Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][O:60][C:61]([C:63]1[CH:68]=[CH:67][C:66]([CH2:69][CH2:70][C:71](O)=[O:72])=[CH:65][CH:64]=1)=[O:62].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:71](=[O:72])[CH2:70][CH2:69][C:66]1[CH:67]=[CH:68][C:63]([C:61]([O:60][CH3:59])=[O:62])=[CH:64][CH:65]=1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: COC(=O)c1ccc(CCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.45 g, 0.9 mmol) in anhydrous NMP (12 ml) was treated with HBTU (0.48 g, 1.2 mmol), 3-(4-(methoxycarbonyl)phenyl)propanoic acid (0.22 g, 1.08 mmol) and diisopropylethyl amine (0.47 mL, 2.7 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (100 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to a yellow residue, 0.59 g that was purified by chromatography (silica gel, ethyl acetate and methanol gradient) to afford methyl 4-(3-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-3-oxopropyl)benzoate (37) as a white solid, 0.18 g (29%), LC/MS (+APCI) m/z 690 (M++1) and 704 (M++1), 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.92 (m, 2 H), 7.60 (m, 1H), 7.49 (m, 1H), 7.29 (m, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 6.91 (m, 1H), 6.82 (m, 2H), 6.35 (m, 1H), 5.67 (s, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.89 (s, 3H), 4.1 to 2.5 (many multiplets, 10H). 13CNMR (100 MHz, CDCl3) δ 171.4, 168.2, 156.1, 149.6, 149.0, 146.2, 138.4, 138.1, 137.0, 135.8, 135.3, 130.2, 129.9, 128.4, 128.2, 122.6, 121.7, 120.8, 107.3, 103.0, 67.0, 57.5, 51.9, 47.7, 41.9, 37.4, 35.9, 31.4
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[O:27][CH:28]=1.O>CN(C=O)C>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1/[CH:30]=[CH:29]/[C:26]1[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)[N:25]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(2,4-difluorophenyl) ethenyl]oxazole (281 mg) was added under ice cooling. After stirring at room temperature for 3 days, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in a mixture of ethyl acetate-THF and dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (275 mg) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:29]1[NH:30][CH:31]=[CH:32][N:33]=1)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[CH2:26][CH2:27][CH3:28])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CCCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (500 mg), 2-propylimidazole (1.10 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 4 hours. The reaction mixture was poured into water (100 ml), the resulting solid precipitate was filtered, air-dried and recrystallized from acetone-hexane to give 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-propyl-1-imidazolyl)oxazole as pale yellow prisms (233 mg, 39%). Melting point 89-90° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH3:9][N:10]1C(=O)O[C:13](=[O:14])[C:12]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:11]12.CS(C)=O>O>[CH3:9][N:10]1[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13](=[O:14])[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 12.3 g. of L-proline, 17.7 g. of N-methyl isatoic anhydride and 100 ml. of dimethyl sulfoxide is heated on a steam bath for 40 minutes. The mixture is cooled and diluted with 250 ml. of cold water. The precipitate is recovered by filtration, washed with water and then ether, air dried and then recrystallized from ethanol yielding the intermediate L-1-(N-methylanthraniloyl)proline, melting point 140°-142° C., [α]D25 -165° C. (1.1%, methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:6][CH2:7][CH3:8].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: CCCN(CCCN)c1ccccn1
Reactant: COc1ccc(Cc2cnc(SC)[nH]c2=O)cc1
Product: CCCN(CCCNc1ncc(Cc2ccc(OC)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-propylamino]pyridine (1.0 g) and 2-methylthio-5-(4-methoxybenzyl)pyrimid-4-one (0.88 g) were fused together on an oil bath at 160° C. for 2.5 hr. On cooling the residue was crystallized from ethanol/water to give a white solid which on recrystallization from acetone/water gave 2-[3-(N-propyl-N-pyrid-2-ylamino)propylamino]-5-(4-methoxybenzyl)pyrimid-4-one 1 H2O; 1.27 g (79%) m.p. indeterminate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1O)=O.O.[NH2:13][NH2:14].O.C(O)(=O)C>C(O)CO>[CH3:1][C:2]1[C:4]2[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:14][N:13]=1
Reactant: NN
Reactant: CC(=O)c1c(O)cccc1O
Solvent: CC(=O)O
Solvent: O
Solvent: OCCO
Product: Cc1n[nH]c2cccc(O)c12
Temperature: 160 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 2,6-dihydroxy acetophenone (0.50 g, 3.31 mmol) in ethylene glycol (7 ml) was slowly added a solution of hydrazine hydrate (3.3 g, 6.59 mmol) in ethylene glycol (2 ml). The reaction mixture was stirred for 20 min at room temperature and for an additional 2 hours at 160° C. After cooling to room temperature and dilution with distilled water (20 ml), the acetic acid (0.25 ml) was added to adjust the pH of the solution to 6. The resulting mixture was extracted four times with ethyl acetate, washed with a 5% sodium sulfite solution, dried over magnesium sulfate, filtered, and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give 0.37 g of 3-Methyl-1H-indazol-4-ol (Yield 68%).
