Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: OCc1ccnc(Cl)c1
Agent: [Na+]
Product: COc1cc(CO)ccn1
Temperature: 25 °C
Yield: 60 %

Procedure:
(2-Chloro-pyridin-4-yl)-methanol (2.82 g, 19.67 mmol) was refluxed with 25 wt. % sodium methoxide (25 ml) solution for 24 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexane (1:1)) to afford 1.8 g (60%) of (2-Methoxy-pyridin-4-yl)-methanol as a pale brown oil. 1H NMR (200 MHz, CDCl3) δ 2.16 (3H, s), 2.21 (3H, s), 5.13 (2H, s), 6.99 (1H, d, J=5.6 Hz), 8.11 (1H, br. s), 8.12 (1H, s), 8.23 (1H, d, J=5.6 Hz).
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>ClCCl>[F:25][CH:2]([F:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:35])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: COCCc1noc(C2CNCC(c3ccc(CC(F)F)cc3)C2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 36.3 mg (0.061 mmol, purity 70%) of the compound from Example 61A in dichloromethane (2.0 ml) was admixed with 0.03 ml (21.6 mg, 0.21 mmol) of triethylamine and then 12.3 mg (0.061 mmol) of 4-nitrophenyl chloroformate were added at RT. The mixture was stirred at RT for 2 h and then the reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 56.2 mg (91% of theory, purity 60%)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[OH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[N+:10]([O-:12])=[O:11])[C:5]#[N:6])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Nc1ccc(CCO)cc1
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-chloro-4-nitrobenzonitrile (Tsuji, K. Chem. Pharm. Bull. 1992, 40, 2399) and 4-aminophenylethyl alcohol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[CH:16]=1.C([Li])CCC.[CH3:22][S:23]SC>CCOCC>[CH3:22][S:23][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[CH:16]=1
Reactant: Brc1ccccc1-c1cn2ccccc2n1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1ccccc1-c1cn2ccccc2n1
Temperature: 25 °C

Procedure:
The product of step (a) above (546 mg) was dissolved in dry ether (10 ml) and stirred under a nitrogen atmosphere at -60°. A solution of n-butyl lithium (1.25 ml of 1.6 M) was added dropwise. After stirring for 5 minutes methyl disulphide (179 ml) was added dropwise and the mixture stirred for a further 45 minutes. The mixture was allowed to warm up to room temperature then quenched with water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic solution was washed with water and brine then dried and evaporated to leave the sub-title compound as a gum. MS MW 240 bp 207.
Reaction SMILES: [OH-].[NH4+:2].Cl([O-])(=O)(=O)=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:15]=4[O+]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1.O>C(O)(C)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:28])([CH3:29])[CH2:23][C:15]=4[N:2]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1
Reactant: Cc1[o+]c2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Reactant: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Yield: 50 %

Procedure:
Aqueous ammonium hydroxide solution (3 mL) was added to a suspension of 9-fluoro-3,3,6-trimethyl-1-oxo-2,3,4,7-tetrahydro-1H-5-oxonia-7-aza-benzo[c]fluorene perchlorate of Example 3b (0.72 g, 1.88 mmol) in isopropanol (2 mL). The reaction mixture was refluxed for 1 h, cooled, and water (5 mL) was added. Aqueous ammonium hydroxide solution was added to the mixture to pH 9. The precipitate was filtered off, washed with water and dried. The crude product was dissolved in acetone, and 37% aqueous hydrochloric acid (0.2 mL) was added. The precipitate was filtered off, suspended in hot water, and the mixture was basicified with ammonium hydroxide to pH 9. The product was filtered off, washed with water, dried and crystallized from toluene to give 0.26 g (50%) of colorless crystals; m.p. 244-246° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39]I)=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:46]([O:50][P:51]([O-:58])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:49])([CH3:48])[CH3:47].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39][O:58][P:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)OCCI)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 60 °C
Yield: 54.1 %

