Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[C:12]=1[CH2:11][CH2:10][CH2:9]2)=[O:4].CN.[C:21](#[N:23])C.C>C(Cl)Cl>[CH3:21][NH:23][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[C:12]=1[CH2:11][CH2:10][CH2:9]2)=[O:4]
Reactant: O=C(Cl)c1cc(-c2cccnc2)n2c1CCC2
Reactant: CC#N
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(-c2cccnc2)n2c1CCC2
Temperature: 20 °C
Reaction time: 7 h

Procedure:
A suspension of 7-chloroformyl-5-(3-pyridyl)-2,3-dihydro-1H-pyrrolizine hydrochloride (14.1 g) in methylene chloride (250 cc) is saturated with a stream of anhydrous methylamine, while the temperature of the reaction mixture is kept at about 25° C. for 7 hours. The solution obtained is stirred at a temperature of about 20° C. for 16 hours and then methylene chloride (250 cc) and distilled water (250 cc) are added to it. The organic phase is separated, washed 3 times with distilled water (750 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. A crude product (12.2 g) melting at 184° 0 is thus obtained. This product is dissolved in boiling acetonitrile (150 cc). The solution obtained is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 1 hour. The crystals which have appeared are separated off by filtration, washed twice with acetonitrile (20 cc in total) cooled to a temperature of about 4° C. and 3 times with diethyl ether (75 cc in total), and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-methyl-5-(3-pyridyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide (7.1 g) is thus obtained in the form of cream crystals melting at 187° C.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:43])([CH:33]([O:37]C(=O)C(C)=C)[CH:34](C)C)[C:15]([O:17][CH2:18]CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=[O:16].C(=O)([O-])O.[Na+]>CO>[F:43][C:14]([F:13])([C:33]([OH:37])([CH3:34])[CH3:2])[C:15]([O:17][CH3:18])=[O:16]
Reactant: C=C(C)C(=O)OC(C(C)C)C(F)(F)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(F)(F)C(C)(C)O
Yield: 65 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 73.3 g of Intermediate 3 in Example 3 and 300 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated. The residue was distilled in vacuum, obtaining 52.0 g (yield 65%) of methyl 2,2-difluoro-3-hydroxy-3-methylbutanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=3)[O:36]2)[CH:32]=[CH:33][CH:34]=1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:41]=3)[O:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: COc1cccc(C2CC(O)c3cc(O)ccc3O2)c1
Product: COc1cccc(C2CC(O)c3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)c1

Procedure:
2-(3-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(3-methoxyphenyl)chroman-4,6-diol (Example 99(b)). 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, 9.1, 2.9 Hz), 7.34 (t, 1H, J 15.7, 7.8 Hz), 7.25 (d, 1H, J 2.4 Hz), 7.22 (d, 1H, 9.1 Hz), 7.00-7.06 (m, 3H), 6.92 (dd, 1H, J 8.8, 2.4 Hz), 6.88 (d, 1H, J 8.8 Hz), 5.64 (d, 1H, J 6.4 Hz), 5.27 (d, 1H, J 10.7 Hz), 4.95-5.00 (m, 1H), 3.79 (s, 3H), 2.30-2.35 (m, 1H), 1.92-2.01 (m, 1H).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][N:21]([CH:23]=[C:9]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])[CH3:22]
Reactant: COC(OC)N(C)C
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of dibenzoylmethane (1.072 g, 4.78 mmol) in 6 mL of toluene was added neat N,N-dimethylformamide dimethylacetal (0.7 mL, 630 mg, 5.25 mmol) dropwise via syringe. The resulting solution was stirred at rt for 1 h and then heated at reflux for 16 h. Once at rt, the reaction was concentrated in vacuo. The residue was dissolved in a minimum of CH2Cl2 and added to 13 cm of flash silica gel in a 5 cm dia. column. Elution with 1 L of 1%, 500 mL of 2% and 300 mL of 3% MeOH/CH2Cl2 gave 975 mg of the desired product as a semisolid. Trituration with 50 mL of hexanes gave 772 mg of the title compound as a light yellow solid, mp 123-124° C. (lit mp 120° C., Schenone, P. et al. J. Het. Chem. 1982,19(6), 1355-61).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(OCC)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:36]
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCOCc1cc(Br)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1COCCCCBr
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (7.03 g, 26.3 mmol) in diethyl ether (88 ml) was treated with triphenylphosphine (8.97 g, 34.2 mmol) and carbon tetrabromide (11.3 g, 34.2 mmol). The cloudy solution was stirred at ambient temperature for about 30 hours. The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by bulb to bulb distillation.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[Cl:7][CH2:8][CH2:9][NH:10][C:11](N[N+]([O-])=O)=[O:12].C(=O)([O-])O.[Na+]>C(O)C>[Cl:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[NH:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1
Reactant: Nc1nncs1
Reactant: O=C(NCCCl)N[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCl)Nc1nncs1
Yield: 71.9 %