Reaction SMILES: CO.Cl.[CH3:4][O:5][NH2:6].[CH3:7][CH:8]1[O:12][CH:11](O)[CH:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1>C(N(CC)CC)C>[CH3:4][O:5][N:6]=[CH:11][CH:10]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:9][CH:8]([OH:12])[CH3:7]
Reactant: CON
Reactant: CC1CC(Sc2ccccn2)C(O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=CC(CC(C)O)Sc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
8.0 mL of methanol and 712 mg of O-methylhydroxylamine hydrochloride were added to 1.5 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolan-2-ol, and thereafter, 1.1 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 2 hours. Thereafter, the solvent was distilled away under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were then added to the residue, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone=4/1), so as to obtain 1.74 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:26][NH2:27]>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([NH:27][CH3:26])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CN
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (100 mg, 0.3 mmol) was reacted with 2M methylamine (0.59 mL) in THF to provide 159. LC/MS (ESI+): m/z 353 (M+H). 1H NMR (400 MHz, DMSO) δ 8.54-8.39 (m, 1H), 7.93 (dd, J=18.0, 11.2, 1H), 7.67-7.46 (m, −1H), 6.47 (d, J=33.7, −2H), 5.94-5.78 (m, −2H), 4.68-4.47 (m, −4H), 3.52-3.55 (s, −3H), 2.90-2.68 (m, 1H), 1.47 (t, J=13.6, 6H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH2:20]>C(O)C>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH:20][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: NCc1ccco1
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCc1ccco1

Procedure:
A solution of 14.7 g of 2-fluoro-5-nitrobenzoic acid and 23.1 g of 2-furylmethylamine in 250 ml of ethanol is boiled under a reflux condenser for 6 hours. After the solvent has been removed by distillation under reduced pressure, the residue is dissolved in 150 ml of water, the pH is adjusted to approximately 2 with 2 N HCl, and the precipitate is filtered off. After the precipitate has been washed several times with water, it is dried in a stream of air. Pale yellow crystals, melting point 190°-192° C. (from isopropanol).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C([O-])(O)=O.[Na+].CO>[CH:33]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:8]=[C:7]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)([CH3:35])[CH3:32]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (29 mg, 0.069 mmol), acetone (18 μL, 0.24 mmol) and sodium triacetoxyborohydride (66 mg, 0.31 mmol) in THF (1.0 mL) was stirred at room temperature over the weekend. The reaction was diluted with saturated NaHCO3 (aq) and methanol. The mixture was concentrated to dryness and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((6-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.35 (19 mg) as its trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([C:15]([NH2:17])=O)[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH2:17])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(C(N)=O)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)[C@@H]1CCc2ccc(CN)cc2C1

Procedure:
A solution of the (R)-7-(dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenecarboxamide (8) (8.68 g) in dry tetrahydrofuran was stirred at room temperature and borane dimethylsulfide complex (10.0 M, 11.1 ml) was slowly added. When the initial reaction subsided, the mixture was heated at reflux for 2 days. The mixture was cooled in ice, and water was added dropwise. When the evolution of gas ceased, 10% hydrochloric acid (75 ml) was added, and the mixture was refluxed for 2 hours. The mixture was cooled in ice and basified with solid sodium hydroxide. The mixture was extracted with diethylether and then with 2:1 diethylether/tetrahydrofuran. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave the title compound a yellow oil (8.15 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[Cl:21][CH2:22][C:23]([N:25]=[C:26]=[O:27])=[O:24].O>ClCCl>[CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:26]([NH:25][C:23]([CH2:22][Cl:21])=[O:24])=[O:27])[C@H:10]1[O:18][CH3:19])[CH3:8]
Reactant: O=C=NC(=O)CCl
