Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[NH:8][C:7]=12.C([O-])=O.[NH4+]>CO.[Pd]>[C:13]1([CH:11]([C:9]2[NH:8][C:7]3=[CH:2][N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)[OH:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC(c1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OC(c1ccccc1)c1cc2ccncc2[nH]1
Yield: 43.4 %

Procedure:
To a solution of (7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (Example 26) (2.10 g, 8.12 mmol) and ammonium formate (3.07 g, 48.7 mmol) in methanol (28 mL) was added 10% Pd/C (0.21 g). The reaction mixture was refluxed for 1.5 h. TLC analysis showed the starting material was consumed. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated to dryness. The crude mixture was dissolved in EtOAc and water. The aqueous layer was extracted with EtOAc (2×) and CH2Cl2. The combined organic extracts were dried over Na2SO4. After filtration and concentration, the crude material was purified by Biotage chromatography to provide phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (0.79 g, 43%) as an off-white solid: mp 178-180° C.; 1H NMR (300 MHz, CD3OD) δ5.99 (1H, s), 6.35 (1H, s), 7.20-7.49 (6H, m), 7.99 (1H, d, J=5.6 Hz), 8.58 (1H, s); ESI MS m/z 224 [C14H12N2O+H]+; HPLC (Method A) >99% (AUC) tR=14.5 min.
Reaction SMILES: [CH:1]([N:4]1[C:30](=[O:31])[C:29]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:27][CH3:28])[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][C:20]=4[C:11]3=[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:9]=2[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl>O1CCOCC1.CO.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[C:30](=[O:31])[C:29]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:27][CH3:28])[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][C:20]=4[C:11]3=[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 50 mg of 10m in 1 ml of dioxane was added 150 μl of 4N HCl in dioxane and a few drops of methanol. The mixture was stirred for 3 hr at RT. The reaction mixture was diluted with 5 ml of 5% aq NaHCO3 and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated and the residue was treated with diisopropyl ether, to give 35 mg of white crystalline 10n; Mp: 227-229° C.; Rf: 0.60 (CH2Cl2/methanol 80/20).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[O:22])[CH2:11]1)=[O:7])(C)(C)C.[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37](C(O)=O)=[C:36]([O:44][CH3:45])[CH:35]=1>>[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH3:32])[CH:24]=3)=[O:22])[CH2:11]2)=[O:7])=[C:36]([O:44][CH3:45])[CH:35]=1
Reactant: Cn1cc(C(=O)NCCCCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(5-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide (0.89 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.42 g) to give N-(5-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]3)=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1cccc(/C=C/c2ccc(N)cc2)c1
Product: COc1cccc(/C=C/c2ccc(N3CC(C(=O)O)CC3=O)cc2)c1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of (E)-4-[2-(3-methoxy-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a brown solid; MS: m/e=336 (M−H)+.
Reaction SMILES: [NH2:1][C:2]([NH:4][N:5]=[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=O)=[O:3]>C(O)(=O)C>[C:9]1([C:6]2[CH:7]=[N:1][C:2](=[O:3])[NH:4][N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)NN=C(C=O)c1ccccc1
Solvent: CC(=O)O
Product: O=c1ncc(-c2ccccc2)n[nH]1
Yield: 90.1 %

Procedure:
[(Aminocarbonyl)hydrazono](phenyl)acetaldehyde (3.00 g, 0.0157 mol) in acetic acid (15.0 mL) was heated at 130° C. for 6 h. After cooling, the solvent was removed under reduced pressure. The residue was triturated with ether, filtered, washed with ether, and dried under high vacuum to give the desired product (2.45 g, 90.1%). Analytical LCMS: (M+H)+=174.0.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:14][C:15]([F:26])([F:25])[C:16](Cl)=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(Cl)Cl>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:16](=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([F:14])([F:25])[F:26])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: FC(F)(F)C(Cl)=Nc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(=Nc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of NaH (3.47 g, 145 mmol, 60% in mineral oil) in THF (200 mL) was added diethyl malonate (18.5 g, 116 mmol) at 0° C. The mixture was stirred for 30 min at this temperature and 2,2,2-trifluoro-N-phenyl-acetimidoyl chloride (19 g, 92 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2Cl2, washed with saturated sodium bicarbonate solution and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to provide 2-(2,2,2-trifluoro-1-phenylimino-ethyl)-malonic acid diethyl ester, which was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.[CH3:26][O:27][C:28]1[C:33]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:25][C@H:20]1[O:21][C@@H:22]([CH3:24])[CH2:23][N:18]([CH2:17][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([C:31]4[CH:32]=[C:33]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[C:28]([O:27][CH3:26])=[N:29][CH:30]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[CH3:11])=[N:16][N:15]=2)[CH2:19]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(C)c3c2)cc1NS(C)(=O)=O
Temperature: 110 °C
Yield: 17.1 %

