Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:32]=[C:33]=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:26]([NH:32][C:33](=[O:34])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine (0.4 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, n-hexyl isocyanate (457 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere a RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 ml) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8g as solid. Yield: 0.619 g, 81%.
Reaction SMILES: N([O-])=O.[Na+].FC(F)(F)C(O)=[O:8].N[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:22][CH:21]=2)=[N:17][CH:18]=1>S(=O)(=O)(O)O.C(O)(=O)C>[OH:8][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:22][CH:21]=2)=[N:17][CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(N)cn2)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(O)cn2)cc1

Procedure:
Sodium nitrite (154 mg, 2.23 mmol) was dissolved in 2.68 ml of concentrated sulfuric acid at 0° C. Then, N—{(S)-3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-methylpropyl}-acetamide trifluoroacetate (832 mg, 2.01 mmol) in 5 ml of acetic acid was slowly added dropwise. After 1 h the ice bath was removed and stirring was continued for an hour. The reaction mixture was added dropwise to 100 ml of boiling water, the mixture was stirred for 1 h and, after cooling, extracted with ethyl acetate. The precipitated solid was filtered off and the filtrate was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 153 mg (37%), M+H+: 301.13.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([S:28][C:29]3[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([S:28][C:29]3[C:30]([CH3:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(Sc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of 4-aminobenzonitrile (184 mg, 1.56 mmol) in 1-methyl-2-pyrridone (2 mL) was added NaH (62 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (118 mg, 0.31 mmol) in 1-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was stirred at room temperature for 4 h, then poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 123 mg (83%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[CH:36][CH:35]=2)[N:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1ccccc1C(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1N
Temperature: 100 °C
Yield: 40.9 %

Procedure:
A suspension of (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (20.0 mg, 0.062 mmol, Example 6), 4-(4-methylpiperazino)aniline (16.6 mg, 0.087 mmol, Appollo Chemical) and p-toluenesulfonic acid hydrate (15 mg, 0.0777 mmol, Aldrich) in isopropanol (2.5 mL) was placed in a sealed tube and heated at 100° C. under microwave conditions for 1 hour. The resulting mixture was concentrated in vacuo and the crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(2-methoxyphenyl)-methanone as a light yellow solid (10.6 mg). HRMS, observed: 419.2190; Calcd for (M+H)+: 419.2195.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([CH:35]=[CH2:36])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH:35]=[CH2:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C=C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 20.3 (0.040 g, 0.082 mmol) in THF/MeOH (2/1) (1.5 mL) was added a 1 M solution of LiOH (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford a 20 (0.022 g, 58% yield). MS ESI (neg.) m/e: 461.2 (M−H)+.
Reaction SMILES: COC(C1C(C2SC=CN=2)C(C(OC)=O)=C(C)NC=1C)=O.[CH:22]([O:25][C:26]([C:28]1[CH:33]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[C:32]([C:39]([O:41][CH:42](C)[CH3:43])=[O:40])=[C:31]([CH3:45])[NH:30][C:29]=1[CH3:46])=[O:27])(C)[CH3:23].C(OC(C1C(C2SC=CN=2)C(C(OCCCC)=O)=C(C)NC=1C)=O)CCC.C(OC(C1C(C2SC=CN=2)C(C(OCCC)=O)=C(C)NC=1C)=O)CC.C(OC(C1C(C2SC=CN=2)C(C(OCC(C)C)=O)=C(C)NC=1C)=O)C(C)C>>[CH2:22]([O:25][C:26]([C:28]1[CH:33]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:31]([CH3:45])[NH:30][C:29]=1[CH3:46])=[O:27])[CH3:23]
Reactant: CC1=C(C(=O)OC(C)C)C(c2nccs2)C(C(=O)OC(C)C)=C(C)N1
Agent: CC1=C(C(=O)OCC(C)C)C(c2nccs2)C(C(=O)OCC(C)C)=C(C)N1
Agent: CCCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCCC)C1c1nccs1
Agent: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC)C1c1nccs1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1nccs1

Procedure:
The following compounds were obtained in an analogous manner: (b) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, (c) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester, (d) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid dibutyl ester, (e) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid dipropyl ester and (f) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid diisobutyl ester.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO.C(OCC)(=O)C>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: Brc1nsc2cccnc12
Reactant: NCCCN
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCCNc1nsc2cccnc12
Temperature: 25 °C

