Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]3[O:11][C@@H:12]([CH2:15][OH:16])[CH2:13][O:14][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][CH:12]2[CH2:13][O:14][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[C:10]=3[O:11]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1nc2ccc3c(c2o1)O[C@@H](CO)CO3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)oc4c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g)[1,3]benzoxazol-8-yl]methanol (1.80 g, 8.14 mmole) in methylene chloride (100 mL) was added p-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was cooled in an ice bath and a solution of diisopropylethylamine (3.55 mL, 20.4 mmole) in methylene chloride (20 mL) was then added dropwise, followed by 4-dimethylaminopyridine (0.65 g, 5.30 mmole). The solution was allowed to warm to room temperature and was stirred under nitrogen overnight. The reaction was diluted to 500 mL in volume with methylene chloride, then washed with aqueous 2 N HCl (200 mL), with saturated aqueous sodium bicarbonate (200 mL), and with brine (150 mL), dried over magnesium sulfate, filtered and evaporated in vacuum to a yellow oil. The crude oil was column chromatographed on silica gel using methylene chloride to remove impurities and 3% methanol/methylene chloride to elute the (R)-enantiomer of the title compound, which becomes a white solid under vacuum (2.56 g, 84%), m.p. 123° C. MS (ESI) m/z 376 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:29](=[O:30])[CH2:28][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)COc4ccccc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added phenoxyacetyl chloride (0.55 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.76 g (93%) of product as an off-white solid: mp 236–238 ° C.; 1H NMR (DMSO-d6) d 11.19 (s, 1H), 10.53 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.6 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H) 7.14–7.01 (m, 3H), 5.21 (dd, J=5.3 and 12.6 Hz, 1H), 4.81 (s, 2H), 3.00–2.86 (m, 1H), 2.67–2.51 (m, 2H), 2.13–2.09 (m, 1H); 13C NMR (DMSO-d6) d 172.77, 169.77, 168.37, 167.59, 166.67, 156.85, 136.58, 135.84, 131.28, 129.74, 124.45, 121.91, 118.50, 116.28, 114.86, 67.03, 49.02, 30.96, 21.93; Anal. Calcd. For C21H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 61.87; H, 4.27; N, 10.25.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:32]=[CH:31][C:30](CBr)=[CH:29][C:28]=1[F:35]>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:21][S:20][C:15]2[C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:29][C:28]=1[F:35]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)c(F)c3)c2CC1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 1-bromo-4-bromomethyl-2-fluorobenzene, to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][C:20]([O:22]CC)=[O:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCOCC1>[Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][C:20]([OH:22])=[O:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(CC)c(Br)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(Br)ccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a stirred solution of ethyl 2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate (2.8 g, 5 mmol) in dioxane (40 ml) was added lithium hydroxide monohydrate (2.8 g, 67 mmol) and water (30 ml). The mixture was stirred at room temperature overnight. It was concentrated under reduced pressure, neutralized with 5% HCl, extracted with CH2Cl2, dried over MgSO4, and concentrated. The crude product was recrystallized in dichloromethane/hexane (60 ml/20 ml) to give a white solid (980 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 8.68 (br, NH)), 7.27 (d, 1H), 7.19 (d, 1H), 4.06 (m, 2H), 3.04 (qrt, 2H), 2.95 (qrt, 2H), 2.80 (m, 2H), 2.09 (m, 2H), 1.24 (t, 3H), 0.874 (t, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:27])[N:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+].Cl>CCO>[C:25]([C:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:27])[N:8]=1)#[N:26]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c1C(=O)O
Reaction time: 0.17 h