Procedure:
6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (45 mg, 0.111 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (36.4 mg, 0.111 mmol), sodium carbonate (35.2 mg, 0.332 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (8.10 mg, 0.011 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by Mass Directed Automated Preparative HPLC (Method B) and the solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (10 mg).
Reaction SMILES: C(O)=O.[CH3:4][C:5](=[CH2:8])[CH:6]=O.[NH2:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)(C)C>[CH3:8][C:5]1[CH:4]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][CH:6]=1
Reactant: C=C(C)C=O
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Solvent: CC(C)O
Solvent: O=CO
Product: CCOC(=O)c1cc(C)cnc1C(=O)OCC
Temperature: 70 °C
Yield: 50 %

Procedure:
Isopropyl alcohol 675 ml and 90% formic acid 61.5 g (1.20 mol) were placed in 1 liter four-neck flask equipped with a reflux condenser. After heating the content to 70° C., 2-methyl-2-propenal 84.3 g (1.20 mol) and ethyl β-amino-β-ethoxycarbonylacrylate 150 g (0.801 mol) were simultaneously added dropwise thereto over a period of 1 hour with air-bubbling and refluxed for 10 hours. After removing isopropyl alcohol, 400 ml of water was added thereto and neutralized with sodium bicarbonate. After standing at 65°-67° C., separated oil layer was concentrated under reduced pressure to obtain 200 g of oily substance, which was distilled under reduced pressure to give 95 g of 5-methyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5])[CH3:2].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([N:11]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:17]=2[F:16])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=Cc1cccc(F)c1F
Reactant: CCOC(=O)c1cc(N)cn1S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(N=Cc2cccc(F)c2F)cn1S(C)(=O)=O

Procedure:
To a solution of 4-amino-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.1 g, 9.04 mmol) in anhydrous benzene (100 mL) was added 2,3-difluoro-benzaldehyde (1.29 g, 9.08 mmol) and catalytic amount of TsOH. The reaction mixture was heated under reflux in the presence of Dean-Stark trap for 24 hours. The solvent was then removed by evaporation and the residue was dried on the high vacuum pump for 16 hours for the next step use (2.9 g crude product). 1H NMR (500 MHz, DMSO-d6) δ8.99 (s, 1H), 7.85 (t, 1H), 7.75 (s, 1H), 7.58 (m, 2H), 7.32 (m, 1H), 4.32 (q, 2H), 3.90 (s, 3H), 2.51 (DMSO), 1.35 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH2:24])=[N:20][NH:21]2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH:24][C:4](=[O:5])[C:3]([F:8])([F:7])[C:2]([F:13])([F:1])[C:9]([F:12])([F:11])[F:10])=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 6 °C
Reaction time: 19 h

Procedure:
0.60 cm3 of heptafluorobutyryl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 10 cm3 of pyridine, after cooling the medium to about 6° C., the mixture is then allowed to return to room temperature over 19 hours and is evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is taken up in 40 cm3 of ethyl acetate and 20 cm3 of water; the precipitate formed is filtered off on a sinter funnel and then rinsed with 2×10 cm3 of methylene chloride and purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) to give 0.77 g of N-[6-chloro-1H-indazol-3-yl]-2,2,3,3,4,4,4-heptafluorobutanamide in cottony form.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)N3CCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)N3CCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-pyrrolidinocarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([Cl:17])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: O=C(Cl)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A catalytic amount of N,N-dimethylformamide (DMF)(10 μL) was added to a mixture of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (1.0 g, 5.1 mmol) and oxalyl chloride (2.2 mL, 25 mmol) in methylene chloride (5 mL) at 0° C. The resulting mixture was stirred at room temperature (about 25° C.) for 2 h. The volatiles were removed under reduced pressure, and the resulting residue was co-evaporated with toluene (2×) to provide the crude product, 1-(4-chlorophenyl)cyclopropanecarbonyl chloride, which was used in next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[OH:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@:12]3([OH:27])[CH2:13][CH2:14][C@@H:15]2[CH:25]=O)[CH2:7]1.C([O-])(O)=O.[Na+]>O.O1CCOCC1>[CH3:1][N:2]([CH3:4])/[N:3]=[CH:25]/[C@H:15]1[CH2:14][CH2:13][C@:12]2([OH:27])[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:24])[C@@H:8]([CH2:7][C@@H:6]([OH:5])[CH2:23][CH2:22]1)[CH2:9][CH2:10]3
Reactant: CN(C)N
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 0.80 g of NaH2PO4.H2O, 1.70 g of Na2HPO4.12H2O and 0.12 ml of N,N-dimethylhydrazine in 200 ml of water a solution of 0.64 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 20 ml of dioxane was added dropwise at room temperature. After 1.5 hrs the solution was alkalinized with an acqueous solution of NaHCO3 and extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash-chromatography (SiO2) using cyclohexane/chloroform/acetone 4/3/3 as eluant to give 0.37 g of the title compound (I-ai), as a white foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12](=[O:23])[NH:13][CH2:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[O:23][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][N:13]=1
Reactant: COC(=O)c1cc(C(=O)NCC(=O)c2ccccc2)c(SC)s1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ncc(-c3ccccc3)o2)c(SC)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
To a cooled (0° C.) solution of 80.1 mg (0.229 mmol) of methyl 5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-carboxylate (as prepared in the previous step) in 2 mL of anhyd DMF was added 26.7 μL (0.286 mmol) of phosphorus oxychloride. After stirring for 20 h at room temperature, the mixture was concentrated in vacuo. The resulting yellow solid was recrystallized twice from MeOH to afford the title compound as a beige powder (48.8 mg, 64%). 1H-NMR (300 MHz, DMSO-d6) δ8.26 (s, 1H), 7.88 (s, 1H), 7.86 (d, 2H, J=7 Hz), 7.51 (m, 2H), 7.40 (m, 1H), 3.86 (s, 3H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H13NO3S2: 332.0 (M+H). Found: 331.9.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[CH:23][C:22]([F:26])=[C:21]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:32])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[CH:23][C:22]([F:26])=[C:21]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:32]
Reactant: CCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN=[N+]=[N-])c(F)c3)cc(=O)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
438 mg (0.984 mmol) of the above 2-[4-(3-azidopropylamino)-3-fluorophenyl]-5-butylamino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 25 mL of tetrahydrofuran, 389 mg (1.48mmol) of triphenylphosphine was added under ice-cooling and the mixture was stirred at room temperature for 1 hour. 25 mL of water was added thereto and the mixture was further stirred for 5.5 hours. The mixture was extracted twice with ethyl acetate, and the organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=9:1:1) to give 380 mg of Compound 126 (yield: 92%), which was converted to hydrochloride according to the conventional method.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCNCC4)on3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCN(CCCCCO)CC4)on3)ccc21