Procedure:
Ten grams of 2-amino-1,3,4-thiadiazole, 16.6 g of 1-(2-chloroethyl)-3-nitrourea and 84 g of sodium hydrogencarbonate were stirred in 100 ml of diluted ethanol at a temperature of 80° C. for 2 hours. While being still hot after the reaction, the precipitated inorganic matters were removed by filtration, and the filtrate was cooled. The precipitated crystals were collected by filtration and washed with water, to obtain 14.7 g (Yield 71%) of 2-{3-(2-chloroethyl)ureido}-1,3,4-thiadiazole. The product was then treated in the same manner as in Example 1 (2), to obtain 2-{3-(2-chloroethyl)-3-nitrosoureido}-1,3,4-thiadiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[NH2:25][CH:26]1[CH2:29][N:28]([C:30](=[O:32])[CH3:31])[CH2:27]1>CC(O)C>[C:30]([N:28]1[CH2:29][CH:26]([NH:25][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)=[O:9])[CH:3]=2)[CH2:27]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CC(N)C1
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Solvent: CC(C)O
Product: CC(=O)N1CC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ncn2)C1
Temperature: 60 °C
Yield: 112.7 %

Procedure:
To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) pyrimi dine-4-carboxamide (240 g, 0.69 mol) in i-PrOH (2.5 L) was added 1-(3-amino azetidin-1-yl)ethanone (120 g) and TEA (100 g). After addition, the solution was heated at 60° C. for 16 h, at which time LCMS showed completion of the reaction. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 420 g, 90% purity. This crude was further purified on preparative HPLC to give the title compound (330 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.27 (s, 1H), 7.12-6.98 (m, 5H), 4.71 (s, 1H), 4.54 (m, 1H), 4.32 (m, 1H), 4.06 (m, 2H), 3.88 (m, 1H), 3.70 (s, 2H), 3.53-3.50 (m, 2H), 2.91-2.83 (m, 4H), 2.65 (m, 2H), 1.88 (s, 3H); LCMS (m/z): 425.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH:16]=[CH2:17])[O:13][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.C12BC(CCC1)CCC2.[OH-:27].[Na+].OO>O1CCCC1>[OH:27][CH2:17][CH2:16][CH:14]1[O:13][C:5]2=[C:6]3[C:11](=[C:2]([CH3:1])[CH:3]=[C:4]2[CH2:15]1)[NH:10][C:9](=[O:12])[CH:8]=[CH:7]3
Reactant: [OH-]
Reactant: C=CC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCO)C2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 72.6 %

Procedure:
5-Methyl-2,3,6,7-tetrahydro-2-vinylfuro[2,3-f]quinoline-7-one (2.17 g) was suspended in tetrahydrofuran (40 ml). 9-Borabicyclo[3.3.1]nonan (0.5 mol, tetrahydrofuran solution, 80 ml) was added thereto while cooling on ice, and the mixture was stirred for 5.5 hours. Subsequently, aqueous 3N-NaOH solution (20 ml) and aqueous 35% hydrogen peroxide (20 ml) were added to the mixture in this order, and the temperature was raised to room temperature. After stirring for 30 minutes, extraction was performed with a solvent mixture of chloroform-methanol (4:1). The organic phase was dried and condensed under reduced pressure. The residue was recrystallized from a solvent mixture of chloroform-ethyl acetate-ether to obtain 1.7 g of 2-(2-hydroxyethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as pale yellow powdery crystals (72.6%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.BrC1C([Cl:25])=C(O)C=CC=1>>[Br:1][C:2]1[C:3]([Cl:25])=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: Oc1cccc(Br)c1Cl
Reactant: Fc1c(Br)cccc1OCC1CCOCC1
Product: Clc1c(Br)cccc1OCC1CCOCC1

Procedure:
Prepared as described for 4-(3-bromo-2-fluoro-phenoxymethyl)tetrahydropyran SM25 using 3-bromo-2-chlorophenol
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][N:14]=1>C(O)C>[C:8]1([CH3:11])[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: COC(=O)c1ccc2nc(-c3ccc(C)cc3)cn2c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
2-Bromo-4′-methylacetophenone 2 (14.5 g, 65.1 mmol) was added to a hot solution of methyl 2-aminopyridine-5-carboxylate 1 (9.0 g, 61.1 mmol) in ethanol (280 ml). The solution was then heated at reflux for 6 h, cooled to room temperature and the white solid filtered and washed with ethanol to give methyl 2-(4-tolyl)-imidazo[1,2-a]pyridine-6-carboxylate 3 (13.9 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:23][CH2:22][CH2:21][Cl:20])[C:6]=2[CH:12]=1
Reactant: O=C1COc2c(F)cc(Br)cc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2c(F)cc(Br)cc2N1CCCCl
Yield: 72.1 %