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of fumagillol (314 mg) in dichloromethane (5 ml) was added dropwise chloroacetyl isocyanate (160 mg) under ice cooling, followed by addition of dimethylaminopyrldine (130 mg). The mixture was stirred at 0° C. for 2 hours. To this reaction mixture was added water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The eluate obtained with a mixture of n-hexane and ethyl acetate (3:1) was concentrated under reduced pressure to give colorless, powdery O-chloroacetylcarbamoylfumagillol (318 mg) (71% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[S:32][C:33]([CH3:39])=[C:34]([CH2:36][CH2:37]O)[N:35]=2)=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][CH2:36][C:34]2[N:35]=[C:31]([C:28]3[CH:29]=[N:30][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])=[CH:26][CH:27]=3)[S:32][C:33]=2[CH3:39])=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1sc(-c2ccc(-c3ccccc3F)nc2)nc1CCO
Reactant: Cc1cc(O)ccc1CCC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid tert-butyl ester (120 mg, 0.5 mmol) and 2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethanol (101 mg, 0.323 mmol) in toluene (3.0 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (0.124 mL, 0.5 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (120 mg, 0.5 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded on silica gel column. Chromatography gave the title compound (130 mg).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Reactant: NCCCC1CCCc2cccnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Yield: 86.5 %

Procedure:
A mixture of 3-(5,6,7,8-tetrahydroquinol-8-yl)-propylamine (4.5 g), 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (5 g) and triethylamine (10 ml) was refluxed in ethanol (200 ml) for 7.5 hours. The solvent was removed in vacuo, the residue was dissolved in chloroform and chromatographed on silica in chloroform and later chloroform/methanol 4:1. The fractions containing the product were concentrated to give the title compound as an oil (6.1 g).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.C(O)C.[OH-].[Na+]>CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(-c2ccc(O)cc2)c1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: COc1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.90 g), 3'-methoxybiphenyl-4-ol (2.05 g), ethanol (40 ml) and aqueous sodium hydroxide (2.1 M, 5 ml). After the reaction was complete it was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was twice purified by column chromatography over silica eluting with dichloromethane:ethyl acetate as an oil (1.35 g). A white solid was obtained after trituration with ether:hexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH:12]S(O)(=O)=O.[CH3:17][C:18]#[N:19]>[NH4+].[OH-]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:19][C:18](=[O:12])[CH3:17])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: CC(C)(O)c1ccc(Cl)nc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)NC(C)(C)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a solution of 2-(6-chloropyridin-3-yl)propan-2-ol, 33-b, (10 g, 58.3 mmol) in MeCN (100 ml) was added dropwise H2SO4 (40 g, 408 mmol) at 0° C., while keeping the internal temperature below 15° C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was then cooled to 0° C. and diluted with NH4OH slowly. The reaction mixture was then extracted with ether (3×100 mL), dried, and concentrated. The product was purified by silica gel (DCM-DCM:MeOH=30:1) to give a white solid, 33-c, (9 g, 72.6%)
Reaction SMILES: C1([C@]2(O)[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.[C:26](=[O:29])([O-])[O-].[Li+].[Li+]>>[OH:29][C@H:26]1[C:9]([CH3:11])([CH3:10])[CH2:5][N:6]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C@@H:7]1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: [Li+]
Product: C[C@@H]1[C@@H](O)C(C)(C)CN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
By an operation in the same manner as in Example 53 and using (2R,3S)-2,4,4-trimethylpyrrolidin-3-ol 0.5 oxalate (146 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (255 mg) and lithium carbonate (140 mg), the title compound was obtained as a colorless solid (yield: 106 mg, yield: 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)=[CH:5][C:4]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)=[CH:42][C:41]=1[O:57][CH3:58]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:58][O:57][C:41]1[CH:42]=[C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)[CH:44]=[CH:45][C:40]=1[O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:26][C:4]1[CH:5]=[C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)cc1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 78.5 %

Procedure:
2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenol (29a) (357.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (30d) (546 mg, 80% yield).