Procedure:
Dissolve the 5-cyano-4-(2′-cyano-biphenyl-4-yl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (37 mg, 0.10 mmol, prepared in example Pz-2) in 2 mL of EtOH, add 1 mL of 2N aqueous NaOH and heat to reflux. After 20 minutes cool the reaction mixture in an ice-bath and add 2 mL of 1N aqueous HCl. Stir 10 minutes and filter, rinsing with 1 mL of EtOH followed by 2 mL of water. Vacuum-dry at 50° C. overnight to give the title compound. Yield=7.0 mg (21%). MS(ES−, m/e)=283 (M+−COOH).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]2[CH2:26][CH2:25]2)=[N:7][C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:9][C:10]=1[CH2:11][O:12][CH3:13])=O.CC(C[AlH]CC(C)C)C>O1CCCC1>[CH:24]1([C:6]2[C:5]([CH2:3][OH:2])=[C:10]([CH2:11][O:12][CH3:13])[N:9]=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:7]=2)[CH2:26][CH2:25]1
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CO
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To a solution of 2.86 g (7.8 mmol) 4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester in 30 ml tetrahydrofurane was dropped at −78° C., 20 ml (24 mmol) of a DIBALH-solution (1.2 M in toluene). The reaction was stirred for 15 min at −70° C., then the dry-ice bath was removed, the reaction temperature was allowed to come to RT and the solution was stirred for 2 h at RT. To the reaction mixture was then dropped carefully, under ice-cooling, 13 ml of 6N HCl. The reaction mixture was then taken up in ether and was washed with water. The ether-phase was concentrated under reduced pressure providing 1.29 g of pure crystalline [4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:14]=[O:15].P([O-])(O)(O)=[O:17].[Na+].S(=O)(=O)(O)N.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([OH:17])=[O:15]
Reactant: Cc1ccc(-c2cc(C)c(C=O)s2)cc1
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: NS(=O)(=O)O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C)c(C(=O)O)s2)cc1
Reaction time: 0.25 h

Procedure:
A solution of 3-methyl-5-p-tolylthiophene-2-carbaldehyde (2.6 g) in 1,4-dioxane (30 mL) was mixed with a solution of sodium dihydrogenphosphate (5.77 g) in water, and sulfamic acid (1.87 g) was added. At 10° C., a solution of sodium chlorite (1.52 g) in water (20 mL) was added dropwise in such a way that the temperature did not rise above 10° C. Twenty minutes after the addition was complete, sodium sulfite (1.98 g) was added and the mixture was stirred for 15 minutes. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated. The product with the molecular weight of 232.30 (C13H12O2S) was obtained in this way; MS (ESI): 233 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:21]2[C:16]([C:17]([NH2:22])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt](=O)=O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:21]2[C:16]([C:17]([NH2:22])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC/C=C/c1ccc2c(N)ncnn12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc2c(N)ncnn12
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a dry flask purged with N2 was added platinum(IV) oxide (635 mg, 2.80 mmol) followed by 7-((1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (6.35 g, 19.9 mmol) as a solution in acetic acid (100 mL). The mixture was stirred under an H2 atmosphere for 16 h. The mixture was filtered through a pad of Celite® rinsing with acetic acid. The solvent was evaporated under reduced pressure and the residue was made basic with saturated aqueous NaHCO3 solution. The resulting solid was collected by filtration and dried in vacuo to afford 5.6 g (88%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.76 (s, 1 H), 7.52 (br s, 2 H), 6.77 (d, 1 H), 6.38 (d, 2 H), 3.57 (t, 2 H), 2.82 (t, 2 H), 1.74-1.62 (m, 2 H), 1.54-1.43 (m, 2 H), 0.83 (s, 9 H), 0.00 (s, 6 H); ES-MS m/z 321.2 [M+H]+, HPLC RT (min) 3.11.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[CH2:26]([CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: COC(=O)CCCCCNc1ccccc1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC(CC)CN(CCCCCC(=O)OC)c1ccccc1
Temperature: 100 °C
Yield: 53069.5 %