Procedure:
6-Bromo-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF44) (0.091 g, 0.37 mmol), Cs2CO3 (0.180 g, 0.55 mmol) and 3-chloro-1-iodopropane (0.083 g, 0.41 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF50(2084)) (0.086 g, 72%). 1H NMR (CDCl3) δ 7.02-6.96 (m, 1H), 6.85 (d, J=5.2 Hz, 1H), 4.65 (s, 2H), 4.04-4.11 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.10-2.18 (m, 2H); 13C NMR (CDCl3) δ 163.8, 151.7 (d, J=250.9 Hz), 133.1 (d, J=14.6 Hz), 131.5 (d, J=3.8 Hz), 115.1 (d, J=21.5 Hz), 114.2 (d, J=10.0 Hz), 113.4 (d, J=3.4 Hz), 67.6, 42.2, 39.5, 30.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][CH:10]([O:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1>CN(C)C=O.O.[Cu]>[CH3:19][O:18][CH:10]([O:9][CH3:8])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:16]=1
Reactant: c1c[nH]cn1
Reactant: COC(OC)c1cccc(Br)c1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(-n2ccnc2)c1
Temperature: 155 °C
Reaction time: 36 h
Yield: 79.4 %

Procedure:
A solution of 296 mg of imidazole and 131 mg of sodium hydride (80% dispersion in mineral oil) in 2 ml of anhydrous dimethylformamide was stirred at room temperature for 1 hour under nitrogen. 1.0 g of 3-bromobenzaldehyde dimethyl acetal and 30 mg copper powder were then added and the mixture was stirred at 150-160° C. under nitrogen for 36 hours. The cooled mixture was diluted with 20 ml of water and extracted with four 25 ml portions of dichloromethane. The combined extracts were washed with two 25 ml portions of 25% aqueous ammonia, followed by two 25 ml portions of brine and then dried over anhydrous magnesium sulphate. The solution was concentrated under reduced pressure to give 0.75 g of 3-(1-imidazolyl)-benzaldehyde dimethyl acetal as a clear viscous oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: C1=COCCC1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1cc2nc(Cl)n(C3CCCCO3)c2cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
To a solution of 2,5,6-trichlorobenzimidazole (2.07 g, 9.33 mmol) in tetrahydrofuran (20 mL) were added 3,4-dihydro-2H-pyran (2.55 mL, 28.0 mmol) and camphor sulfonic acid (216 mg, 0.93 mmol). The mixture was stirred at room temperature for 3 hours, and the reaction mixture was neutralized by addition of 0.1M aqueous sodium hydroxide, then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (C-300, hexane:ethyl acetate=4:1) to give the title compound (487 mg, 9%).
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[Cl-:14]>C(Cl)(Cl)Cl>[Cl:14][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: [Cl-]
Reactant: O=c1[nH]c2ccccc2cc1CO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccccc2cc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 Grams of 3-hydroxymethylcarbostyril was suspended in 100 ml of chloroform, then a solution containing 2 g of thinyl chloride in 20 ml of chloroform was added dropwise thereto at a room temperature with stirring condition. The reaction mixture was further sitrred at a room temperature for 1 hour. The reaction mixture was concentrated under a reduced pressure, and the residue obtained was recrystallized from methanol to obtain 2.9 g of 3-chloromethylcarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:19]=1[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][O:9][Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:32][O:31][CH2:30][O:29][C:18]1[CH:17]=[C:7]([CH2:8][OH:9])[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:19]=1[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCOc1cc(CO[Si](C)(C)C(C)(C)C)cc(OCOC)c1C/C=C/c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCOc1cc(CO)cc(OCOC)c1C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
To a solution of [3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzyloxy]-tert-butyl-dimethyl-silane (220d) (55 g, 0.12 mol) in THF (250 mL) was added TBAF (47.2 g, 0.18 mol) in one portion. The mixture was stirred at room temperature for 0.5 hr. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The reaction mixture was washed with brine (50 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in high vacuum to give the title compound (45 g, 92% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.16˜7.41 (m, 5H), 6.82 (s, 2H), 6.47 (m, 2H), 5.22 (s, 4H), 4.71 (s, 2H), 3.62 (d, 2H), 3.45 (s, 6H).
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:16](C(OCC1C=CC=CC=1)=O)[C@H:17]([C:30]([NH:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[NH2:16][C@H:17]([C:30]([NH:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
NMM (0.4 g, 4 mmol) and isobutylchloroformate (0.53 g, 4 mmol) are added to the obtained solution, cooled to -15° C. and kept under nitrogen atmosphere and, two minutes later, a DMF solution of Lys(Boc)-PheNH2 (1.6 g, 4 mmol), obtained by cleavage of the benzyloxycarbonyl group from Z-Lys(Boc)-PheNH2 through catalytic hydrogenation over 10% Pd-on-carbon, is added.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][O:8][CH:9]([CH2:19][O:20]CC2C=CC=CC=2)[CH2:10][O:11]CC2C=CC=CC=2)[C:5]2[C:28]([Cl:35])=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:4]=2[N:3]=1.B(Cl)(Cl)Cl.C(Cl)Cl>CO>[Cl:1][C:2]1[N:6]([CH2:7][O:8][CH:9]([CH2:19][OH:20])[CH2:10][OH:11])[C:5]2[C:28]([Cl:35])=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:4]=2[N:3]=1
Reactant: Clc1c(Cl)c(Cl)c2c(nc(Cl)n2COC(COCc2ccccc2)COCc2ccccc2)c1Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: OCC(CO)OCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 50.7 %

