Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[CH:15]>[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 250 mL sealed reaction vessel was added methyl 5-bromopyridine-2-carboxylate (5 g, 23 mmol), copper(I) iodide (0.43 g, 2.3 mmol), bis(triphenylphosphine) palladium(II) chloride (3.23 g, 4.6 mmol), and triethylamine (80 mL). The mixture was allowed to stir for approximately 10 minutes upon which 3,3-dimethylbut-1-yne (2.83 g, 34.5 mmol) was added. The tube was sealed, stirred at room temperature overnight, and heated at 60° C. for one hour. The mixture was allowed to cool, and then concentrated under vacuum to a residue. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (1:10) as eluent to give the product (4.62 g, 92%) as a tan solid which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[C:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][C:7]=1[C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:30](=[O:32])[CH3:31])[CH:35]=1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c1
Yield: 41.5 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 3-acetamidophenyl-boronic acid (15.9 mg, 0.089 mmol) as described in Example 35 part c), affording N-[2′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-3-yl]acetamide (12.0 mg, 41%). δH (360 MHz, CDCl3) 2.20 (3H, s), 7.35-7.47 (5H, m), 7.54-7.60 (2H, m), 7.84 (1H, d, J 8.4), 7.87 (1H, s), 8.56 (1H, d, J 8.8), 9.28 (1H, d, J 4.6). m/z (ES+) 426 [MH]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][CH2:4][C:5]#[CH:6].C([Li])CCC.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][CH2:4][C:5]#[C:6][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cl
Reactant: C#CCO[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CCO[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethyl(prop-2-ynyloxy)silane (15 ml) in tetrahydrofuran (100 ml) was added butyllithium (2.6 M in hexane, 38 ml) at −78° C. The resulting mixture was stirred at the same temperature for 0.5 hour, and ethyl chloroformate (10 ml) was added thereto. The resulting mixture was stirred at −78° C. for 1.5 hours, and poured into ice water. The resulting materials were extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution successively. The extract was dried over anhydrous sodium sulfate, and the solvents were evaporated in vacuo to afford ethyl 4-(trimethylsilyloxy)but-2-ynoate (16.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([O-:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[F:8][C:6]1[CH:5]=[C:4]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=S([O-])c1cc(F)cc(F)c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cc(F)cc(F)c4)ccc31)C1CCC(C2)N1
Yield: 13 %

Procedure:
Intermediate 21 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3,5-difluorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (40 mg, 13%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.17 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.44-7.50 (m, 2H), 7.34 (d, J=8.7 Hz, 1H), 6.91-6.96 (m, 1H), 5.26 (br s, 1H), 4.71 (br s, 1H), 3.62 (s, 3H), 3.39 (br s, 1H), 2.48 (d, J=16.0 Hz, 1H), 2.18-2.35 (m, 2H), 1.91-1.99 (m, 1H), 1.50-1.68 (m, 1H), 1.37 (s, 9H)
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25](=[O:39])[C@H:26]([O:35]C(=O)C)[C:27]([CH3:34])([CH3:33])[CH2:28][O:29]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]([O:12]C(=O)C)[C@H:10]1[NH:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([NH:57][C@@H:58]3[C@@H:64]([O:65]C(=O)C)[C@H:63]([O:69]C(=O)C)[C@@H:62]([CH2:73][NH:74][C:75](=[O:89])[C@H:76]([O:85]C(=O)C)[C:77]([CH3:84])([CH3:83])[CH2:78][O:79]C(=O)C)[O:61][C@:59]3([CH2:90][C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)[OH:60])=[O:56])=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)=[O:42])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25](=[O:39])[C@H:26]([OH:35])[C:27]([CH3:33])([CH3:34])[CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:11]([OH:12])[C@H:10]1[NH:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([NH:57][C@@H:58]3[C@@H:64]([OH:65])[C@H:63]([OH:69])[C@@H:62]([CH2:73][NH:74][C:75](=[O:89])[C@H:76]([OH:85])[C:77]([CH3:84])([CH3:83])[CH2:78][OH:79])[O:61][C@:59]3([CH2:90][C:91]3[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=3)[OH:60])=[O:56])=[CH:51][CH:50]=2)=[CH:47][CH:48]=1)=[O:42])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCC(C)(C)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)c2ccc(-c3ccc(C(=O)N[C@@H]4[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](CNC(=O)[C@H](OC(C)=O)C(C)(C)COC(C)=O)O[C@@]4(O)Cc4ccccc4)cc3)cc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1COCCO1
Product: CC(C)(CO)[C@@H](O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)c2ccc(-c3ccc(C(=O)N[C@@H]4[C@@H](O)[C@H](O)[C@@H](CNC(=O)[C@H](O)C(C)(C)CO)O[C@@]4(O)Cc4ccccc4)cc3)cc2)[C@@H](O)[C@@H]1O

