Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([CH2:15][CH3:16])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(O)C.O1CCOCC1.O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH2:15][CH3:16])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1nc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of ethyl 3-tert-butyl-1-ethyl-1H-pyrazole-5-carboxylate (0.35 g, 1.6 mmol) in a mixture of ethanol:dioxane:water (1:1:1, 6 mL) was added lithium hydroxide (0.15 g, 6.2 mmol). The reaction mixture was stirred overnight at RT. The solution diluted with EtOAc (50 mL) and 5% citric acid (50 mL). The organic phase separated, washed with brine (20 mL), dried (Na2SO4) and evaporated under reduced pressure to afford 3-tert-butyl-1-ethyl-1H-pyrazole-5-carboxylic acid (0.30 g, 98% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 6.64 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.22 (s, 9H); MS (ESI) m/z: 197.3 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(OCC)C>[Si:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCO)cc1
Reaction time: 1.5 h

Procedure:
To a stirring suspension of lithium aluminum hydride (893 mg, 23.5 mmol) in diethyl ether (30 mL) at 0° C. under nitrogen was added dropwise a solution of methyl 2-(4-(tert-butyldimethylsilyloxy)phenyl)acetate (3300 mg, 11767 μmol) in diethyl ether (20 mL). The mixture was stirred for 90 min, then quenched with solid sodium sulfate hexahydrate (10 g). The suspension was stirred for 45 min and the salts were removed via filtration with ether washings. The solvents were removed under reduced pressure and the residue was purified on 120 grams of silica eluting with 0-20% EtOAc/hexane to give a colorless oil. MS (ESI pos. ion) m/z (MH+): 255. Calc'd exact mass for C14H24O2Si: 254. 1H NMR (400 MHz, Chloroform-d) δ ppm 0.19 (s, 6 H) 0.98 (s, 9 H) 1.39 (t, J=6.02 Hz, 1 H) 2.80 (t, J=6.53 Hz, 2 H) 3.82 (q, J=6.19 Hz, 2 H) 6.78 (d, J=8.53 Hz, 2 H) 7.08 (d, J=8.53 Hz, 2 H).
Reaction SMILES: N[C:2]1[C:7](F)=CC=C[C:3]=1[OH:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=1[NH:18][C:19](=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.CO.C(OCC)(=O)C.O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:7][CH:2]2[CH2:3][O:9]2)[C:12]=1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Nc1c(O)cccc1F
Reactant: Nc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(F)cccc1OCC1CO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
To a stirred solution of 2-amino-3-fluorophenol (300 mg, 2.36 mmol) in water-methanol (10 ml) acetic acid anhydride was added until all 2-amino-3-fluorophenol was consumed. The solution was concentrated to a residue of N-(2-fluoro-6-hydroxyphenyl) acetamide. To a mixture of N-(2-fluoro-6-hydroxyphenyl)acetamide (399 mg, 2.36 mmol) and potassium carbonate (652 mg, 4.72 mmol) in DMF (5 ml) epibromohydrin (388 mg, 2.8 mmol) was added and the mixture was stirred at 70° C. for 3 hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by RP-HPLC (10-40% CH3CN) to give the desired product as a solid (242 mg, 1.08 mmol).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:28]([CH:29](O)[CH3:30])=[CH:27][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:24]([CH3:26])[CH3:25])[N:20]=[C:21]([CH3:23])[N:22]=1)[N:11]=3.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:2][CH:29]([C:28]1[C:6]([F:5])=[CH:7][C:8]2[O:17][CH2:16][CH2:15][N:14]3[C:10](=[N:11][C:12]([C:18]4[N:19]([CH:24]([CH3:26])[CH3:25])[N:20]=[C:21]([CH3:23])[N:22]=4)=[CH:13]3)[C:9]=2[CH:27]=1)[CH3:30]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(F)cc2OCC3)n(C(C)C)n1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
Phosphorus tribromide (0.53 mL of a 1.0 M solution in DCM) was added to a solution of 1-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]ethanol (98 mg, 0.26 mmol) in DCM (1 mL) at 0° C. The mixture was warmed to RT and stirred for 20 h. Water (2 mL) and sat. NaHCO3 (2 mL) were added and the mixture was extracted with DCM. The combined organics were washed (brine), dried (Na2SO4) and concentrated in vacuo to give the title compound (100 mg, 0.23 mmol, 88%) as a pale yellow solid. The product was taken on without further purification. 1H NMR (CDCl3, 300 MHz): δ 8.72 (1H, d, J=8.7 Hz), 7.60 (1H, s), 6.75 (1H, d, J=11.0 Hz), 5.82 (1H, sept., J=6.6 Hz), 5.45 (1H, q, J=7.0 Hz), 4.52-4.49 (2H, m), 4.44-4.41 (2H, m), 2.42 (3H, s), 2.11 (3H, d, J=7.0 Hz), 1.60 (6H, d, J=6.6 Hz)
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[CH3:14])/[CH2:9][CH:10]([CH3:13])[CH:11]=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C1CCCCC1.[Pd].ClCCl>[CH:1]1([CH2:7][CH:8]([CH3:14])[CH2:9][CH:10]([CH3:13])[CH:11]=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C/C(=C\C1CCCCC1)CC(C)C=O
