Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH2:44]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (1.00 g, 3.11 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (1.288 g, 9.33 mmol) and 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine (1.264 g, 3.42 mmol), (prepared as described for the starting material in Example 10), in DMF (35 ml) was stirred at 80° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography, 5% methanol/95% dichloromethane and the product was recrystallised from ethanol to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (1.011 g, 63%).
Reaction SMILES: [OH:1][CH:2]([CH3:43])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][CH:42]=[C:12]23)[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[O:36]=[C:34]1[O:33][N:32]=[C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:15]3[C:16](=[O:17])[N:11]([C@H:8]4[CH2:9][CH2:10][C@H:5]([O:4][CH2:3][C:2](=[O:1])[CH3:43])[CH2:6][CH2:7]4)[C:12]4[N:13]([N:40]=[CH:41][CH:42]=4)[C:14]=3[CH2:37][CH2:38][CH3:39])=[CH:24][CH:23]=2)[NH:35]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Reaction time: 15 h

Procedure:
To a solution of 4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.38 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.55 g), and the mixture was stirred for 15 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.34 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:19][C:20](=[O:26])[C@H:21]([C@@H:23]([CH3:25])[OH:24])[NH2:22])C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:22][C@H:21]([C:20]([O:19][CH3:17])=[O:26])[C@@H:23]([CH3:25])[OH:24])=[O:15])[CH2:10][CH2:11][CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC)[C@@H](C)O

Procedure:
The preparation was performed in a similar manner as Example 1.001 (d) Method B from N-(tert-butoxycarbonyl)-L-norvaline (13.0 g, 59.8 mmol) and L-threonine ethyl ester hydrochloride (9.23 g, 54.4 mmol) to give methyl N-(tert-butoxycarbonyl)-L-norvalyl-L-threoninate. MS (APCI): m/z 333 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2.[Li]CCCC.CCCCCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[F:12][C:10]1[CH:11]=[C:2]([B:28]([OH:33])[OH:29])[CH:3]=[C:4]2[C:9]=1[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2
Reactant: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nnc2n1-c1c(F)cc(B(O)O)cc1CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
7-Bromo-9-fluoro-4,5-dihydro-1-methyl[1,2,4]triazolo[4,3-a]quinoline (1-5, 3.90 g, 13.8 mmol) was dissolved under nitrogen atmosphere in dry THF and cooled to −78° C. A 2.5 M n-BuLi solution in hexane (V=6.60 ml, 16.6 mmol) was added dropwise and stirred at −78° C. for 30 min. Triisopropyl borate (V=4.5 ml, 19.3 mmol) was added in one portion and the temperature raised to −50° C. for additional 30 min. The mixture was allowed to warm up to 0° C. and quenched with a 1M KHSO4 solution in order to reach pH 3. The solution was basified with a 2M NaOH solution and washed twice with ethyl acetate. The water layer was neutralized with conc. HCl and the precipitate was successively washed with water and ether and dried under reduced pressure to obtain the title compound as a white solid; MS (ESI): m/z=248.04 [M+H]+.
Reaction SMILES: N([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5]1)=[N+]=[N-].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H]([OH:29])C1.C(N(CC)CC)C.[Si](Cl)(C(C)(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[Si:11]([O:10][CH2:9][C@H:8]1[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5][C@@H:4]1[OH:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3'-azido-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 1du. 2'-Deoxyuridine (11.4 g, 50 mmol) was thoroughly dried by coevaporating in vacuo with anhydrous DMF (2×100 mL). DMF (100 mL) was then added, followed by triethylamine (8.36 mL, 60 mmol), 4-dimethylaminopyridine (0.31 g, 2.5 mmol), and tert-butyldimethylsilyl chloride (8.29 g, 55.0 mmol). The reaction mixture was stirred for 1 h at RT, diluted with dichloromethane (600 mL) and extracted with H2O (3×200 mL), and saturated aq. NaCl (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified on silica (2-10% MeOH/CH2Cl2) to afford 80% yield (13.7 g, 40.0 mmol) of 5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine. Triphenylphosphine (16.8 g, 64.0 mmol) and DMF (100 mL) were added, and to this stirring mixture was added a solution of diisopropylazodicarboxylate (12.6 mL, 64.0 mmol) in DMF (20 mL). After stirring 2 h at RT, the reaction mixture was concentrated in vacuo to ca. 30 mL, and poured into Et2O (1200 mL). The desired 2,3'-anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine began precipitating out after 10 min of rapid stirring. The resulting mixture was placed in the refrigerator overnight, the precipitate was collected by filtration, washed with additional cold Et2O (2×300 mL), and dried in vacuo to afford 90% yield (11.7 g, 36.0 mmol) of 2,3'-anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine as a white solid, which was not purified further. The 2,3'-anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxyuridine (33.8 g, 104.2 mmol) was then reacted with LiN3 (7.65 g, 156.3 mmol) in DMF (300 mL) at 95°-100° C. for 48 h. The resulting brown, homogeneous mixture was then cooled to RT, concentrated in vacuo to an oil, dissolved in EtOAc (800 mL), and extracted with H2O (200 mL). The aqueous layer was extracted twice more with EtOAc (75 mL), and the combined organics were washed with H2O (3×250 mL) and once with saturated. aq. NaCl (250 mL). The EtOAc solution was dried over Na2SO4, filtered, and concentrated in vacuo, to afford 87% yield (33.2 g, 90.3 mmol) of 3'-azido-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 1du, as a brownish foam, which was taken on directly to hydrogenation.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>C(Cl)Cl>[CH:1]1([O:7][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a mixture of cyclohexanol (2.40 g, 24.0 mmol) and Rh2(OAc)4 (50 mg, 0.11 mmol) in DCM (50 mL) was added ethyl 2-diazoacetate (2.73 g, 23.9 mmol) and the mixture was stirred at rt for 5 min. It was then filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=15:1) to give the title compound as colorless oil (3.8 g, 85%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:28]3[S:24][C:25](=[O:30])[NH:26][C:27]3=[O:29])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(C(COc2ccc(C=O)cc2)S(C)(=O)=O)nc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCc1ccc(C(COc2ccc(C=C3SC(=O)NC3=O)cc2)S(C)(=O)=O)nc1
Temperature: 125 °C