Procedure:
Biphenyl-4,4'-dicarboxylic acid bis-[[benzyl 3,4-di-O-acetyl-6-((R)-2,4-diacetoxy-3,3-dimethyl-butyrylamino)-2,6-didesoxy-α-D-glucopyranosid-2-yl]-amide] was deacetylated as described in Ex. 11.F. and gave biphenyl-4,4'-dicarboxylic acid bis-[[benzyl 2,6-didesoxy-6-((R)-2,4-dihydroxy-3,3-dimethyl-butyrylamino)-α-D-glucopyranosid-2-yl]-amide], [α]+119.0° (c 0.2; dioxan), MS: m/z 1025.8 ([M+Na]+).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:21]([CH3:30])[N:22]=CC1C=CC=CC=1)[NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2OCCO2)[CH:11]=1)#[N:2].Cl.[NH:32]1[CH2:37][CH:36]=[CH:35][CH2:34][CH2:33]1.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:30][N:21]1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:32]3[CH2:33][CH:34]=[CH:35][CH2:36][CH2:37]3)[CH:11]=2)=[N:3][C:1]([NH2:2])=[N:22]1
Reactant: CN(N=Cc1ccccc1)C(=NC#N)NCCCOc1cccc(C2OCCO2)c1
Reactant: C1=CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CC=CCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N'-cyano-N-[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidamide (2.62 g) in tetrahydrofuran (40 ml) was stirred at room temperature for 0.5 h with 2 N hydrochloric acid (5 ml). The mixture was treated with 1,2,3,6-tetrahydropyridine (9 ml) and stirred at room temperature for a further 1 h. The mixture was treated with sodium borohydride (1.5 g), stirred at room temperature for 18 h, diluted with ethyl acetate, filtered and the filtrate evaporated in vacuo. The resulting oil was partitioned between ethyl acetate and water. The organic phase was evaporated in vacuo and the residue was purified by column chromatography on silica, using methanol. Evaporation of the eluates gave the title compound which was recrystallised from a mixture of benzene and cyclohexane (1.26 g) m.p. 102°-3°. TLC silica; methanol-ammonia 80:1; Rf 0.6.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[I-].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]2=[O:24])=[CH:10][C:9]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:15](=[O:24])[C:16]3[CH2:23][CH2:22][CH2:21][CH2:20][C:17]=3[C:18]2=[O:19])=[CH:10][C:9]=1[O:25][CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Reaction time: 5 h

Procedure:
A mixture of 1.0 g. of chloroacetonitrile, 2.2 g. of potassium iodide and 25 ml. of acetone was stirred at room temperature for 1 hour and then, 3.5 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide and 1.8 g. of potassium carbonate were added and the mixture was refluxed with stirring for 5 hours. The solvent was distilled off under a reduced pressure and 2N-HCl was added to the residue to precipitate the product. The precipitate was separated by a filtration and washed with water and dried and recrystallized from ethanol to obtain 2.7 g. of Compound No. 229 shown in Table 1.
Reaction SMILES: [F:1][CH:2]([F:9])[CH2:3][N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[CH2:10]=[O:11]>>[F:1][CH:2]([F:9])[CH2:3][N:4]1[C:8]([CH2:10][OH:11])=[N:7][CH:6]=[N:5]1
Reactant: C=O
Reactant: FC(F)Cn1cncn1
Product: OCc1ncnn1CC(F)F
Temperature: 25 °C

