Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.Br[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[F:38][CH:36]([F:37])[O:35][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:2])=[O:39])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-c2ncccn2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.10 g), 2-bromopyrimidine (0.076 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (0.016 g), 1,4-dioxane (2.0 mL) and 2.0M aqueous cesium carbonate solution (0.38 mL) was heated by microwave irradiation at 90 to 130° C. for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in tetrahydrofuran (5.0 mL) and 1.0M aqueous lithium hydroxide solution (0.38 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 0.1M aqueous hydrochloric acid solution and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.021 g).
Reaction SMILES: C(N(CC)CC)C.S(O)(O)(=O)=O.[CH:13]1[C:29]2[CH2:28][C@H:27]3[N:30]([CH2:32][CH2:33][C@@:19]45[C@H:26]3[CH:25]=[CH:24][C@H:22]([OH:23])[C@@H:20]4[O:21][C:17]([C:18]=25)=[C:15]([OH:16])[CH:14]=1)[CH3:31].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1.CC[OH:43].O>CN(C=O)C>[CH:13]1[C:29]2[CH2:28][C@H:27]3[N:30]([CH2:32][CH2:33][C@@:19]45[C@H:26]3[CH:25]=[CH:24][C@H:22]([OH:23])[C@@H:20]4[O:21][C:17]([C:18]=25)=[C:15]([OH:16])[CH:14]=1)[CH3:31].[C:34]([O-:39])(=[O:40])[CH2:35][CH2:36][C:37]([O-:43])=[O:38]
Reactant: CCO
Reactant: O=C1CCC(=O)O1
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])CCC(=O)[O-]
Reaction time: 36 h

Procedure:
Triethylamine (9.584 ml, 69.45 mmol) was added dropwise to a suspension of morphine sulphate (9.286 g, 27.78 mmol) in dry DMF (140 ml) at 0° C. under nitrogen. After stirring for ten minutes, succinic anhydride (2.781 g, 27.78 mmol) was added portionwise to the reaction. The reaction was monitored by TLC (50% EtOH/H2O) and by analytical HPLC (RtI of Mor-Suc was 5.06'). The reaction was complete in 24 to 48 h and the product precipitated out. The precipitate was filtered and washed with a small volume of cold DMF and THF. Both 1H NMR and HPLC indicated that the product was of sufficient purity for the next reaction (Mor-Suc 6.11 g; 57% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])(=[O:12])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)OCCCCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.5 %

Procedure:
A mixture of 1.22 g (10 mmol) of 3-hydroxybenzaldehyde, 2.3 g (11 mmol) of 5-bromopentyl acetate, 3.82 g (27.7 mmol) of anhydrous, granular potassium carbonate, and 25 mL of dimethyl sulfoxide was stirred at room temperature for 20 hr. The resulting brown slurry was diluted with ether and washed with water and saturated brine. Completion of the usual work-up gave 2.59 g (100%) of 3-[[5-(acetyloxy)pentyl]oxy]benzaldehyde as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:30])[C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N:15]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][C:9]=1[CH3:29].CC([O-])=O.[Na+].Cl.NO>CO>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:30])[C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([NH2:15])=[CH:10][C:9]=1[CH3:29]
Reactant: Cc1cncc(C)c1-c1c(C)cc(N=C(c2ccccc2)c2ccccc2)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: Cc1cncc(C)c1-c1c(C)cc(N)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To a solution of 9 (0.36 g, 0.93 mmol) in anhydrous MeOH (10 mL) at room temperature was added with stirring NaOAc (0.197 g, 2.40 mmol) and hydroxylamine hydrochloride (0.125 g, 1.80 mmol). The reaction mixture was then stirred at room temperature for 1.5 h. The resulting solution was next partitioned between an aqueous 0.1 M NaOH solution (50 mL) and CH2Cl2 (50 mL×3). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was next purified by flash chromatography on silica gel, eluting with ethyl acetate, to give 0.207 g (99.0%) of the title compound as yellow solid: mp 134-135° C.; 1H NMR (400 MHz, CD2Cl2): δ 8.311 (s, 2H), 6.482 (s, 2H), 1.903 (s, 6H), 1.769 (s, 6H); 13C NMR (100 MHz, CD2Cl2): δ 149.130, 148.547, 146.482, 135.882, 132.333, 127.592, 114.635, 19.979, 16.876; MS (ESI): m/z 227.5 [(M+H)+, 100]; Anal. Calcd. for C15H18N2: C, 79.61; H, 8.02; N, 12.38. Found; C, 79.26; H, 7.91; N, 12.04.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])[C:8](=[N+:14]=[N-:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(P(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])/[C:8](=[N:14]/[NH2:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1sccc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)/C(=N\N)C(=O)c1sccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(3-chloro-2-thienyl)-2-diazo-3-oxopropanoate (662 mg, 2.56 mmol) was dissolved in dioxane (10 mL), treated with tri-n-butylphosphine (0.663 mL, 2.69 mmol, 1.05 equiv) and stirred at ambient temperature for 30 minutes. The mixture was poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>CN(C)C=O.O>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CN(C)C(=O)CCCCl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 16 %

