Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16](=O)[CH3:17]>>[C:1]1([NH:7][N:8]=[C:16]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[NH2:9])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnccc1N
Reactant: NNc1ccccc1
Product: CC(=NNc1ccccc1)c1cnccc1N
Temperature: 100 °C

Procedure:
Phenylhydrazine (4.0 ml) was added to 5.00 g 1-(4-amino-3-pyridinyl)ethanone, and the mixture was stirred at 100° C. for seventeen hours. A similar procedure was followed using 4.0 g 1-(4-amino-3-pyridinyl)ethanone and 3.20 ml phenylhydrazine. The products of the two reactions were combined and purified by flash chromatography to yield 9.74 g solid. Recrystallization of 1.24 g from CH3OH/water yielded 0.28 g solid, m.p. 168°-170° C.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:28])[CH:10]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.ClC(Cl)(Cl)C(=N)O[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>O1CCCC1.B(F)(F)F.CCOCC>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([O:28][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:10]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])[C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])=[CH:3][CH:2]=1
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(-c2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Boron trifluoride etherate (8.0 μL, 65 μmol) was added to a stirred solution of tert-butyl 5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-hydroxypentanoate (7.88 g, 16.3 mmol) and 4-methoxybenzyl 2,2,2-trichloroethanimidoate (6.88 g, 24.5 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. A further portion of boron trifluoride etherate (8.0 μL, 65 μmol) was then added and stirring was continued at room temperature for a further 2 h. Two further additions of boron trifluoride etherate (8.0 μL, 65 μmol) followed by stirring at room temperature for 2 h were carried out before evaporation of the solvent. The residue was chromatographed on silica gel (5% to 10% diethyl ether: cyclohexane) to give the title compound (3.39 g, 34%) as a pale yellow oil which was a mixture of diastereomers. LC/MS: 4.81 min; z/e 605, calcd (M+1) 605. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.45 (4H), 7.35-6.80 (7H), 4.50 (2H), 3.80 (3H), 3.60 (3H), 2.95 (1H), 2.80 (1H), 2.65 (1H), 1.85 (4H), 1.45 (9H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C1C(=O)N([Br:21])C(=O)C1>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:21][CH2:13][C:4]1[C:3]([C:1]#[N:2])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C#N)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(C#N)c1CBr
Yield: 98.2 %

Procedure:
A suspension of methyl 3-cyano-2-methylbenzoate (10.6 g, 60.5 mmol), NBS (16.2 g, 90.7 mmol) and azobisisobutyronitrile (AIBN) (100 mg) in tetrachloromethane (200 mL) was refluxed under nitrogen atmosphere for 6 hours. TLC analysis indicated the complete consumption of methyl 3-cyano-2-methylbenzoate (TLC solvent: 10% ethyl acetate in hexane). The reaction mixture was filtered and washed with chloroform (3×20 mL). The combined filtrate and washings were concentrated under reduced pressure. The residue was washed through a short column of silica gel using 10% ethyl acetate in hexanes as an eluent. The eluent was concentrated and the resultant product dried under vacuum overnight to provide 15.1 g of methyl 2-bromomethyl-3-cyanobenzoate (98% yield). 1H NMR spectrum (in DMSO-d6): δ 8.15 (d, J=8.0 Hz, 1H); 8.12 (d, J=7.9 Hz, 1H); 7.67 (t, 1H); 5.04 (s, 2H); 3.89 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([Cl:8])Cl)#[N:2].C[Si](C)(C)[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(Cl)Cl>[Cl:8][P:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C[Si](C)(C)N1CCOCC1
Reactant: N#CCCOP(Cl)Cl
Solvent: ClCCl
Product: N#CCCOP(Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 2-Cyanoethyldichlorophosphite (3.0 g, 17.5 mmol, 2.2 mL) in CH2Cl2 (45 mL) was added dropwise 4-(trimethylsilyl)morpholine (3.1 mL, 2.8 g, 17.5 mmol) at 0° C. The resulting mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure to give a pale yellow oil (3.87 g, 86%) as a product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH3:22][O:23][C:24](=[O:28])[C:25](Cl)=[O:26]>>[CH3:22][O:23][C:24](=[O:28])[C:25]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:26]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: COC(=O)C(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Yield: 44 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using chloro-oxo-acetic acid methyl ester instead of methoxyacetyl chloride, to the title compound (88 mg, 44%) which was obtained as a white solid. MS: m/e=369.0 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.[C:15]([N:18]1[CH2:22][C:21](=O)[N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Nc1ccnn1-c1ccc(F)cc1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1ccnn1-c1ccc(F)cc1