Agent: O=[Cr](=O)([O-])Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C=O)CC(C)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
(E)-5-cyclohexyl-2,4-dimethylpent-4-enal (2.18 g; 11 mmol) was hydrogenated at 20 bar and room temperature in cyclohexane (20 ml) in the presence of 5% w/w palladium on charcoal (0.18 g). The thus obtained crude product was dissolved in dry dichloromethane (20 ml) and added drop-wise to a mixture of anhydrous sodium acetate (5 g) and finely ground pyridinium chlorochromate (PCC; 4.84 g; 22 mmol) in dry dichloromethane (50 ml) at 0° C. under nitrogen. The reaction was then stirred for 2 hours at room temperature. Diethyl ether (400 ml) was added to the reaction. After stirring for 30 minutes, the reaction was filtered through a short pad of silica gel, rinsing with diethyl ether. The product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 20:1) followed by bulb-to-bulb distillation (60° C./0.1 mbar). The product was obtained with a yield of 51% as a mixture of diastereoisomers.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](C2C(N3N=CC=N3)=CC=CN=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.Cl.CN(C1C=NC(C(F)(F)F)=CN=1)[C@H]1CCC[C@@H]1N.[F:51][C:52]1[CH:53]=[CH:54][C:55]([C:61]2[N:66]=[CH:65][CH:64]=[CH:63][N:62]=2)=[C:56]([CH:60]=1)C(O)=O>>[F:51][C:52]1[CH:60]=[CH:56][C:55]([C:61]2[N:62]=[CH:63][CH:64]=[CH:65][N:66]=2)=[C:54]([CH:53]=1)[C:19]([NH:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[NH:12][C:3]1[C:2]([CH3:1])=[N:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][N:4]=1)=[O:20]
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Agent: Cl
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 76) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 60 mg, 0.20 mmol) and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 41 mg, 0.20 mmol) except this was purified only by column chromatography (silica, 0 to 100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([O:22]C)=[O:21])[C:3]=1[Cl:24].[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([OH:22])=[O:21])[C:3]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2ccc(OC(F)F)c(F)c2)c(F)c(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(F)c(-c2ccc(OC(F)F)c(F)c2)nc(C(=O)O)c1Cl
Reaction time: 12 h
Yield: 59.2 %

Procedure:
To a flask charged with MeOH (2 mL) was added methyl 4-amino-3-chloro-6-(4-(difluoromethoxy)-3-fluorophenyl)-5-fluoropicolinate (190 mg, 0.52 mmol) and sodium hydroxide 2 M solution (1 mL, 1 mmol). Following 12 h of mechanical stirring, the reaction mixture was concentrated using a rotary evaporator with a water bath temperature of 40° C. Water was added to the resulting oil and the solution was slowly acidified by the addition of concentrated HCl until a tan precipitate formed. Filtration using filter paper and a Büchner funnel afforded the title compound as a tan solid (108 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH:16]=[C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][CH3:27])[C:18]=3[CH3:28])[O:14][C:13]2=[O:29])=[C:4]1[CH3:30])[CH3:2].[CH2:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[CH3:42])[CH3:32].OO>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:29])[O:14][C:15]([C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]([CH2:31][CH3:32])[C:34]=3[CH3:42])([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][CH3:27])[C:18]=3[CH3:28])[CH:16]=2)=[C:4]1[CH3:30])[CH3:2]
Reactant: CCn1c(C)cc2ccccc21
Reactant: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Agent: OO
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)(c3c(C)n(CC)c4ccccc34)OC2=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 5.5 g (0.0138 mole) of 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone, 8.0 g (0.05 mole) of 1-ethyl-2-methylindole, 100 ml of acetic anhydride and 0.25 ml of 30 percent hydrogen peroxide was stirred approximately eighteen hours at room temperature. The solid was collected by filtration and a small sample showed an infrared maximum at 1800 cm-1 and a smaller maximum at 1745 cm-1. The solid and the filtrate were recombined, and stirred eighteen hours at approximately 60° C. The solid was collected by filtration and dried at 60° C. in vacuo to obtain 3,5,5-tris(1-ethyl-2-methyl-3-indolyl)-2(5H)-furanone (Formula III: R=R2 =CH3CH2 ; R1 =R3 =CH3 ; Y=Y1 =H) as a white solid which melted at 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2Cl)c2ccccc2N1
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccc2Cl)c2ccccc2N1

Procedure:
A mixture of 23 g. (0.085 mole) of 1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepin-2-one [Sternbach et al., J. Med. Chem. 6, 261 (1963)] and 21 g. of P2S5 in 1500 ml. of pyridine was heated rapidly to the reflux temperature and refluxed for 45 min. It was then concentrated to dryness in vacuo and the residue was treated with 150 ml. of saturated NaCl solution and extracted (thrice) with methylene chloride. The CH2Cl2 solution was washed (water), dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in 1 l. of abs EtOH treated with Darco and filtered hot. The solution was then concentrated to 200 ml. and allowed to cool giving 19 g. (78%) of yellow crystalline compound, m.p. 228-229° C. The ir and nmr support the structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8](OCC)=[O:9])[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([OH:13])[CH2:8][OH:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(C(O)CO)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 2-amino-4-thiazolglyoxylate (10 g, 50 mmol) in anhydrous THF (150 mL) was added dropwise to a suspension of lithium aluminum hydride (1.9 g) in anhydrous THF (200 mL), and the mixture stirred under nitrogen at RT for 1 h. Excess ethyl acetate was then added to destroy residual reductant, after which an excess of Glauber's Salt was added and the resultant suspension stirred at RT for 40 min. The slurry was then filtered, and the filtrate evaporated in vacuo, and then dissolved in methanol and adsorbed onto silica gel. This mixture was then applied to a flash silica column, and the product eluted using 10% methanol in dichloromethane. Homogenous fractions were combined and evaporated under vacuum to give (±)-2-amino-4-(1,2-dihydroxyethyl)-1,3-thiazole product as a pale orange colored solid, (2.6 g, 32.5%) with the following structure: ##STR42##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:38][Si](CC)(CC)CC)[C:17]2[C:12](=[CH:13][C:14]([C:22]3[O:23][CH:24]=[CH:25][N:26]=3)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:27][C@H:28]2[CH2:31][C@H:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:29]2)[C:10]1=[O:37].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:38])[C:17]2[C:12](=[CH:13][C:14]([C:22]3[O:23][CH:24]=[CH:25][N:26]=3)=[CH:15][C:16]=2[C:18]([F:19])([F:20])[F:21])[N:11]([CH2:27][C@H:28]2[CH2:29][C@H:30]([N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[CH2:31]2)[C:10]1=[O:37]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(-c2ncco2)cc3C(F)(F)F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(-c2ncco2)cc3C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Example 14-2 (160 mg, 0.234 mmol) in tetrahydrofuran (6 mL) was added tetra-n-butylammonium fluoride (100 mg, 0.383 mmol) under nitrogen, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform/methanol=10/1) to give the titled compound (80 mg, 60%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=2[O:23]C)=[N:10][C:9]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:23])=[N:10][C:9]=1[C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(NC(=O)c3ccc(OC)cc3OC)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1)c1ccc(O)cc1O
Yield: 67.1 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-2,4-dimethoxy-benzamide prepared in Example 35 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 67.1%, mp: 217-219 └. 1H-NMR (400 Hz, Acetone-d6) δ: 4.40 (2H, s, CH2), 6.53 (1H, d, J=2.24 Hz, ArH), 6.58 (1H, dd, J=8.96 Hz, 2.24 Hz, ArH), 7.04 (2H, d, J=8.68 Hz, ArH), 7.32˜7.40 (5H, m, ArH), 7.65 (2H, d, J=8.68 Hz, ArH), 8.29 (1H, d, J=8.72 Hz, ArH); EI-MS m/e (%): 418.2 (M+, 33), 282.1 (100); HREI-MS Calcd. for C23H18N2O4S: 418.0987. found: 418.0970.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](OCC)=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccccn2)nc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nn(-c2ccccn2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of ethyl 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (15.00 g) in tetrahydrofuran (150 mL) was added lithium aluminum hydride (1.93 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Sodium sulfate 10 hydrate (21.03 g) and hexane (100 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitate was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give [3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methanol (11.38 g). The crystals were recrystallized from acetone-hexane. melting point: 116-117° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>O1CCCC1.CCOCC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[OH:8])=[CH:12][CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc(F)cc1)c1cccnc1