Procedure:
3-Bromoisothiazolo[4,5-b]pyridine (1.90 g, 8.8 mmol) and 1,3-diaminopropane (6.70 g, 90 mmol) in methanol (15 ml) was heated at 64° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water yielded N1-(isothiazolo[4,5-b]pyridin-3-yl)propane-1,3-diamine. 1H NMR (300 MHz, DMSO-d6): 8.55 (d, 1H), 8.05 (d, 1H), 7.32 (dd, 1H), 6.25 (br s, 1H), 3.65 (m, 2H), 2.85 (t, 2H), 1.85 (t, 2H), 1.45 ppm (br s, 2H). MW=208 confirmed by LC-MS, tr=5.91 min (Method Y) MH+=209.
Reaction SMILES: [CH2:1]([C:3]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([NH2:12])=[O:11])([CH2:5][CH3:6])[CH3:4])[CH3:2].[CH3:18][CH2:19][CH2:20]Br.O>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1(C)C=CC=CC=1>[CH2:18]([NH:12][C:10](=[O:11])[C:9]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:8]=1[O:7][C:3]([CH2:5][CH3:6])([CH2:1][CH3:2])[CH3:4])[CH2:19][CH3:20]
Reactant: CCC(C)(CC)Oc1cccc(Cl)c1C(N)=O
Reactant: CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCNC(=O)c1c(Cl)cccc1OC(C)(CC)CC
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of 2-[(1,1-diethylethyl)oxy]-6-chlorobenzamide (1.00 g, 3.9 mmol) and tetrabutylammonium bisulfate (0.13 g, 0.4 mmol) in 50% aqueous sodium hydroxide (25 mL) and toluene (15 mL) was heated to 100° C. and n-propyl bromide (0.43 mL, 4.7 mmol) in toluene (10 mL) was added over 30 min. The reaction was heated for 1 h, was cooled and poured into water. The mixture was extracted with ether and the organic layers were washed with brine, dried (MgSO4) and concentrated to a white solid. The crude product was purified by radial chromatography to afford 0.78 g (67%) of N-propyl 2-[(1,1-diethylethyl)oxy]-6-chlorobenzamide as a white solid: mp 100°-102° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[C:13](OC)(=[O:18])[C:14]([O:16]C)=[O:15].CCC([O-])(C)C.[K+].C1(C)C=CC=CC=1>C1COCC1.O>[F:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:13](=[O:18])[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COC(=O)C(=O)OC
Reactant: COc1ccc(C(C)=O)cc1F
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)CC(=O)C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.5 %

Procedure:
To a solution of 3-fluoro-4-methoxyacetophenone (2.59 g, 15.4 mmol) and dimethyl oxalate (2.0 g, 16.9 mmol) in THF (25 ml) was portionwise added a 1.7 M solution of potassium tert-amylate in toluene (25 ml, 42.5 mmol). The mixture was stirred at room temperature for 14 hours. Water (1.0 ml) and more THF (25 ml) were added, and stirring at room temperature was continued for 30 hours. Water (250 ml) was added, and the mixture was washed with a mixture of heptane and toluene. The aqueous phase was filtered, acidified with concentrated hydrochloric acid (6.0 ml), and filtered. After drying, 3.09 g (84%) of 4-(3-fluoro-4-methoxyphenyl)-4,2-dioxobutyric acid was obtained. A mixture of this acid (1.99 g, 8.29 mmol), ethanol (75 ml), and hydrazine hydrate (0.80 ml, 2 equiv.) was refluxed for 18 hours. Water (250 ml) and concentrated hydrochloric acid (4.0 ml) were added, and the mixture was filtered. After drying under reduced pressure 1.76 g (90%) of 5-(3-fluoro-4-methoxyphenyl)-2H-pyrazole-3-carboxylic acid acid was obtained as a solid. This acid was used to prepare the title amide using General Procedure (D).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCO
Product: Fc1ccc(-c2cn3cccc(OCc4ccccc4)c3n2)cc1
Yield: 24.9 %