Procedure:
To a stirred solution of 0.65 g (0.0018 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzaldehyde dissolved in 10 mL toluene was added 0.211 g (0.0018 mol) thiazolidin-2,4-dione followed by addition of 0.161 g (0.03 mol) acetic acid and 0.228 g (0.03 mol) piperidine. Reaction mixture was refluxed at 120-130° C. for 4 hr. After completion of reaction on TLC, subsequent work-up gave the titled product. Yield of the product was 0.24 g (29%). The product obtained was identical to the product obtained in example 69.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH2:17][CH:18]([C:27]([O:29][CH3:30])=[O:28])[O:19][CH2:20]2.CI.[NH4+].[Cl-]>C1COCC1.O>[CH3:30][O:29][C:27]([C:18]1([CH3:1])[CH2:17][C:16]2[C:21](=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:15]=2[O:14][CH3:13])[CH2:20][O:19]1)=[O:28]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COC(=O)C1(C)Cc2c(OC)ccc(OC)c2CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of di-isopropylamine (616.8 μl, 4.37 mmol) in THF (10 ml) was cooled to 0° C. and degassed briefly. n-Butyl lithium (1.6M in hexane, 2.60 ml, 4.17 mmol) was added. After stirred for 30 minutes at 0° C., the solution was further cooled to -78° C. A solution of 5,8-dimethoxy-3-methoxycarbonylisochroman (1.0 g, 3.97 mmol) in THF (10 ml), pre-degassed, was added slowly. The resulting yellow solution was stirred for 1 hour at -78° C. before the addition of methyliodide (1.01 ml, 16 mmol). After stirred further for 45 minutes, sat. NH4Cl solution was added. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and evaporated to give a crude product which was chromatographed (hexane:EtOAc=3:1) to give the desired product as a solid (650 mg, m p. 73.0°-74.5° C.) and another fraction (192 mg) which contained 66% of titled product and 34% of the starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:19]/[C:20](=[O:21])[CH3:22]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)/C=C/c1ccccc1Cl
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
In a 250 ml single neck flask was charged 14 g (99.6 mmoles, 1.0 eq) of o-chlorobenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of a 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.8 g of (E)-4-(2-chlorophenyl)-3-buten-2-one as a faintly yellow oil in 76.9% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:28])[NH:16][C@@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:28])[NH:16][C@@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])[CH2:18][O:19][CH3:29])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CCOC(C)=O
Product: COC[C@@H](NC(=O)[C@@H]1C[C@@](C)(F)CN1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (2S,4R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc)=0.90; MS (UPLC-MS): 433.4/435.4 [M+H]+, 477.4 [M+HCOO]−; tR (HPLC conditions a): 3.73 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:26][C:27]1[O:28][C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:31]=1>C1COCC1.[NH4+].[Cl-].CCOCC>[C:1]([N:4]([CH2:26][C:27]1[O:28][C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:31]=1)[C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COC(=O)COc1cccc(NC(C)=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(C)=O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 41.4 %