Procedure:
To a solution of chiral 2-iodoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 11, 20 mg, 0.026 mmol) in dimethyl formamide (2 mL) was added potassium di-tert-butylphosphate (Accela ChemBio, 21.8 mg, 0.088 mmol). The reaction mixture was heated at 60° C. for 6 h. The mixture was diluted with ethyl acetate, washed with water and then brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography to give chiral 2-(di-tert-butoxyphosphoryloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (12 mg, 54% yield). MS (ES+) m/z calcd. for C41H50Cl2F2N3O8PNa: [(M+Na)+]: 874. found: 874.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(Cl)Cl.[I:15]I>CC(O)=O>[I:15][C:4]1[NH:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Reactant: II
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nc(C(F)(F)F)c(I)[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 107.1 %

Procedure:
To 2-methyl-4-(trifluoromethyl)-1H-imidazole (1 g, 6.7 mmol) was added CHCl3 (4.5 mL) and AcOH (13.5 mL) followed by I2 (1.78 g, 6.99 mmol) and HIO4.2H2O (1.52 g, 6.7 mmol), and the resulting reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was then poured into ice cold 10% aqueous sodium bisulphite solution (100 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to obtain 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (1.98 g) which was used as such in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].CC(C)([O-])C.[K+].Cl.Cl[CH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH3:33]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH3:33]
Reactant: CN1CCCC1CCCl
Reactant: COc1ccccc1CCc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1CCc1ccccc1OCCC1CCCN1C
Yield: 20.2 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(2-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 23), 1.47 g of potassium t-butoxide and 1.61 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 300 mg (yield 20%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Br:13]N1C(=O)CCC1=O>Br.C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1Cl
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1Cl

Procedure:
A stirred mixture of 36.9 g of methyl o-chlorophenylacetate, 36.0 g of N-bromosuccinimide, and 2 drops of 48% hydrobromic acid in 500 ml of carbon tetrachloride is refluxed for 20 hours and then filtered through magnesium silicate. Evaporation under reduced pressure gives methyl α-bromo-o-chlorophenylacetate as a straw-colored liquid.
Reaction SMILES: COC1C=C(C)C(S(N2CCCCC2COCC(O)=O)(=O)=O)=C(C)C=1.N1(CCC2CCNCC2)CCCC1.C(=O)([O-])O.[Na+].[CH3:44][O:45][C:46]1[CH:51]=[C:50]([CH3:52])[C:49]([S:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]2[CH2:62][O:63][CH2:64][C:65]([N:67]2[CH2:72][CH2:71][CH:70]([CH2:73][CH2:74][N:75]3[CH2:79][CH2:78][CH2:77][CH2:76]3)[CH2:69][CH2:68]2)=[O:66])(=[O:55])=[O:54])=[C:48]([CH3:80])[CH:47]=1.C[Si](C)(C)[Cl:83]>ClCCl.C(C(C)=O)C.C(OCC)C>[ClH:83].[CH3:44][O:45][C:46]1[CH:51]=[C:50]([CH3:52])[C:49]([S:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]2[CH2:62][O:63][CH2:64][C:65]([N:67]2[CH2:72][CH2:71][CH:70]([CH2:73][CH2:74][N:75]3[CH2:79][CH2:78][CH2:77][CH2:76]3)[CH2:69][CH2:68]2)=[O:66])(=[O:54])=[O:55])=[C:48]([CH3:80])[CH:47]=1
Reactant: C[Si](C)(C)Cl
Agent: C1CCN(CCC2CCNCC2)C1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCC(CCN3CCCC3)CC2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(2-(pyrrolidin-1-yl)ethyl)piperidine (73 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/methanol/ammonia solution (25 aq.) (400:100:5). 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone (160 mg, 0.299 mmol) was dissolved in methyl ethyl ketone (3 ml), and trimethylchlorosilane (75 μl, 0.358 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.
Reaction SMILES: [Na].Cl.CO[C:5]([C:7]1[C:8]2[C:9](CN)=[CH:10][NH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=O.C[OH:19]>>[CH2:5]1[C:7]2[C:8]([C:12](=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:10]=[N:11]1
Reactant: CO
Reactant: COC(=O)c1cccc2[nH]cc(CN)c12
Agent: Cl
Agent: [Na]
Product: O=C1C=CC=C2CN=CC=C12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium metal (19.2 g) is dissolved in absolute methanol (1 l.) with ice-water cooling. To the clear solution is added a solution of 3-(aminomethyl)indole-4-carboxylic acid methyl ester hydrochloride (102.7 g), described in Example 3, in absolute methanol (1 l.). The addition is done in portions within a few minutes. After stiring for 1.5 hr at room temperature the solution is concentrated to near dryness and ice cold water (250 ml) is added to the crystalline residue. The precipitate is collected, washed with cold water and dried to give the title compound, mp. 232°-234°C, identical to the product of Preparation A of this example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(O)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[S:21])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(=S)n(C)c(=O)[nH]2)cc1OC
Yield: 106.9 %

