Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:13]=1[CH2:14]Br>>[F:21][C:17]1[CH:16]=[C:13]([CH2:14][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:12]([F:11])=[CH:19][C:18]=1[F:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1cc(F)c(CBr)cc1F
Product: O=[N+]([O-])c1ccc(OCc2cc(F)c(F)cc2F)cc1
Yield: 92 %

Procedure:
Prepared in analogy to example 8 from 4-nitrophenol and 2,4,5-trifluoro-benzylbromide. Colorless solid. Yield=92%. MS: m/e=283.0 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: [C-]#N
Reactant: Cc1ccc(F)nc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C#N)nc1
Temperature: 150 °C
Reaction time: 72 h
Yield: 40.9 %

Procedure:
To a solution of 2-fluoro-5-methylpyridine (39 g; 351.5 mmol) in 141 ml of dimethylsulfoxide was added 17.23 g of sodium cyanide (351.5 mmol). After stirring for 3 days at 150° C., an additional 3 g of sodium cyanide was added and heating was continued for 5 hours. The reaction mixture was cooled to 25° C. then poured into 525 ml of ice water. The solution was filtered through a coarse fritted funnel and a dark brown solid was collected. The solid was air dried to give 17 g of the desired cyanopyridine: Anal Calc'd. for C7H6N2: C, 71.17; H, 5.12; N, 23.71. Found: C, 69.91; H, 5.24; N, 23.26.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.ON1C2C=CC=CC=2N=N1.N=C=N.C(N(CC)C(C)C)(C)C.[CH3:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](O)=[O:58]>CN(C)C=O>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:57](=[O:58])[CH2:56][O:55][CH2:54][CH2:53][O:52][CH3:51])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: COCCOCC(=O)O
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCC(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (138.0 mg, 0.2984 mmol), 1-hydroxybenzotriazole (40.8 mg, 0.302 mmol), and PS-Carbodiimide (1.37 mmol/g loading; 873 mg, 1.20 mmol) in anhydrous N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (260 μL, 1.5 mmol) was added. A small amount of sonication was used to get majority of solid into solution. 2-(2-Methoxyethoxy)acetic acid (45.7 mg, 0.334 mmol) in anhydrous DMF (1 mL) was added, and the reaction was vigorously shaken at rt for 5.5 h. An additional 0.2 eq of 2-(2-methoxyethoxy)acetic acid (8.1 mg, 0.060 mmol) in anhydrous N,N-dimethylformamide (0.5 mL) was added (after 7 h), and the reaction was shaken overnight at rt. The resin was filtered off (M-size frit) and rinsed several times with DMF. The filtrate was concentrated in vacuo at medium temp (bath temp: max 43° C.), redissolved in MeOH and DCM, and concentrated again under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 2%→5%→10%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound, as an off-white solid. The material was further purified by trituration in MeOH/sonication, affording the title compound, as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=2.36-2.56 (s, br, rotamers, 2H), 3.19 (s, 3H), 2.38-2.45 (m, 2H), 3.49-3.55 (m, 2H), 3.58 & 3.64 (t, J=5.2 Hz, rotamers, 2H), 4.08 & 4.10 (s, br, rotamers, 2H), 4.14 & 4.18 (s, rotamers, 2H), 6.37 (s, br, 1H), 6.77 & 6.78 (s, rotamers, 1H), 7.80 (dd, J=8.8, 2.0 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 8.85 (s, 1H), 9.17 (s, 1H), 9.54 (s, —NH), 11.95 (d, J=9.2 Hz, —NH). MS (ES+): m/z 465.01 (100) [MH+]. HPLC: tR=2.24 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:42][OH:43])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:40]#[N:41])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:46])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:42][OH:43])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:33][CH2:34][S:35](=[O:38])(=[O:39])[CH2:36][CH2:37]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:40]([NH2:41])=[O:46])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(N6CCS(=O)(=O)CC6)nc54)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(N6CCS(=O)(=O)CC6)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
In a 25 mL round-bottomed flask, 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (22 mg, 36.6 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1.1 mg, 2.56 μmol, Eq: 0.07) were combined with Ethanol (200 μl) and Water (200 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo, then diluted with acetonitrile and water and filtered and purified by HPLC to obtain 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (15.5 mg, 68%, [M+H]+ 619).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17](=O)[CH2:16][O:15][C:14]([CH3:21])([CH3:20])[C:13]=3[CH:22]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17](=[S:32])[CH2:16][O:15][C:14]([CH3:21])([CH3:20])[C:13]=3[CH:22]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(F)c3)cc21
Product: CC1(C)OCC(=S)Nc2ccc(-c3cc(F)cc(F)c3)cc21