Procedure:
A solution of methyl [3-(acetylamino)phenoxy]acetate (1.00 g, 4.5 mmol) in dry THF (20 mL) was added dropwise to a solution of LDA (0.53 g, 5 mmol) in dry THF (5 mL) maintained at about -78° C. under an atmosphere of N2. The mixture was warmed to about 0° C. and stirred about 5 minutes, cooled to about -78° C. and a solution of 2-bromomethyl-4,5-diphenyloxazole (1.41 g, 4.5 mmol) in THF (10 mL) added dropwise. The solution was allowed to warm to room temperature, stirred for about 18 hours and diluted with a mixture of saturated NH4Cl solution and Et2O. The organic phase was separated, washed with H2O and saturated NaCl solution, and dried over MgSO4. The solvent was evaporated and the residue chromatographed on a column of silica gel using a mixture of EtOAc and hexanes (13:7) as eluent to give methyl [3 -[N-acetyl-[(4,5-diphenyl-2-oxazolyl)methyl]amino]phenoxy]acetate (0.85 g, 42%). IR (Film) 1750 (CO2CH3), 1670 (NCOCH3) cm-1 ; 1H NMR (CDCl3) δ1.92 (3H, s, COCH3), 3.70 (3H, s, CO2CH3), 4.55 (2H, s, OCH2), 5.10 (2H, s, NCH2) 6.75-6.95 (3H, m, aromatic H), 7.20-7.40 (7H, m, aromatic H), 7.45-7.60 (4H, m, aromatic H); MS m/z 457 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[C:25]=2[O:34][CH3:35])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:36].[Li+]>C(COC)OC.O.[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[C:25]=1[O:34][CH3:35])[C:20]([OH:36])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(OC)c1OC
Reactant: [OH-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reaction time: 2 h