Procedure:
1-(2,2-Difluoroethyl)-1H-[1,2,4]triazole (4.0 g, 0.030 mol) was heated at reflux in 37% aqueous formaldehyde for 2 days. The solution was allowed to cool to room temperature and was washed with dichloromethane (3×50 ml). The solution was then saturated with sodium chloride, and washed again with dichloromethane (3×50 ml). The combined organic washings were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0 to 7.5% methanol in dichloromethane, yielding [2-(2,2-difluoroethyl)-2H-[1,2,4]triazol-3-yl]methanol as a solid (2.4 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 4.65 (2H, td, J=13.2, 4.3 Hz), 4.83 (2H, s), 6.17 (1H, tt, J=55.2,4.3 Hz), 7.86 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[CH3:14][N:15]([CH3:20])[S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClC(Cl)C>[CH3:14][N:15]([CH3:20])[S:16]([N:9]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=2[N:7]=[CH:8]1)(=[O:18])=[O:17]
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncn(S(=O)(=O)N(C)C)c2cc1OC
Yield: 86.3 %

Procedure:
A suspension of 5,6-dimethoxybenzimidazole (6.2 g) in dichloroethane (100 ml) was added to N,N-dimethylsulfamoyl chloride (5.3 g) and triethylamine (6 g) was added dropwise while stirring. After the mixture was reacted at room temperature for 24 hours, the reaction solution was washed with an aqueous sodium hydrogen carbonate solution and then with a saturated saline solution and dried over anhydrous Na2SO4. The solvent was distilled off, precipitated crystals were filtered, washed with n-hexane and dried to give the title compound (8.57 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[N:4]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na].[NH:51]1[CH:55]=[N:54][CH:53]=[N:52]1>ClCCl>[N:51]1([CH2:2][C:3]2[CH:8]=[CH:7][N:6]3[C:9]([C:12]4[CH:13]=[C:14]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:15]=[CH:16][CH:17]=4)=[CH:10][N:11]=[C:5]3[N:4]=2)[CH:55]=[N:54][CH:53]=[N:52]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3nc(CO)ccn23)c1
Agent: BrC(Br)(Br)Br
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(Cn4cncn4)ccn23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
To a solution of 3′-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)-biphenyl-2-carbonitrile (0.1 g, 0.31 mmol) in dichloromethane (5 ml) was added carbon tetrabromide (153 mg, 0.46 mmol) and triphenylphosphine (121 mg, 0.46 mmol). This mixture was stirred at ambient temperature for 6 h after which time 1,2,4-triazole sodium salt (84 mg, 0.93 mmol) was added and the reaction stirred at ambient temperature for a further 18 h. The solvent was removed in vacuo and the residue purified by silica gel chromatography eluting with dichloromethane on a gradient of methanol (0-10%). Further purification by high performance liquid chromatography gave 3′-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (15.3 mg): δH (400 MHz, DMSO) 5.76 (2H, s), 7.32 (1H, d, J 7), 7.52-7.84 (8H, m), 8.16 (2H, d, J 5), 8.73 (1H, s), 9.22 (1H, s); m/z (ES+) 378 (M++H).
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:25]([O-])=[O:26].[Na+]>O>[ClH:1].[ClH:1].[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([N+:21]2[N-:25][O:26][C:23](=[NH:24])[CH:22]=2)[CH2:17][CH2:16]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: N#CCNN1CCN(CCCCC(=O)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=c1c[n+](N2CCN(CCCCC(=O)c3ccccc3)CC2)[n-]o1
Reaction time: 1 h
Yield: 137.3 %

Procedure:
5.0 g of 4-(4-benzoylbutyl)-1-(cyanomethylamino)piperazine dihydrochloride was dissolved in 50 ml of water, and under ice cooling, a solution of 2.0 g of sodium nitrite in 20 ml of water was added dropwise. The reaction was carried out for 1 hour. The reaction mixture was extracted with chloroform. Chloroform was evaporated, and the residue was dissolved in 30 ml of methanol. Then, 30 ml of 12% ethanolic hydrochloric acid was added, and the reaction was carried out for two days at room temperature. The precipitated crystals were collected by filtration to give 3.7 g of the title compound having a melting point of 168° C. (decomp.).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13].I[CH3:15]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.O1CCCC1>[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:15]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1N
Reaction time: 8 h

Procedure:
Tetrabutylammonium iodide (0.4 g), sodium hydroxide (4.0 g) in water (40 ml) and iodomethane (3.4 ml) were added to 2-amino-3-nitrophenol (4.0 g) dissolved in tetrahydrofuran (80 ml) at ambient temperature. This mixture was stirred overnight then concentrated in vacuo. After pouring into water (200 ml) it was extracted into ethyl acetate (2×200 ml) then washed with aqueous sodium bicarbonate (100 ml) and saturated brine (100 ml). The solution was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo to afford the title compound as a dark solid (4.4 g).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([O:4][C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([OH:27])=O)[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH3:3].CN1CCCCC1.[C:36]1([CH2:42][CH2:43][CH2:44][NH2:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([NH:45][CH2:44][CH2:43][CH2:42][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:27])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH3:28]
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: 0 °C