Procedure:
Compound 155 (0.52 g, 51%) was prepared from 154 (1.5 g, 2.6 mmole), BCl3 (5M solution in CH2Cl2, 14 mL), CH2Cl2 (30 mL) and MeOH (20 mL) by the method described for 166 which on recrystallization from EtOAC gave 155: m.p. 155°; 1H NMR (DMSO-d6): d 5.76 (s, 2H, C-1'), 4.63 (t, 2H, exchanges with D2O, 2×OH), 3.54-3.48 (m, 1H, C-3'), 3.43-3.25 (m, 4H, C-4' and 5'H). Anal. Calcd. for C11H9N2Cl5O3 : C, 33.46; H, 2.28: N, 7.09. Found: C, 33.60; H, 2.15; N, 6.91.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:20]1([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[CH:27][C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[CH:31][CH:30]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc(N5CCOCC5)cc4)nc23)CCCCC1

Procedure:
(1-Methyl-cyclohexyl)-[2-(4-morpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-morpholin-4-yl-phenylboronic acid following general procedures as described in these Examples. MP 233-235° C., M+H=405.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH2:13])([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: CCCCP(=O)(CCCN)OCC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCP(=O)(CCCNCc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.14 g of 3-aminopropyl(n-butyl)phosphinic acid ethyl ester are mixed with 2.51 g of p-chlorobenzaldehyde, and first 1.2 g of glacial acetic acid and then a solution of 0.42 g of sodium cyanoborohydride in 5 ml of methanol are added, whereupon an exothermic reaction takes place. The mixture is then stirred at room temperature for 2.5 hours and adjusted to pH 8, and the volatile constituents are removed under reduced pressure. The residue is dissolved in dichloromethane, washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=7.30-7.32 (4H,m); 4.02 (2H,q); 3.74 (2H,s); 2.67 (2H,t); 2.5-2.22 (1H,S); 1.79-1.64 (6H,m); 1.53 (2H,m); 1.42 (2H,m; 1.31 (3H,t); 0.81 (3H,t); 31P-NMR spectrum (in CDCl3 ): δ=58.16.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 54.3 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.329 g, 1.0 mmol) and 4-butylpiperidine (0.283 g, 2.0 mmol) in MeCN (2 mL) and shaken at 60° for 20 h. The reaction mixture was concentrated, and the product purified by flash CC (SiO2; EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH47-A) (0.186 g, 54%). 1H NMR (CD3OD) δ 7.26-7.19 (M, 3H), 7.04-7.00 (m, 1H), 2.93-2.88 (m, 3H), 2.77 (d, J=10.4 Hz, 2H), 2.62-2.58 (m, 2H), 2.29-2.06 (m, 3H), 1.93-1.86 (m, 2H), 1.68-1.62 (m, 2H), 1.31-1.22 (m, 9H), 0.91-0.86 (m, 2 CH3); 13C NMR (CD3OD) δ 173.2, 140.3, 129.1, 128.5, 128.4, 124.4, 166.9, 64.9, 56.0, 55.6, 37.5, 36.9, 33.4, 33.3, 32.9, 30.1, 30.1, 26.2, 24.0, 17.2, 14.4.