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (5.32 g, 49.7 mmol) in tetrahydrofuran (100 ml) was cooled to-78° C. and treated dropwise with 25 ml (50 mmol) of a 2 M solution of 4-fluorophenyl magnesium bromide in ether. The reaction mixture was then slowly warmed up to 0° C. over 1 h and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. Filtration of the residue on a short silica gel pad (elution ethyl acetate) followed by distillation in vacuo gave 9.42 g (93%) of the title material as a clear oil which crystallized upon standing. bp 120-130° C./0.2 torr (bulb to bulb distillation, air bath temperature), mp 45-47° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.88 (1H, s, CH benzhydryl), 7.05 (2H, m, aromatics), 7.25-7.36 (3H, m, aromatics), 7.73 (1H, d, J=7.9 Hz, aromatic), 8.44 (1H, d, J=5.2 Hz, aromatic), 8.55 (1H, s, aromatic). Anal. Calcd for C12H10FNO: C, 70.92; H, 4.96; N, 6.89. Found: C, 70.61; H, 4.86; N, 6.71.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:33]([CH3:35])[CH3:34]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH:33]([CH3:35])[CH3:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)Br
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)C)CC1
Yield: 13 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13), sodium hydride and 2-bromopropane, to give the desired product as a light brown foam (13%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.ClC1C=CC(C([NH:21][C:22]2[CH:23]=[N:24][C:25]([OH:28])=[CH:26][CH:27]=2)=O)=CC=1>>[OH:28][C:25]1[N:24]=[CH:23][C:22]([NH:21][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Product: O=C(Nc1ccc(O)nc1)c1ccc(C(F)(F)F)cc1

Procedure:
Starting from 4-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][C:9]1[C:14]([C:15]2[C:24](=[O:25])[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[OH:26])=[CH:13][CH:12]=[C:11]([Cl:27])[N:10]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:9]1[C:14]([C:15]2[C:24](=[O:25])[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[O:26][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:13][CH:12]=[C:11]([Cl:27])[N:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)nc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1c(-c2ccc(Cl)nc2Cl)c(=O)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pivaloyl chloride (0.096 ml) was added dropwise to a solution of 7-(2,6-dichloro-pyrid-3-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 1.6) (0.20 g) and pyridine (0.068 ml) in dichloromethane (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 hour and was then diluted with more dichloromethane. The organic phase was washed with aqueous sodium hydrogen carbonate (saturated) and brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 2:1) to give Compound No. A14 of Table A as a white solid (0.088 g).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:16]=[CH:15][N:14]=1)=[O:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:22]1([CH3:27])[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]([NH2:9])=[O:11])[CH:18]=1
Reactant: Cc1ccccc1CCc1ccnc(NC(=O)NC(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccccc1CCc1ccnc(NC(N)=O)c1
Temperature: 85 °C
Yield: 37.3 %

Procedure:
To the crude 1-benzoyl-3-[4-(2-o-tolyl-ethyl)-pyridin-2-yl]-urea (225 mg, 0.63 mmol) in ethanol (2 mL) is added potassium carbonate (86 mg, 0.63 mmol). The resulting mixture is heated at 85° C. for 30 min. Solvent is removed and the residue is purified by silica flash column chromatography eluting with EtOAc in Heptane (gradient from 0% to 100%) to give 60 mg of the titled product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13].Cl.N1C(C)=CC(C)=CC=1C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH3:16][C:11]([NH:10][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])([CH3:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(O)c1cnccn1
Reactant: COC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)C(C)(C)NC(=O)c1cnccn1
Reaction time: 2 h

Procedure:
To a suspension of 2-pyrazinecarboxylic acid (1.22 g, 9.8 mmol), methyl 2-amino-2-methylpropanoate.HCl (1.50 g, 9.8 mmol) and collidine (3.9 mL, 29.4 mmol) in CH2Cl2 (25 mL) was added HATU (4.47 g, 11.8 mmol) in one portion. After 2 h, DMF (5 mL) and CH2Cl2 (25 mL) was added in order to solubilize the reaction. After stirring an addition 3 h, the reaction was diluted with EtOAc and the washed with 1 N HCl, 1N NaOH, saturated NaHCO3, and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The material was used without further purification. 1H NMR (300 MHz, CDCl3) δ 9.16 (d, J=1.4 Hz, 1H); 8.75 (d, J=2.4 Hz, 1H); 8.53 (dd, J=1.5, 2.5 Hz, 1H); 8.33 (s, 1H); 3.79 (s, 3H); 1.70 (s, 6H). LC/MS: Rt=1.45 min, ES+224 (Formic Acid method).