Procedure:
5-Amino-1-(4-fluorophenyl)pyrazole HCl (21 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 20.76 g. product. mp 162°-164°
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])O[C:16]=3[CH3:23])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[NH3:28]>C(O)C>[F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:28][C:16]=3[CH3:23])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)o1
Reactant: N
Solvent: CCO
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)[nH]1

Procedure:
3-(4-(4-Trifluoromethoxyphenoxy)phenyl)-2,6-dimethylpyran-4-one (4.1 g) was dissolved in ethanol (10 ml) and heated in a stainless steel autoclave with 0.880 ammonia (35 ml) at 150° for 24 hr. After cooling the crystalline precipitate was filtered off, washed with ethyl acetate and dried in vacuo to afford the title compound (2.78 g), m.p. 244°-248°, NMR δH (d6 -DMSO) 11.1 (1H, br. s) 7.4 (2H, m), 7.1-7.3 (4H, m), 7.02 (2H, m), 5.95 (1H, s), 2.2 (3H, s), 2.08 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C1(C)C(C)=CC=CC=1.N1C=CC=CC=1>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCCc2cc(C)ccc21
Temperature: 25 °C
Yield: 36.1 %

Procedure:
A solution of 6-methyl-1,2,3,4-tetrahydroquinoline (3.0 g) and ethyl acetoacetate (2.8 g) in xylene (7.0 ml) containing 2 drops of dry pyridine was refluxed for 12 hours. The solution was then allowed to cool to room temperature, washed in turn with 2N hydrochloric acid (2× 20 ml) and water (2 × 20 ml), dried over anhydrous magnesium sulphate and evaporated under reduced pressure at 100° to dryness, yielding 1-acetoacetyl-6-methyl-1,2,3,4-tetrahydroquinoline (1.7 g) as a crude solid, to be used directly in the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].CCN(CC[O:17]C1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl>C1CCCCC1>[Br:1][C:2]1[CH:7]=[C:6]([OH:17])[CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9]
Reactant: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Reactant: Cc1cccc(Br)c1C
Agent: Cl
Solvent: C1CCCCC1
Product: Cc1cc(O)cc(Br)c1C
Yield: 74 %

Procedure:
The general process was applied to a solution of 3-bromo-o-xylene (185 mg, 1.0 mmol) in 1.0 mL cyclohexane. The borylation step was carried out with HBPin (320 mg, 2.5 mmol) and dppe (8.0 mg, 0.02 mmol, 2 mol %) at 100° C. for 50 hours. After removal of the cyclohexane, the oxidation step was then performed as described above, after which the crude material was dissolved in CH2Cl2 and passed through a plug of silica gel. Evaporation of solvent gave 148 mg pure 10 (74%) as a white wax solid; mp 98-99° C. (lit. 101-102). 1H NMR (300 MHz, CDCl3): δ 6.91 (d, J=2.5 Hz, 1 H), 6.59 (d, J=2.7 Hz, 1 H), 2.25 (s, 6 H); 13C NMR (75 MHz, CDCl3): δ 153.2, 139.3, 128.3, 125.2, 116.9, 116.2, 21.4, 18.3; IR (neat): 3252, 2919, 1606, 1576, 1477, 1451, 1279, 1119, 839 cm−1; LRMS: m/e 200 (M+), 185, 121, 91; HRMS (EI): m/z 199.9839 [(M+); calcd for C8H9BrO: 199.9837]. For a previous preparation see Jacquesy et al., Chem. Soc., Chem. Commun. 110-111 (1980) (bromination of 3,4-dimethylphenol in superacid SbF5-HF, 83% yield) or Fischer and Henderson, Can. J. Chem. 61: 1045-1052 (1983).
Reaction SMILES: [ClH:1].[CH2:2]([C@@H:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:7]1)[CH2:3][CH2:4][CH3:5].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[ClH:1].[ClH:1].[CH2:2]([C@H:6]1[CH2:7][N:8]([C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:9][CH2:10][N:11]1[CH2:30][C:26]1[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1Cc1cccnc1

