33](CC)[CH2:34][CH3:35])[CH3:32].S(Cl)(C)(=O)=O.O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH:26]([CH2:28][N:33]4[CH2:34][CH2:35][CH2:32][CH2:31]4)[CH2:25][C:24]3=[O:30])=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CO)CC4=O)cc3)CC2)c(C)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CN5CCCC5)CC4=O)cc3)CC2)c(C)c1
Temperature: 25 °C

Procedure:
1-{4-[4-(2,4-Dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-hydroxymethylpyrrolidin-2-one (150 mg) described in Example 338 was dissolved in dichloromethane (2 mL), triethylamine (0.16 mL) and mesyl chloride (0.06 mL) were added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (3 mL), pyrrolidine (0.15 mL) and potassium carbonate (51 mg) were added, and the mixture was stirred at 60° C.-70° C. for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(pyrrolidin-1-ylmethyl)pyrrolidin-2-one. The obtained 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(pyrrolidin-1-ylmethyl)pyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.1 mL) was added, and the precipitate was collected by filtration to give the title compound (112 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:2].N1C(C)=CC=CC=1C.Cl[CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:2]
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCNC(=O)c1cc(I)ccc1N
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1cc(I)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
A magnetically stirred solution of 1.1 gram of N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (3.1 mmol), prepared by the method shown in part (b) of example 1, 0.48 mL of 2,6-lutidine (4.1 mmol), 1.2 grams of chlorodiphenylmethane (4.7 mmol), and 10 mL of dimethylformamide was heated to 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting oil was dissolved in 35 mL of methylene chloride and washed with 2×50 mL 10% citric acid, 1×50 mL water, dried over sodium sulfate, decanted and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 10/90 ethyl acetate/hexane to 25/75 ethyl acetate/hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.82, υν positive) to yield 0.92 gram (56%) of N-(2-diphenylmethylamino-5-iodobenzoyl)-b-alanine ethyl ester. 1H NMR (CDCl3, dTMS) 8.40 (1H, d, 3JHH =5 Hz, NHCHAr2), 7.56 (1H, d, 3JHH =2 Hz, ArH o-CON), 7.18-7.36 (1H, m, 4JHH =2 Hz, ArH Ph, ArH p-CON), 6.73 (1H, t, 3JHH =6 Hz, NHCH2), 6.29 (1H, d, 3JHH =9 Hz, ArH m-CON), 5.52 (1H, d, 3JHH =5 Hz, CHNH), 4.15 (2H, q, 3JHH =7 Hz, OCH2), 3.61 (2H, q, 3JHH =6 Hz, CH2NH), 2.58 (2H, t, 3JHH =6 Hz, CH2CO), 1.25 (3H, t, 3JHH =6 Hz, CH3CH2O).