Procedure:
A solution of 1.354 g (2.685 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2,3,4-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 43.36 ml of dimethoxyethane and 21.86 ml of water is treated, at RT, with 10.74 ml of a 1M solution of lithium hydroxide in water, and this reaction mixture is stirred for 2 h. It is then transferred to a separating funnel, diluted with 132 ml of sat. ammonium chloride solution and 11 ml of a 10% citric acid solution (both cold), and this mixture is then extracted with ethyl acetate and a little THF. The title compound, which is dried under HV and subjected to further processing without being purified, is obtained after washing the organic phase with (cold) saline and drying it over sodium sulfate. TLC Rf (C)=0.03. MS (M-H2O)+ =485.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=3)=[N:9][N:10]=2)[N:7]=1.O1[CH2:23][CH2:22]OCC1>>[N:6]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=4)=[N:9][N:10]=3)[N:7]=2)[CH2:23][CH2:22][CH2:14][CH2:15][CH2:16][CH2:11][CH2:8]1
Reactant: C1COCCO1
Reactant: Clc1cccc(-c2nnc3ccc(Cl)nn23)n1
Product: Clc1cccc(-c2nnc3ccc(N4CCCCCCC4)nn23)n1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A mixture of 6-chloro-3-(6-chloropyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (620 mg), heptamethylenimine (1.32 g) and 1,4-dioxane (20 ml) was stirred at 100° C. for 9 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The extract was washed successively with 5% aqueous solution of citric acid, water, saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant crude crystal was recrystallized from ethanol, to obtain 6-azocan-1-yl -3-(6-chloropyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (370 mg) as grayish white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1)#[N:2].C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:26])=[C:4]([NH:18][C:19]2[O:23][N:22]=[C:21]([CH3:24])[CH:20]=2)[CH:5]=1)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)on1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C(N)=O)on1
Reaction time: 0.08 h
Yield: 4.7 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisoxazol-5-ylamino)phenylamino)-4-methylpentanamide (20 mg, 0.061 mmol) in DMSO (1 mL), K2CO3 (150 mg, 1.08 mmol) and H2O2 (50% aq., 0.800 mL) were added. After being stirred at 90 C for 5 min, the mixture was purified by HPLC to give the titled compound (1 mg). MS 346.3 (M+H); UV 202.2, 279.2 nm
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: Cc1cc(Oc2ccc(CCOC(=N)N)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(CCOc3nc(=O)c(Cc4cnn(C)c4)c[nH]3)cc2)ccc1Cl
Temperature: 130 °C
Yield: 5.5 %

Procedure:
To the solution of 2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl imidocarbamate (50 mg, 0.120 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (30 mg, 0.153 mmol) in NMP (2 mL), was added K2CO3 (50 mg, 0.362 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (3 mg, 5.56% yield). LCMS: rt=3.39 min, [M+H+]=451
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([S:15][C:16]3[C:24]([Br:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[N:10]([CH2:11][CH2:12][CH2:13][OH:14])[C:6]=2[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O1CCOCC1>[CH3:33][S:34]([O:14][CH2:13][CH2:12][CH2:11][N:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=[C:9]1[S:15][C:16]1[C:24]([Br:25])=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nccc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCCO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCn1c(Sc2cc3c(cc2Br)OCO3)nc2c(N)nccc21
Temperature: 40 °C
Yield: 45707.7 %

Procedure:
Compound 0403-51 (264 mg, 0.624 mmol) was dissolved in hot anhydrous dioxane (8.6 mL). The solution was cooled to 40° C. and was treated with NEt3 (189 mg, 1.87 mmol) and MsCl (107 mg, 0.935 mmol) for 20 min. The mixture was concentrated and purified by column chromatography on silica gel (CH2Cl2/MeOH=50/1) to give the title compound 0404-51 as a white solid (143 g, 50%): LCMS: 501 [M+1]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccccc2s1
Product: c1ccc2sc(N3CCNCC3)nc2c1

Procedure:
2-Chlorobenzothiazole (5.00 g), is heated in alcohol (75 ml) with 3.05 g piperazine (3.05 g) for 20 hr. The mixture is partitioned between methylene chloride/ether and aqueous sodium bicarbonate, the phases are separated, the organic phase is dried with sodium sulfate and concentrated to give 2-piperazinobenzothiazole which is reacted at 70° in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (7.45 g) and potassium carbonate (2.44 g) for 6 hr and at 20°-25° for 3 days. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated, the organic phase is dried with sodium sulfate and concentrated. The concentrate is chromatographed on silica gel eluting with methanol/methylene chloride (6/94) to give the title compound which is recrystallized from ethyl acetate.