Procedure:
Prepared from 7-(3,5-difluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and Lawesson's Reagent using the procedure of example 10. 1H-NMR (DMSO-d6) δ 12.01 (s, 1H), 7.70-7.63 (m, 2H), 7.59-7.48 (m, 2H), 7.41 (d, J=8.82 Hz, 1H), 7.28-7.18 (m, 1H), 4.51 (s, 2H), 1.62 (s, 6H); MS (FI) m/z 318 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=O)[CH3:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:18])[NH2:17].C(O)(=O)C>C(O)C>[CH3:15][N:16]([CH3:18])[N:17]=[C:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)[CH3:13]
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CN(C)N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NN(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]-ethanone (40 g), N,N-dimethylhydrazine (50 ml), glacial acetic acid (2 ml) and ethanol (35 ml) was heated under reflux for 78 hours. Removal of the solvent gave a residue which was distilled (104°-106°/0.1 mm Hg) to give 1-[1-(4-chlorophenyl)cyclobutyl]ethanone N,N-dimethylhydrazone.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[N:20]1([CH2:26]Cl)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[N:12]([CH2:26][N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c3[nH]c4ccnn4c(=O)c3cnc21
Reactant: ClCN1CCNCC1
Product: CCn1ncc2c1ncc1c(=O)n3nccc3n(CN3CCNCC3)c12

Procedure:
By reacting the product of Example 1 with piperazinomethyl chloride instead of 1-bromo-3-methylbutane as in Example 2, 3-ethyl-3,11-dihydro-11-(1-piperazino)methyl-6H-pyrazolo[1,5-a]pyrazolo[4', 3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]1([CH2:26][O:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([N:34]3[C:39](=[O:40])[C:38]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]5[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=5)=[CH:44][CH:43]=4)=[C:37]([CH2:56][CH2:57][CH3:58])[N:36]4[N:59]=[CH:60][N:61]=[C:35]34)[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23]1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][CH2:21][C:22]1([CH2:26][O:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([N:34]3[C:39](=[O:40])[C:38]([CH2:41][C:42]4[CH:43]=[CH:44][C:45]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=5[C:54]5[NH:3][C:4](=[O:7])[O:5][N:55]=5)=[CH:46][CH:47]=4)=[C:37]([CH2:56][CH2:57][CH3:58])[N:36]4[N:59]=[CH:60][N:61]=[C:35]34)[CH2:30][CH2:29]2)[CH2:23][CH2:24][CH2:25]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO[Si](C)(C)C(C)(C)C)CCC3)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO)CCC3)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogen carbonate (0.77 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-{[4-(trans-4-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.31 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.089 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.1 mL) was added and the mixture was stirred at 70° C. for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.22 g, 76%).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH2:12]([NH:17][CH:18]([CH2:21][O:22][CH3:23])[CH:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C1C=CC=CC=1>[CH2:12]([N:17]([CH:18]([CH2:21][O:22][CH3:23])[CH:19]=[O:20])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCNC(C=O)COC
Reactant: O=C=Nc1nnc(C2CC2)s1
Solvent: c1ccccc1
Product: CCCCCN(C(=O)Nc1nnc(C2CC2)s1)C(C=O)COC

Procedure:
5-Cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-pentylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-pentyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].Cl.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: COc1ccc(Cl)c(N)c1
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Cl)c(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A mixture of 0.2 g (0.87 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.22 g (1.04 mmol) of 2-chloro-5-methoxyaniline hydrochloride and 0.1 g (0.87 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol(97:3 to 90:10) to yield 0.19 g of 8-(2-chloro-5-methoxy-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as beige solid, mp 296-298° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:9]2[NH:10][C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:8]=2[C:7]([C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[N:6]1)#N.C(O)(=[O:36])C>[Ni]>[O:18]=[C:11]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[C:8]2[C:7]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])=[N:6][N:5]([CH2:4][CH2:3][CH:1]=[O:36])[C:9]=2[NH:10]1
Reactant: CC(=O)O
Reactant: N#CCCn1nc([C@H]2CCCN2C(=O)OCc2ccccc2)c2c3c(c(=O)[nH]c21)CCCC3
Agent: [Ni]
Product: O=CCCn1nc([C@H]2CCCN2C(=O)OCc2ccccc2)c2c3c(c(=O)[nH]c21)CCCC3
Reaction time: 6 h

Procedure:
A solution of Example 72A (2.0 g, 4.5 mmol) in acetic acid (10 ml) was treated with Raney nickel (200 mg) at rt. The reaction mixture was stirred under hydrogen for 6 h. Solid material was filtered off and the filtrate was concentrated. The residue was separated by flash chromatography to give Example 77A. Yield: 0.5 g (25%). MS (DCI): m/z 449 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(O)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(O)nn1C
Reaction time: 2.5 h
Yield: 17.4 %