Procedure:
3-(Benzyloxy)pyridin-2-amine (2.52 g, 13 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (2.73 g, 13 mmol) in ethanol (30 mL) were heated at 75° C. for 16 hours. The mixture was concentrated and the residue was purified by silica gel chromatography, eluting with dichloromethane and then 10% methanol in dichloromethane to yield 1.03 g (25%) of 8-(benzyloxy)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine. 1H NMR (CDCl3): δ 8.01 (dd, 2H), 7.82 (s, 1H), 7.78 (d, 1H), 7.55 (d, 2H), 7.41 (m, 3H), 7.14 (t, 2H), 6.65 (t, 1H), 6.48 (d, 1H), 5.44 (s, 2H); MS m/z 319 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.[OH-].[OH-].[Pd+2]>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])=[CH:5]3)[CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCN(C(=O)c2cc3cc(Br)ccc3[nH]2)CC1
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc3[nH]c(C(=O)N4CCN(C)CC4)cc3c2)c1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
A suspension of (5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 3, 0.057 g) in dry toluene (0.5 mL) was treated with Pd(OH)2 (0.001 g) under N2 atmosphere. The resulting mixture was then treated with 3-methoxyphenylboronic acid (0.057 g) and then K3PO4 (0.12 g), and heated at 95° C. for 24 h. The reaction mixture was cooled to ambient temperature and diluted with water (2 mL) and toluene (10 mL). The organic layer was separated and washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-12% methanol/dichloromethane) to give the title compound (0.005 g). 1H NMR (400 MHz, CDCl3): δ 9.96 (br s, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 7.17 (m, 1H), 6.87 (dd, J=2.2, 8.1 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 3.99 (br s, 4H), 3.86 (s, 3H), 2.52 (t, J=4.9 Hz, 4H), 2.35 (s, 3H). MS (electrospray): exact mass calculated for C21H23N3O2, 349.18; m/z found, 350.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([OH:16])=O.FC1C=CC(NC2C=NN(C)C=2C(O)=O)=CC=1>>[F:1][C:2]1[C:3]2[NH:8][C:9]3[CH:10]=[N:11][N:12]([CH3:17])[C:13]=3[C:14](=[O:16])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(Nc2ccccc2F)c1C(=O)O
Agent: Cn1ncc(Nc2ccc(F)cc2)c1C(=O)O
Product: Cn1ncc2[nH]c3c(F)cccc3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of step 2 in EXAMPLE 1 (CJ-022998) using 4-[(2-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 2, step 1), instead of 4-[(4-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([NH:18][CH:19]([CH3:34])[CH2:20][CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][N:18]([CH:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH3:17])[CH:19]([CH3:34])[CH2:20][CH2:21][CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C=O
Reactant: CC(CCCN1C(=O)c2ccccc2C1=O)NC(C)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(C(C)CCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1
Yield: 58 %

Procedure:
Using General Procedure B: Reaction of 3-methyl-pyridine-2-carbaldehyde and 2-[4-(1-pyridin-2-yl-ethylamino)-pentyl]-isoindole-1,3-dione in CH2Cl2 with NaBH(OAc)3 gave 2-{4-[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-pentyl}-isoindole-1,3-dione, as (one diasteroisomer (0.101 g) and a mixture of two diastereoisomers (0.0770 g), with a total yield of 58%. Deprotection with H2NNH2.H2O using General Procedure E gave a colorless oil. Conversion to the HBr salt using General Procedure D gave a white solid, which was isolated as a pure diastereoisomer. 1H NMR (D2O) δ 1.08 (d, 3H, J=6.3 Hz), 1.32 (d, 3H, J=6.6 Hz), 1.37-1.59 (m, 3H), 1.61-1.85 (m, 1H), 2.50 (s, 3H), 2.71-2.76 (m, 1H), 2.90-2.95 (m, 2H), 4.35 (s, 2H), 4.68 (q, 1H, J=6.6 Hz), 7.84 (t, 1H, J=6.6 Hz), 8.01 (t, 1H, J=6.9 Hz), 8.20 (d, 1H, J=8.1 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.56-8.63 (m, 2H), 8.81 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 17.01, 17.19, 19.97, 24.75, 27.37, 39.88, 46.16, 56.59, 59.71, 125.76, 127.08, 127.18, 136.58, 138.12, 142.58, 148.25, 148.62, 153.57, 156.65. ES-MS m/z 313 (M+H). Anal. Calcd. for C19H28N4.3.1HBr.0.4H2O: C, 40.00; H, 5.64; N, 9.82; Br, 43.42. Found: C, 39.93; H, 5.66; N, 9.71; Br, 43.54.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.O.OC1C2C(=CC(O)=CC=2)OC(=O)C=1.[N+:29]([O-])([OH:31])=[O:30]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[C:3]=1[N+:29]([O-:31])=[O:30]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2oc(=O)cc(O)c2c1
Agent: O=c1cc(O)c2ccc(O)cc2o1
Solvent: O
Product: COc1ccc2oc(=O)c([N+](=O)[O-])c(O)c2c1