Procedure:
To a suspension of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (1.5 g) in dioxane (15 ml) was added phosphorus pentasulfide (1.27 g) and the mixture was refluxed for 2 hours. After being cooled, ethanol (15 ml) was added thereto, and the mixture was refluxed for 2 hours again. After being cooled, the resulting precipitates were collected by filtration and washed successively with ethanol and diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.85 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][O:15][CH3:16])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1F.CCO>CN(C=O)C.Cl>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH3:16]
Reactant: COC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-methoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 mg, 40.8 μmol) was dissolved in DMF (0.1 mL). NaH (1.5 mg, 61.1 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. Then, 2,4-dichloro-1-fluorobenzene (20.2 mg, 122 μmol) was added. The mixture was stirred at 100° C. for 1 hour, then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (12.8 mg, 99% purity). MS m/z: [M+H]+ calcd for C13H17Cl2NO2, 290.06. found 290.0.
Reaction SMILES: [C:1]1([S:17]([O-:20])(=[O:19])=[O:18])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na+].C1(S(O)(=O)=O)C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[Ag:42]=O>O>[C:1]1([S:17]([O-:20])(=[O:18])=[O:19])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Ag+:42]
Reactant: O=[Ag]
Agent: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)O
Agent: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: [Ag+]

Procedure:
Five parts of sodium 9,10-anthraquinone-1-sulfonate was dissolved in 400.0 parts of ion-exchanged water at 45° C. The obtained solution was, passed through a column packed with 6.9 parts of an ion-exchanged resin (DUOLITE C20) to obtain a solution containing 9,10-anthraquinone-1-sulfonic acid. To the obtained solution, 2.0 parts' of silver oxide was added and the resultant mixture was stirred over night. The mixture was filtrated to obtain 3.9 parts of silver 9,10-anthraquinone-1-sulfonate.
Reaction SMILES: NN=CC1C=C(C(NCC2C=CC(CCC(OCC)=O)=CC=2)=O)C=CC=1.[NH2:27][N:28]=[CH:29][C:30]1[CH:31]=[C:32]([C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])=[CH:41][CH:40]=2)=[O:37])[CH:33]=[CH:34][CH:35]=1>>[NH2:27][N:28]=[CH:29][C:30]1[CH:31]=[C:32]([C:36]([NH:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[CH:43][CH:44]=2)=[O:37])[CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2cccc(C=NN)c2)cc1
Agent: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C=NN)c2)cc1
Product: NN=Cc1cccc(C(=O)Nc2ccc(CCC(=O)O)cc2)c1