Procedure:
3(S)-Butyl-1-(1-naphthoyl)piperazine hydrochloride (0.200 g, 0.601 mmol) was reacted with pyridine-3-carboxaldehyde (0.062 mL, 0.661 mmol), sodium triacetoxyborohydride (0.321 g, 1.52 mmol), in dichloroethane (7 mL) at pH 5-6 in the presence of crushed molecular sieves as described in Example 8, Step A. The crude product was purified by silica gel chromatography with 30% acetone in hexane, followed by preparative HPLC (80-75% solvent A). After ion exchange, the title compound was isolated. FAB ms (m+1) 388. Anal. Calc. for C25H29N3O.2.3 HCl.0.95 H2O. C, 61.49; H, 6.85; N, 8.60. Found: C, 61.49; H, 7.01; N, 8.76.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8](C=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCCN
Reactant: CCCCc1ccc(C=O)cc1
Agent: Cl
Product: CCCCc1ccc(NCCCCCCC(=O)OC)cc1
Yield: 42.4 %

Procedure:
Following the procedure described in Step A of Example 68, reductive amination of 4-butyl-benzaldehyde (1.50 g, 9.26 mmol) with 7-aminoheptanoic methyl ester hydrochloride (1.51 g, 7.72 mmol) provided the title compound (955 mg). 1H NMR (300 MHz, CDCl3) δ7.29 (d, 2H), 7.16 (d, 2H), 3.85 (s, 2H), 3.67 (s, 3H), 3.54 (m, 1H), 2.70 (t, 2H), 2.59 (t, 2H), 2.29 (t, 2H), 1.60 (m, 6H), 1.32 (m, 6H), 0.92 (t, 3H); MS 306 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Br[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[CH:11]([P:6]([O:5][CH2:3][CH3:4])([O:8][CH2:9][CH3:10])=[O:7])[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21])([CH3:16])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.98 g, 74.7 mmol) was added portionwise to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (12.6 g, 49.8 mmol) in anhydrous DMF (150 mL) at 23° C. over 20 min. The reaction mixture was cooled to 0° C., and then a solution of methyl 4-(1-bromoethyl)benzoate (12.1 g, 49.8 mmol) in anhydrous DMF (100 mL) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 5 h, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water (2×). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate in petrolum ethers to give the title compound. MS: m/z=829.4 (2M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].I[CH3:14]>C1COCC1.O>[CH3:14][O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCCCCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCCc1cccs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 4-thiophen-2-yl-butan-1-ol (4.55 g, 29.09 mmol) in 20 ml of THF was carefully added to a stirred suspension of oil-free sodium hydride (1.05 g, 43.75 mmol) in 15 ml of THF. When the addition was complete, the mixture was heated to 50° C. and stirring continued for 1 hour. Iodomethane (2.7 ml, 43.75 mmol) was then added and the turbid solution was stirred at 50° C. for another 2 hours. After cooling, a few drops of water were added and the mixture was partitioned between 1N-HCl and ether. The organic layer was washed with saturated sodium bicarbonate solution and brine. Drying over sodium sulfate and careful evaporation (product is volatile) gave a pale yellow oil. Yield: 4.45 g (90%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](O)=[O:24]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)=[O:24])[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccn1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccccn2)ncn1Cc1ccccc1
Yield: 87 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.0 g (4.6 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and picolinic acid instead of 3-pyridylacetic acid hydrochloride to obtain 1.29 g of 1-benzyl-4-(2-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 87%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1)(=[O:25])[CH3:24]
Reactant: Nc1nc(Oc2ccccc2)nc2nc(-c3ccco3)nn12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(Oc2ccccc2)nc2nc(-c3ccco3)nn12

Procedure:
A solution of 7-amino-2-(2-furyl)-5-phenoxy-[1,2,4]triazolo[1,5-a][1,3,5]triazine (950 mg) in acetic anhydride was heated under reflux for 1.5 hours. The solvent was then evaporated in vacuo and the residue was purified by chromatography on silica eluting with dichloromethane containing ethyl acetate (5% v/v). The amorphous solid thereby obtained was crystallised from toluene to give 7-acetylamino-2-(2-furyl)-5-phenoxy-[1,2,4]-triazolo[1,5-a][1,3,5]triazine as colourless prisms, m.p. 168°-170° C.; microanalysis, found; C, 60.9; H, 4.2; N, 22.6%; C16H12N6O3 0.45 C7H8 requires: C, 60.9; H, 4.1; N, 22.3%; NMR 2.3 (s, 3H equivalent, toluene CH3), 2.35 (s, 3H, CH3CO), 6.7 (q, 1H, furyl-4H), 7.1-7.6 (complex, 6H, furyl-3H+ phenyl-H+toluene), 7.95(d, 1H, furyl-5H), 11.5 (broad s, 1H, NH); m/e 336 (M+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[CH3:26][S:27][C:28]1[N:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][N:29]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH:34]([C:31]3[CH:30]=[N:29][C:28]([S:27][CH3:26])=[N:33][CH:32]=3)[OH:35])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Reactant: CSc1ncc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 5 °C
Yield: 79.6 %