Procedure:
The preparation was carried out as already described starting from 130 mg of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperidine and 79 mg of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C(NC1N=C(C2O[N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)C=C(C)N=1)C.[CH2:30]([NH:34][C:35]1[N:40]=[C:39]([C:41]([OH:43])=O)[CH:38]=[C:37]([CH3:44])[N:36]=1)[CH:31]([CH3:33])[CH3:32]>>[CH2:30]([NH:34][C:35]1[N:40]=[C:39]([C:41]2[O:43][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:38]=[C:37]([CH3:44])[N:36]=1)[CH:31]([CH3:32])[CH3:33]
Reactant: Cc1cc(C(=O)O)nc(NCC(C)C)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)nc(NCC(C)C)n1

Procedure:
rac-3-{4-[5-(2-Isobutylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-isobutylamino-6-methyl-pyrimidine-4-carboxylic acid; white crystalline solid; LC-MS: tR=0.90 min*; [M+H]+=428.25; 1H NMR (D6-DMSO): δ 0.93 (d, J=6.8 Hz, 6H), 1.91 (m, 1H), 2.35 (s, 6H), 2.41 (s, 3H), 3.18 (m, 2H), 3.50 (t, J=5.5 Hz, 2H), 3.75 (dd, J=5.5 and 8.8 Hz, 1H), 3.79-3.91 (m, 2H), 4.64 (t, J=5.5 Hz, 1H), 4.96 (d, J=5.0 Hz, 1H), 7.28 (s, 1H), 7.65 (s br, 1H), 7.76 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:16])[C:12]([O:14][CH3:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CO.[NH4+].[Cl-]>C1COCC1.[Zn]>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:16])[C:12]([O:14][CH3:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: COc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn2ncnc(Oc3ccc(N)cc3F)c2c1C
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazine (35 mg, 0.11 mmol) in THF (1.0 mL) was added MeOH (1.0 mL) followed by Zn (100 mg, 1.5 mmol) and NH4Cl (43 mg, 0.80 mmol). The reaction was heated at 60° C. for 3 h. The solution was filtered through Celite® and concentrated in vacuo. The product mixture was purified by a SCX cartridge (eluted with ammonia in methanol (2 M) to give the title compound (15 mg, 50%) as a white solid.
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.O>CN(C=O)C>[SH:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccncc1)c1ccc(Cl)cc1
Reactant: S
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)c1ccc(S)cc1
Yield: 48.5 %

Procedure:
A suspension of sodium hydrogen sulfide (6 g) in DMF (100 ml) was heated to reflux for 1 h, then cooled and 4-(4-chlorobenzoyl)pyridine (5 g) was added. The mixture was heated at reflux for 2 h, then cooled and added to water. The brown solution was washed with ether, then acidified with citric acid and extracted with dichloromethane (2×100 ml). The solvent was dried and evaporated to give the title compound as beige powder (2.4 g, 50%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([NH2:32])=O)[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.O=P(Cl)(Cl)Cl>C(N(CC)CC)C>[OH:1][CH:2]1[CH:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]#[N:32])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1cnn(-c2nc(NC3CCCC3)c3ncn([C@@H]4O[C@H](CO)C(O)C4O)c3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
429 mg of the 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxamide prepared in Example 5A was dissolved in 5 mL of dimethylformamide(DMF). To this solution was added 0.68 mL of triethylamine followed by chilled (0° C.) POCl3 (0.44 mL). The mixture was stirred and allowed to warm to room temperature. Stirring at room temperature continued 4 hours. The solvent was removed and the residue purified using TLC with a 10:1 dichloromethane:methanol solution to yield 1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carbonitrile.