Procedure:
The above compound was synthesized under conditions similar to the conditions described in Example 19 replacing the compound of Example 15 with the compound of Example 17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][OH:13]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:13][CH3:12])=[N:6][CH:7]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a vial are introduced 1 ml of MeOH and 50.8 mg (2.21 mmol) of Na. After dissolution of the metal, the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 500 mg, 2.11 mmol) in MeOH (2 ml). The reaction mixture is stirred for 1 h at 0° C. and for 15 h at rt, then concentrated and quenched with water. The precipitate was filtered, washed with water (2×) and dried under vacuum to give the title compound as a pale yellow solid (HPLC: tR 3.06 min (Method A).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:40]([NH:42][CH2:43][CH2:44][O:45][C@H:46]1[O:65][C@H:64]([CH2:66][O:67][C@H:68]2[O:76][C@H:75]([CH2:77][OH:78])[C@@H:73]([OH:74])[C@H:71]([OH:72])[C@@H:69]2[OH:70])[C@@H:62]([OH:63])[C@H:49]([O:50][C@H:51]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:56]([OH:57])[C@H:54]([OH:55])[C@@H:52]2[OH:53])[C@@H:47]1[OH:48])=[O:41])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][O:28][C@@H:29]1[O:37][C@@H:36]([CH3:38])[C@@H:34]([OH:35])[C@@H:32]([OH:33])[C@@H:30]1[OH:31])=[O:24])=O)C1C=CC=CC=1>O.[Pd]>[NH2:11][C@H:12]([C:40]([NH:42][CH2:43][CH2:44][O:45][C@H:46]1[O:65][C@H:64]([CH2:66][O:67][C@H:68]2[O:76][C@H:75]([CH2:77][OH:78])[C@@H:73]([OH:74])[C@H:71]([OH:72])[C@@H:69]2[OH:70])[C@@H:62]([OH:63])[C@H:49]([O:50][C@H:51]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:56]([OH:57])[C@H:54]([OH:55])[C@@H:52]2[OH:53])[C@@H:47]1[OH:48])=[O:41])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][O:28][C@@H:29]1[O:37][C@@H:36]([CH3:38])[C@@H:34]([OH:35])[C@@H:32]([OH:33])[C@@H:30]1[OH:31])=[O:24]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](N)C(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
In a 100 mL flask, N2-[(benzyloxy)carbonyl]-N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-N-(2-{[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl]oxy}ethyl)-L-lysinamide (950 mg, 0.843 mmol) was dissolved in water (10 mL). The flask was degassed and filled with N2. To the resulting mixture was added Pd/C (10%, 179 mg, 0.169 mmol). The mixture was stirred under H2 balloon for 18 hr. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the title compound. UPLC Method B: m/e=993.326 [M+1]; Rt=1.37 min.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH3:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:30][C:29]1[S:28][C:27]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([O:40][CH3:39])[CH:46]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: COc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1
Yield: 17 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-methoxyphenyl boronic acid gave 268 as a brown solid (153 mg, 17% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.92 (s, 1H), 7.47-7.29 (m, 6H), 6.98 (d, J=7.7 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 3H), 3.12-2.95 (m, 4H), 2.47 (d, J=6.0 Hz, 2H), 1.76 (d, J=11.7 Hz, 2H), 1.30-1.17 (m, 3H). Alkyl NH2 not seen. LCMS (ES+) m/z 442 (M+1)
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][C:14]2[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH:18]=[CH:19][C:13]=2[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH2:39][C@H:40]3[O:42][CH2:41]3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH:9]1[CH2:15][C:14]2[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH:18]=[CH:19][C:13]=2[CH2:12][CH2:11][CH2:10]1)[CH2:41][C@H:40]([OH:42])[CH2:39][O:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[NH:29][CH:30]=[CH:31]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCNC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: c1cc2cc(OC[C@@H]3CO3)ccc2[nH]1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccc3[nH]ccc3c1)CCC2
Reaction time: 3 h
Yield: 53.4 %

Procedure:
Under nitrogen, to a solution of 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-butylacetamide (200 mg) and (2S)-1-(1H-indol-5-yloxy)-2,3-epoxypropane (130 mg) in dichloromethane (10 ml) was added ytterbium(III) trifluoromethanesulfonate (33 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-(1H-indol-5-yloxy)propyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide (160 mg)