Procedure:
A mixture of 6.1 g (0.020 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 3.7 g (0.025 mole) of 4-chloro-N,N-dimethylbutanamide, 8.5 g (0.080 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 mL of N,N-dimethylformamide was heated on a steam bath for 16 h. The mixture was poured into 1.5 L of water and extracted thrice with 500 mL portions of ethyl acetate. The ethyl acetate fractions were combined, washed with water and brine, dried (MgSO4), and concentrated under reduced pressure to give a viscous oil. The oil was purified by column chromatography using 300 g of silica gel on a 65 cm×4 cm column, eluted with methanol-methylene chloride (1:15). Fractions containing the desired product were combined and concentrated under reduced pressure to give a viscous oil. The oil was converted to the oxalic acid salt and the solid was recrystallized from 2-propanol/ethyl acetate to yield 1.6 g (16%) of the title compound as a white solid, mp 156°-158° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].N[C@H](C(O)=O)CCCCN.N[C@@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCSC.N[C@@H](C(O)=O)CCSC.N[C@@H](C(O)=O)[C@@H](CC)C.N[C@H](C(O)=O)CCCN>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: N=C(N)NCCC[C@@H](N)C(=O)O
Agent: CC[C@@H](C)[C@@H](N)C(=O)O
Agent: CSCC[C@@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: N=C(N)NCCC[C@H](N)C(=O)O

Procedure:
D-Arg, Lys, D-Lys, homo-Arg, D-homo-Arg, Met, Me, D-Met, D-Ile, Orn, D-Om
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.O>[N+:16]([C:13]1[CH:14]=[CH:15][C:2]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]([CH:12]=1)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)([O-:18])=[O:17]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(COC2CCCCO2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(COC2CCCCO2)c1
Temperature: 120 °C
Yield: 89.8 %