Procedure:
In a three-neck flask, methyl 6-(phenylamino)hexanoate (25.0 g, 0.113 mmol) and potassium carbonate (25.0 g, 0.169 mol) were added to dimethylformamide (100 ml) and stirred. The mixture was heated to 100° C., added with 3-(bromomethyl)heptane (26.2 g, 0.135 mol), and allowed to react with stirring for 12 hours. The reaction product was transferred into a separate funnel, and was then added with water and ethyl acetate, after which the organic layer was isolated therefrom, dehydrated using sodium sulfate, and then distilled under reduced pressure. Subsequently, the obtained material was separated through silica column chromatography, thus obtaining 20.0 g of a yellowish transparent liquid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)([CH3:31])[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:29]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:16]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)([CH3:31])[CH3:30]
Reactant: Cn1c(CN2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)c1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)n(C)c2n1
Temperature: 145 °C
Yield: 67.7 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-(3-morpholin-4-yl-azetidin-1-ylmethyl)-9H-purine (83 mg, 0.20 mmol), 2-isopropylbenzimidazole (39 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), Xphos (19 mg, 0.04 mmol) and Cs2CO3 (133 mg, 0.41 mmol) in dioxane (2 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 547 as a beige foam (72 mg, 68%). LCMS (Method I): RT 2.50 min, [M+H]+ 532.3. 1H NMR (CDCl3, 400 MHz): δ 7.89-7.84 (m, 1 H); 7.80-7.75 (m, 1 H); 7.29-7.21 (m, 2 H); 4.34 (m, 4 H); 4.00-3.92 (m, 3 H); 3.88-3.81 (m, 7 H); 3.76 (m, 4 H); 3.64 (m, 2 H); 3.24 (m, 2 H); 3.13 (m, 1 H); 2.40 (m, 4 H); 1.47 (s, 3 H) and 1.46 (s, 3 H)
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][C@H:7]([CH2:10][CH:11]=[CH2:12])[CH2:8][OH:9]>CN(C=O)C>[CH2:6]([C@H:7]1[CH2:10][CH2:11][CH2:12][O:9][CH2:8]1)[CH:5]=[CH2:4]
Reactant: C=CC[C@H](CO)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@H]1CCCOC1
Temperature: 7.5 °C
Reaction time: 0.08 h
Yield: 83.5 %

Procedure:
DMF (350 mL) was added to a round bottom flask containing NaH (60% w/w, 15 g, 0.376 mmol) and a magnetic stir bar. The suspension was cooled to 5-10° C. in an ice bath and stirred for 5 min. A solution of (R)-2-(3-chloropropyl)pent-4-en-1-ol (30.6 g, 188 mmol) in DMF (350 mL) was added via addition funnel over 25 min. Caution: Gas evolution and exotherm. The resulting creamy suspension was stirred for 30 min. The reaction was warmed to room temperature and the resulting beige suspension was stirred for 2 h, at which time it was judged complete by TLC. The reaction mixture was cooled to 0° C. and quenched by addition of H2O (250 mL) and HCl (3N, 250 mL). The phases were separated and the aqueous phase was extracted with petroleum ether (4×250 mL). The combined with organic layers were washed with H2O, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish the crude product as a yellow oil. The crude material was purified by flash chromatography (ISCO; 120 g column; Hexane to 30% EtOAc/Hexane) to provide (R)-3-allyl-tetrahydro-2H-pyran as a clear oil (19.8 g, 157 mmol, 83%); 1H NMR (400 MHz. CDCl3) δ 5.72-5.82 (m, 1H), 5.00-5.06 (m, 2H), 3.86-3.91 (m, 2H), 3.37 (m, 1H), 3.08 (t, J=12 Hz, 1H), 1.85-1.98 (m, 3H), 1.59-1.69 (m, 3H), 1.15-1.21 (m, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:12]([O:3][CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([O:10][CH3:11])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H]1C[C@@H]1CO
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Sodium hydride (60%, oil, 0.907 g, 22.68 mmol) was added to a solution of methyl (1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylate (2.27 g, 17.44 mmol) in THF (110 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred at room temperature for 1 hr, and cooled to 0° C. To the reaction mixture were added benzyl bromide (2.70 mL, 22.68 mmol) and tetra-n-butylammonium iodide (0.644 g, 1.74 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into cooled 0.5N hydrochloric acid (350 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→25% ethyl acetate/hexane) to give methyl (1S,2S)-2-((benzyloxy)methyl)cyclopropanecarboxylate (1.38 g, 6.27 mmol, 36%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[C:7](Cl)=[N:8][C:9]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[Cl:12]>C(O)CO>[Cl:12][C:11]1[N:10]=[C:9]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:8]=[C:7]([O:2][CH2:3][CH2:4][OH:5])[C:6]=1[O:5][C:4]1[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Solvent: OCCO
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1OCCO