Procedure:
To a solution of 5-hydroxy-2H-pyrazole-3-carboxylic acid methyl ester (2.3 g, 16 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (5.27 g, 16 mmol) and methyl iodide (2.3 g, 1.0 mL, 16 mmol) and the resulting mixture stirred for 2.5 h. The mixture was then filtered off to afford the title compound (434 mg, 17%) as a white solid after trituration with ethyl acetate. MS: m/e=157.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[CH2:21][C:22]1[S:26][C:25]([O:27][CH2:28][CH3:29])=[N:24][N:23]=1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:21][C:22]3[S:26][C:25]([O:27][CH2:28][CH3:29])=[N:24][N:23]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Reactant: CCOc1nnc(CCl)s1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nnc(COc2ccc(Oc3cccc(Cl)n3)cc2)s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
At room temperature (about 20° C.), 4.9 g of 4-(6-chloro-2-pyridinyloxy)-phenol in 40 ml of anhydrous dimethylformamide is dripped into 0.6 g of 100% strength sodium hydride in 20 ml of anhydrous dimethylformamide. To complete the exothermic reaction (evolution of hydrogen) the mixture is stirred for 30 minutes at 50° C. Subsequently, 4 g of 5-chloromethyl-2-ethoxy-1,3,4-thiadiazole in 20 ml of anhydrous dimethylformamide is dripped in and the mixture is stirred for 2 hours at 60° C. and overnight at room temperature. The mixture is then poured into 200 ml of ice water. The crude product which crystallizes out is filtered off and recrystallized from isopropanol. There is obtained 5.4 g of 5-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]-2-ethoxy-1,3,4-thiadiazole of m.p.: 92° C.-94° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[C:17]2[CH:18]=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[C:15]2[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=3)[CH:26]=[N:27][C:14]1=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[C:17]2[CH:18]=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[C:15]2[CH:24]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][O:35][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:32][CH:33]=3)[CH:26]=[N:27][C:14]1=2)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)n1c2cnc(C#N)cc2c2cc(-c3ccc(CO)cc3)cnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c2cnc(C#N)cc2c2cc(-c3ccc(COS(C)(=O)=O)cc3)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 130.3 %

Procedure:
Methanesulfonyl chloride (60 μL, 0.70 mmol) was added to a solution of 6-cyano-3-(4-hydroxymethyl-phenyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid tert-butyl ester (224 mg, 0.60 mmol) and triethylamine (110 μL, 0.80 mmol) in DCM (20 mL). The mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was diluted with DCM (200 mL) and washed with water (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as yellow oil (374 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[C:18](=O)([O-])[O-:19].[K+].[K+]>O.CN(C)C=O.CO>[Br:1][C:2]1[C:3]([O:19][CH3:18])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(Br)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (4.88 g, 16.5 mmol) was suspended in a mixed solvent of methanol (30 ml) and N,N-dimethylformamide (50 ml), potassium carbonate (4.57 g, 33.0 mmol) was added, followed by stirring at 60° C. for 30 minutes. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated away. The residue was suspended in a mixed solvent of methanol (30 ml) and N,N-dimethylformamide (50 ml), potassium carbonate (4.57 g, 33.0 mmol) was added, followed by again stirring at 60° C. for 14 hours. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated away. The precipitated solid was washed with a mixed solvent of ethyl acetate/isopropyl ether and collected by filtration to obtain the entitled compound (2.599 g, 64%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:18]2[N:17]=[CH:16][C:15](=[O:26])[NH:14][C:13]=2[N:12]=1.[OH2:27].[OH:28]OS([O-])=O.[K+]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:11]1[N:20]=[C:19]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:18]2[N:17]=[CH:16][C:15](=[O:26])[NH:14][C:13]=2[N:12]=1)(=[O:28])=[O:27]
Reactant: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12

Procedure:
2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone (0.38 g) was stirred in acetonitrile (150 ml) and water (150 ml) with oxone (3.79 g) for 18 hrs. Acetonitrile was removed in vacuo to leave an aqueous suspension. The solid was collected and dried in vacuo to afford the subtitled compound (0.30 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO[C:16]([N:20](C)C)(OC)[CH3:17].C[N:24](C=O)C>>[CH3:17][C:16]1[NH:20][N:24]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:9]=1
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: COC(C)(OC)N(C)C
Product: Cc1cc(-c2ccc(C)c([N+](=O)[O-])c2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-methyl-3-nitro-phenyl)-ethanone and (1,1-dimethoxy-ethyl)-dimethyl-amine in DMF was heated at 90° C. for 3 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the residue was dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixture was cooled to 0° C., and hydrazine hydrate (5 ml) at 0° C. was added. The mixture was stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue was purified by “flash chromatography” (0 to 30% EtOAc in hexanes) to give 8.5 g of 5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a yellowish solid, which was recrystallyzed from EtOAc to give 8.2 g of yellow powder.
Reaction SMILES: [CH:1]([O-:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[CH:1]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[F:11])=[O:3]
Reactant: O=C[O-]
Reactant: Nc1ccccc1F
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccccc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under argon gas, formate (6.1 mL) was added to acetic anhydride (15.5 mL) at 0° C. and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran (10 mL). Tetrahydrofuran (20 mL) solution containing 2-fluoroaniline (5.56 g) was added into the diluent at room temperature and stirred at room temperature for 1 hour. A title compound having the following physical properties was obtained by concentrating the reaction mixture. The obtained title compound was used for the following reaction without further purification.