Procedure:
The title product of Example 2 (7.4 g, 17.9 mmol) dissolved in 75 ml of CH2Cl2 was flushed with Ar and cooled to 0° C. N-methylpiperidine (NMP, 2.2 ml, 17.9 mmol) was added to the reaction before it was cooled to -78° C. and charged with 2.5 ml (17.9 mmol) of IBCF. The reaction was allowed to warm to -15°, maintained at this temperature for 15 min., cooled to -78°, and charged with 2.4 g (17.9 mmol) of 3 phenylpropyl amine (PPA). The crude product, obtained after a reaction work up by the method of Example 1, was chromatographed on a Waters prep 500 using a Porasil cartridge eluting with 2% to 3% ethanol (EtOH)/CH2Cl2. The title product was obtained as a white solid (4.54 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.[NH4+].[Cl-].CC(=O)OCC>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][C:23](=[O:26])[CH:24]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)CC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (13.5 ml, 96 mmol) in THF (300 ml) at −78° C. was added dropwise n-BuLi (2.5M in Hex, 32 ml). The mixture was warmed to −10° C. and re-cooled to −78° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10 g, 50 mmol) in THF (50 ml) was then added dropwise and the mixture stirred at −78° C. for another 15 min. A solution of tert-butyl bromoacetate (12.6 ml, 85 mmol) in THF (30 ml) and HMPT (5 ml) was then added dropwise and the mixture stirred at −78° C. for 4 h and then gradually warmed to rt. The mixture was taken up in sat. aq. NH4Cl and extracted with EA. The yield after work up and chromatography (eluent Hex/EA 4:1) was 7.6 g (50.6%; yellowish oil).
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:68][CH2:69][CH2:70][O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.[I-].[Na+]>CC(C)=O>[CH2:72]([O:71][CH2:70][CH2:69][CH2:68][N:39]1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:53]=3)=[C:45]2[C:37]([O:36][C@@H:9]2[O:10][C@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:8]2[O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[N:38]1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CCCOCc3ccccc3)c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (1 g) in acetone (10 mL) were added cesium carbonate (0.78 g), benzyl 3-bromopropyl ether (0.32 mL) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 2 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give 1-(3-benzyloxy-propyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.77 g). This material was dissolved in methanol (10 mL). To the solution was added 10% palladium-carbon powder (0.25 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/2) to give the title compound (0.54 g).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:23]=3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: Oc1ccc2ccccc2n1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc3ccccc3n1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.5 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.50 g), 2-quinolinol (621 mg), and potassium carbonate (987 mg) in DMF (15 ml) was stirred at room temperature for 12 hr. After being stirred at 60° C. for 6 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was diluted with dilsopropylether. The crystals were collected by filtration and recrystallized from hexane-ethyl acetate to obtain 2-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]quinoline (680 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][N:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=2[CH:22]=[N:21]1.N1C2C=CC=C(N)C=2C=N1>>[N:12]1([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][NH:9][C:10]([NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:23]=3[CH:22]=[N:21][N:20]4[CH3:19])=[O:11])=[CH:7][C:2]=2[F:1])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C=NCc1ccc(N2CCCCCC2)c(F)c1
Reactant: Cn1ncc2c(N)cccc21
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCCC4)c(F)c3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.03 (s, 1H), 8.19 (s, 1H), 7.67 (d, 1H), 7.24 (t, 1H), 7.12-6.95 (m, 5H), 4.22 (s, 2H), 3.99 (s, 3H), 3.35 (m, 4H), 1.78 (m, 4H), 1.55 (m, 4H); MS (ESI) (M+H)+ 396.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].N[C@@H](C(O)=O)CO.[NH2:14][C@H:15](C(O)=O)[C@@H:16]([CH3:18])O>>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH2:3][CH2:18][CH2:16][CH2:15][NH2:14]
Reactant: C[C@H](N)C(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: N[C@H](CO)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Ser: Ala, (N-methyl)Ser, D-Ser, Thr