Procedure:
5-(2-Methoxyphenoxy)-4,6-dichloro-2-(2-pyrimidinyl)pyrimidine and ethylene glycol are treated in the same manner as in Reference Example 1-(1) to give 2-{6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yloxy}-ethanol (5.37 g) as a powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:17][C:16]=2[CH3:25])[C:11]([CH3:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:29]([O:37][CH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH2:47][O:48][C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:42]Br)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[C:29]([O:37][CH2:38][C:39]1[CH:40]=[C:41]([CH2:42][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:26])[C:8]2[CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:17][C:16]=3[CH3:25])[C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:44]=[CH:45][C:46]=1[CH2:47][O:48][C:49](=[O:56])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1ccc(-c2cc(NC(=O)OC(C)(C)C)ccc2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(-c2cc(N(Cc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)C(=O)OC(C)(C)C)ccc2C)c(C)c1
Reaction time: 0.25 h

Procedure:
900 mg (2.5 mmol) of tert-butyl(6,2′-dimethyl-4′-propionylbiphenyl-3-yl)carbamate are dissolved in 30 ml of dimethylformamide. 110 mg (2.8 mmol) of 60% sodium hydride are added and the medium is stirred for 15 minutes. 1.23 g (2.8 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide are then added and the medium is stirred for 12 hours at room temperature. After the usual work-up, the residue obtained is purified by chromatography on a column of silica (eluent: 8 heptane/2 ethyl acetate). A colorless oil is obtained (m=1 g, Y=55%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[CH2:24](B(O)O)[CH2:25][CH:26]([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:24]([C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CCB(O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nncn12
Temperature: 100 °C
Yield: 44 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 2.61 mmol), isopentylboronic acid (484 mg, 4.18 mmol), Pd(PPh3)4 (300 mg, 0.261 mmol), 2 M aqueous K2CO3 (2.6 mL, 5.2 mmol) and toluene (15 mL) under N2. The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.43 g (44%) of tert-butyl 4-(5-isopentyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate as a yellow solid. MS m/z: 375 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:39])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=2)=[CH:6][C:5]([I:40])=[CH:4][N:3]=1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:39])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5]([I:40])=[CH:4][N:3]=1
Reactant: Cc1cc(CCC(=O)Nc2cc(I)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CC(=O)O
Product: Cc1cc(N)nc(CCC(=O)Nc2cc(I)cnc2N)c1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
672 mg of N-(2-amino-5-iodo-pyridin-3-yl)-3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]-propion-amide (compound B9) are dissolved in 13 ml of aqueous acetic acid (50% strength) and heated at 80° C. for 4 h. Subsequent workup according to the procedure described herein for example B5 yields 116 mg of the title compound as an oil after chromatography on silica gel (eluent: dichloromethane/methanol 8:1). ESI-MS: 398.0 (MH+). TLC: Rf=0.32 (dichloromethane/methanol 8:1).
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])C(=O)[O-])(C)C.Cl>CO.O1CCOCC1>[NH2:5][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]carbamate (4.3 g, 11.3 mmole) in MeOH (100 mL) at RT was added 4M HCl in dioxane (50 mL). After stirring for 3 h at RT, the reaction solution was concentrated to a white solid (quant.): LCMS (ES) m/z 281 (M+H)+.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[CH:26]1([CH2:29][N:30]2[C:35](=[O:36])[C:34]([C:37]([O:39]C)=[O:38])=[CH:33][C:32]([C:41]3[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=3)=[N:31]2)[CH2:28][CH2:27]1>>[C:37]([C:34]1[C:35](=[O:36])[N:30]([CH2:29][CH:26]2[CH2:28][CH2:27]2)[N:31]=[C:32]([C:41]2[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=2)[CH:33]=1)([OH:39])=[O:38]
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)nn(CC2CC2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: CSc1ccc(-c2cc(C(=O)O)c(=O)n(CC3CC3)n2)cc1
Yield: 98.2 %

Procedure:
Following the procedure of Example 1 (7), 2-cyclopropylmethyl-4-methoxycarbonyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as a yellow crystalline powder (yield: 98.2%).