Procedure:
To a solution of 1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 4.36 g, 10.4 mmol) in tetrahydrofuran (100.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0M in tetrahydrofuran. 5.06 mL) was added slowly. The reaction was allowed to warm to 5° C. over 60 minutes, then cooled to −40° C., followed by adding 2-methylsulfanyl-pyrimidine-5-carbaldehyde (607, 1.30 g, 8.43 mmol, dissolved in tetrahydrofuran 15.0 mL). The reaction was allowed to warm to 10° C. over 2 hours. The reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound (608, 3.00 g, 79.6%). MS (ESI) [M+H+]+=447.2.
Reaction SMILES: Br.[CH3:2][N:3]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:4](=[O:7])[CH2:5][NH2:6].C(O)(=O)C>C(O)(C)C>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[C:9]2[N:8]([CH:12]=[CH:11][CH:10]=2)[N:3]([CH3:2])[C:4](=[O:7])[CH2:5][N:6]=1
Reactant: CN(C(=O)CN)n1cccc1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CN1C(=O)CN=C(c2ccccc2Cl)c2cccn21
Yield: 26.9 %

Procedure:
A solution containing 1-(N-methyl-aminoacetamido)-2-(2-chlorobenzoyl)pyrrole hydrobromide (12.6 g, 43.4 mmol) and glacial acetic acid (15 g, 0.25 mol) in 100 ml of isopropanol was refluxed under nitrogen for 12 hours and thereafter evaporated to an oil. This oil was flash chromatographed (silica, 4:1 ethyl acetate-hexane) to give 3.2 g (27%) of crystals, m.p. 132°-134°. This was combined with 0.5 g from an earlier run and recrystallized from acetone to give 3.5 g of crystals, m.p. 132°-133.5°.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][O:14][C:15](=[O:37])[C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([OH:25])[CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:37])[C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[NH:24][C:1](=[O:2])[O:25][C:20]=2[CH:19]=1
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(O)c1)NC(=O)OCc1ccccc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
A methylene chloride (15 mL) solution of carbonyl diimidazole (498 mg, 3.07 mmol) was added at 0° C. to a solution of (R)-3-(4-amino-3-hydroxy-phenyl)-2-benzyloxycarbonylamino-propionic acid methyl ester (1.17 g, 3.07 mmol), diisopropylethylamine (1.60 mL, 9.21 mmol), and methylene chloride (85 mL). The mixture was stirred at 0° C. for 4 h. The solvents were removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate/hexanes as eluent to afford the title compound as a white solid (51%). 1H-NMR (CDCl3, 500 MHz) δ 9.07 (s, 1H), 7.37-7.29 (m, 5H), 6.96 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 5.36 (d, J=8.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.07 (d, J=12.5 Hz, 1H), 4.65 (dd, J=13.5, 5.5 Hz, 1H), 3.74 (s, 3H), 3.17 (dd, J=14.0, 5.5 Hz, 1H), 3.07 (dd, J=14.0, 6.0 Hz, 1H). 13CNMR (CDCl3, 125 MHz) δ 171.9, 155.7, 155.5, 144.1, 136.2, 130.8, 128.6, 128.42, 128.38, 128.2, 125.1, 111.1, 109.8, 67.2, 55.1, 52.6, 38.3. Mass spec.: 371.18 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C:12]([OH:16])(CO)[CH2:11][O:10][C@@H:9]1[C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C:12](=[O:16])[CH2:11][O:10][C@@H:9]1[C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)(CO)CO[C@@H]1c1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 3 h

Procedure:
To a solution of tert-butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate (223 mg, 0.59 mmol) in tetrahydrofuran (4 mL) was added a solution of sodium periodate (143 mg, 0.67 mmol) in water (1.3 mL) and the mixture stirred for 3 hours. The mixture was concentrated and purified by flash chromatography (silica, gradient 5-20% ethyl acetate in chloroform) to yield tert-butyl[(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate as white solid.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[O:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Product: CC1(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)CCOCC1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. 1H NMR (CDCl3) δ 10.21 (s, 1H), 8.77 (d, 2H, J=6.0 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.73 (m, 2H), 7.51-7.54 (m, 1H), 7.31-7.36 (m, 3H), 7.24-7.26 (m, 2H), 3.58-3.80 (m, 4H), 1.95-1.99 (m, 2H), 1.70-1.74 (m, 2H), 1.22 (s, 3H). MS: m/z 471 (M++1).