Procedure:
A mixture of 394B (125 mg, 0.49 mmol), phenol (55 mg, 0.59 mmol) and t-BuOK (65 mg, 0.58 mmol) in toluene (1 ml) was heated at 120° C. for 2 h. and then diluted with water, extracted with EtOAc, dried and concentrated to give 394C (145 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([N+]([O-])=O)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([OH:40])[CH2:38][OH:39]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([O:39][CH2:38][CH2:37][OH:40])=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: OCCOc1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A slurry of 198 mg (0.50 mmol) 2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine (synthesis see example 6) in 1 ml ethane-1,2-diol was treated with 326 mg (1.00 mmol) cesium carbonate. The resulting slurry was stirred at 80° C. for two days. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was filtered off, washed with water and chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isoquinolin-8-yloxy}-ethanol as colourless crystals; HPLC/MS: 1.53 min, [M+H] 412.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
Methyl 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate (850 mg) was dissolved in a mixed solvent of ethanol (3.29 mL)/tetrahydrofuran (3.29 mL), 1N aqueous sodium hydroxide solution (3.29 mL) was added, and the mixture was stirred at room temperature for 20 hrs. 1N Hydrochloric acid (3.29 mL) was added to the reaction mixture and the mixture was diluted with water (20 mL). The precipitated crystals were collected by filtration, washed with water (10 mL), and dried under reduced pressure to give the title compound (738 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:45]=[CH:44][C:8]([CH2:9][N:10]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]3[C:19]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[N:20][CH:21]=[C:22]([CH:25]=3)[CH:23]=[O:24])[N:12]=2)=[CH:7][CH:6]=1.[Cl-].[NH4+].O>CO.C(Cl)Cl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:45][CH:44]=2)[C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]3[CH:25]=[C:22]([CH2:23][OH:24])[CH:21]=[N:20][C:19]=3[NH:26][C:27]3[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[N:12]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CO)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
Sodium borohydride (103 mg, 2.72 mmol) was added to a suspension of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 144, step 1) (522.8 mg, 0.905 mmol) in a mixture of methanol (5.0 mL) and DCM (5.0 mL) at 0° C. The resulting solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. and stir for 45 min. Saturated aqueous ammonium chloride (10 mL) and water (20 mL) were subsequently added, and the resulting mixture was extracted with DCM (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methanol (504.5 mg, 0.870 mmol, 96% yield) as a yellow-orange solid. m/z (ESI, +ve ion) 580.2 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C([Li])CCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[Cl:7][C:4]1[S:3][C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: Clc1ccc(Br)s1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)s1
Temperature: -80 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A stirred solution of 5.1 mL (0.046 mole) of 2-bromo-5-chlorothiophene in 200 mL of tetrahydrofuran was cooled to -85° C., and 19.7 mL (0.049 mole) of n-butyllithium (0.049 mole--2.5M in hexanes) was added dropwise during a 15 minute period. The reaction mixture temperature was maintained at -85° C. to -80° C. throughout the addition. Upon completion of addition, the reaction mixture temperature was maintained at about -80° C. for one hour. After this time, a solution of 12.5 mL (0.046 mole) of tributyltin chloride in 50 mL of tetrahydrofuran was added to the cold reaction mixture during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at -80° C. for one hour, then it was allowed to warm gradually to ambient temperature. The reaction was quenched with an aqueous solution saturated with ammonium chloride, and then the reaction mixture was extracted with three 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 18.4 grams of (5-chlorothien-2-yl)tributyl tin. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([Mg]Cl)CCC.[Li]CCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1.C[O:28][B:29](OC)[O:30]C>C1(C)C=CC=CC=1.CCCCCCC.C1COCC1>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([B:29]([OH:30])[OH:28])=[CH:14][CH:15]=1)#[N:26]
Reactant: N#Cc1ccccc1-c1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: N#Cc1ccccc1-c1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
Dry THF (4 mL) is cooled to at −3° C. under nitrogen. BuMgCl (0.6 mL, 1.2 mmol, 2M in THF) is added. n-BuLi (1.5 mL, 2.4 mmol, 1.6 M in hexanes) is then added dropwise over 20 min at −3° C. to 0° C. After the addition, the solution is stirred at 0° C. for 45 min. The solution is cooled to −45° C. and treated dropwise over 20 min at −45 to −40° C. with a solution of 2-(4-bromophenyl)benzenecarbonitrile (0.5 g, 1.9 mmol) in a total of 4 mL THF. The resulting yellowish-orange solution is allowed to warm to −25° C. over 1 h. After 1 h, the solution is cooled to −73° C. Trimethylborate (0.43 mL, 3.87 mmol) is added dropwise over 15 min at −73° C. The solution is stirred 1 h at −73° C. The reaction is allowed to warm to −63° C. The reaction is quenched with 5 mL of 1N HCl and allowed to warm to 0° C. with stirring. The mixture is extracted with 10 mL ethyl acetate. The organic solution is shaken with brine, dried (Na2SO4).and concentrated to obtain 0.435 g of crude product. This in 5 mL of 1:1 toluene/heptane is heated to 95° C. with stirring for 10 min. Upon cooling to rt and then to 10° C., the solid is collected by filtration and rinsed three times 1:1 toluene/heptane. The solid is vacuum-dried to provide title compound (0.232 g, 95.65% HPLC, Hitachi 7000 series, SB phenyl column, 218 nm, 65% MeCN/35% water with 0.05% TFA, 1 mL/min).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCc2ccccc2C1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.36 mL (10.87 mmol) of 1,2,3,4-tetrahydroisoquinoline. Yield: 1.4 g (77% of theory); C18H20N2O4 (M=328.36); calc.: molecular ion peak (M+H)+: 329; found: molecular ion peak (M+H)+: 329; Rf value: 0.7 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:45][N:46]([CH3:63])[NH:47][C:48]([C:50]1([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([N:53]1[CH2:54][CH2:55][C:50]([CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:48]([NH:47][N:46]([CH3:63])[CH3:45])=[O:49])[CH2:51][CH2:52]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-(1H-indole-3-yl)propionic acid (0.37 g, 1.2 mmol) in methylene chloride (15 ml) and dimethylformamid (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.16 mg, 1.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 9, 1.20 mmol) and the mixture was stirred for 30 min. Then 4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide (0.26g, 1.0 mmol) and diisopropylethylamine (0.69 ml, 4.0 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chloride/(10% ammonia in methanol) (9:1) to give 0.43 g of (2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indole-3-ylmethyl)-2-oxoethyl)carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2,2-dimethyl-propan-1-one was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with pivaloyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.98-2.03 (m, 4H), 3.06-3.14 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.40-4.46 (m, 2H), 5.09-5.15 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.39 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=458.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[CH2:20]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CN
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-aminomethyl-5-[(Z) -6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (13 mg) in pyridine (0.3 ml) was added benzyl isocyanate (0.02 ml) and the mixture was stirred at room temperature for 60 minutes. Water (0.1 ml) was added and the solvent was evaporated in vacuo to give (2R,4R,5S)-4-(3-benzylureidomethyl)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane as a residue. The residue was dissolved in methanol (1.5 ml) and added 0.3 ml of 1N aqueous sodium hydroxide and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and the crude product was purified with preparative TLC (ethyl acetate as an eluent) to give (2R,4R,5S)-4-(3 -benzylureidomethyl)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-1,3-dioxane (20 mg).