Procedure:
Fuming nitric acid (30 ml) was added to a stirred suspension of 4-hydroxy-6-methoxycoumarin (m.p. 271°-2°(d); (C10H7NO5 requires C, 50.64; H, 2.97; N, 5.91. Found: C, 50.78; H, 3.18; N, 5.47).
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24](F)[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.C[N:34]1N=C(NC(C2C=C(OC3C=CC(C#N)=CC=3)C3CC(C)(C)OC=3C=2)=O)C=N1>>[CH3:6][N:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[CH:26][CH:27]=3)[C:13]3[CH2:14][C:15]([CH3:17])([CH3:18])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:5]=[N:34]1
Reactant: Cn1ncc(NC(=O)c2cc(Oc3ccc(C#N)cc3)c3c(c2)OC(C)(C)C3)n1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Product: Cn1ncc(NC(=O)c2cc(Oc3ccc(C(=N)NO)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide (188a) (130 mg, 0.334 mmol) and used without further purification for the next step.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O.C(Cl)Cl>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:31][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(S(C)(=O)=O)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(S(C)(=O)=O)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (2.6 g, 6.32 mmol) was suspended in MeOH (100 mL). DCM (40 mL) was added and the reaction cooled to −40° C. 3.8 M sodium hydroxide (1.663 mL, 6.32 mmol) in water (10.00 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% in water, 0.387 mL, 6.32 mmol) was added and the reaction stirred at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (63.2 mL, 379.13 mmol) and the reaction stirred for 30 min. The solvent was evaporated in vacuo. DCM (250 mL) and water (250 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-45% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.200 g, 49.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.85-1.91 (m, 1H), 2.18-2.29 (m, 2H), 2.35-2.41 (m, 1H), 2.98 (s, 3H), 3.00-3.13 (m, 1H), 3.38-3.44 (m, 1H), 3.67 (s, 3H), 4.13-4.19 (m, 1H), 5.20 (t, 1H), 5.47 (s, 1H), 7.34 (d, 2H), 7.83 (d, 2H). MS m/z 381 (M+H)+
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]3[N:15]=[CH:16][NH:17][C:18](=S)[C:13]=3[CH:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]>[Ni].O>[C@@H:1]1([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[CH:18][C:13]=3[CH:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: OC[C@H]1O[C@@H](n2ccc3c(=S)[nH]cnc32)[C@@H](O)[C@@H]1O
Agent: [Ni]
Solvent: O
Product: OC[C@H]1O[C@@H](n2ccc3cncnc32)[C@@H](O)[C@@H]1O

Procedure:
A mixture of 5 g of 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-thione, 5 g of Raney nickel, and 250 ml of water is stirred and heated under reflux for one hour and filtered while hot. The filtrate is evaporated in vacuo to a small volume and cooled to provide pure 7-β-D-arabinofuranosyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [C:1]([C:5]([CH:7]=[O:8])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1>C1C=CC=CC=1>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:16][CH:7]([OH:8])[C:5](=[O:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)C=O
Reactant: NC(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)C(O)NC(=O)c1ccc(Cl)cc1
Yield: 54 %

Procedure:
14 g (0.123 mol) of freshly distilled tert.-butylglyoxal were dissolved in 150 ml of absolute benzene. 19.1 g (0.123 mol) of p-chlorobenzamide were added and the mixture was heated for 15 hours under reflux. On cooling, the reaction product crystallised out. 16.1 g (54% of theory) of 1-(p-chlorobenzamido)-3,3-dimethyl-1-hydroxy-butan-2-one of melting point 130° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:22]>O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
39.6 g of p-cyanobenzylamine, 42.1 g of hexamethylenetetramine and 400 ml of water were mixed and after adjusting the pH of the solvent to 2.5 by sulfuric acid, the mixture was reacted at 90° C. for 2 hours while stirring. The reaction solution was cooled to room temperature and then cooled on ice. The crystals precipitated were collected by filtration, washed with water and dried to obtain 13.2 g (yield: 33%) of p-cyanobenzaldehyde. The purity was 99.8% or more.