Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([OH:12])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:21](=[O:22])([O:23][CH2:24][CH3:25])[O:12][C:4]1[CH:5]=[C:6]([C:8]([Cl:10])([Cl:11])[Cl:9])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: CCOC(=O)Cl
Reactant: Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 6.17 grams (g) (0.025 mole (m)) of 2-chloro-6-hydroxy-4-(trichloromethyl)pyridine in 100 milliliters of toluene. To this solution was added 2.53 g (0.025 m) of triethylamine. To this mixture was then added 2.71 g (0.025 m) of ethyl chloroformate dissolved in 20 ml of toluene. The mixture was stirred at 50° C. for 4 hours. The salt which formed was removed by filtration and the toluene was removed by evaporation under reduced pressure. Using a short path distillation (Kugelrohr) at 130° C. and 80 millimeters of mercury, 6-chloro-4-(trichloromethyl)-2-pyridinyl ethyl carbonate was obtained in a yield of 6.65 g (83 percent of theory). The product had a refractive index of n(25/d)=1.5354. The structure of the product was confirmed by its NMR spectrum (Compound No. 1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[OH-].[Na+].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1>O.O1CCCC1>[OH:6][CH:4]1[CH2:5][N:2]([C:17]([O:16][CH2:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:18])[CH2:3]1
Reactant: OC1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (2 g, 18.26 mmol, 1.00 equiv) and sodium hydroxide (1.53 g, 38.25 mmol, 2.10 equiv) in water (10 mL) and tetrahydrofuran (25 mL) was added Cbz-Cl (3.27 g, 19.17 mmol, 1.05 equiv) dropwise with stirring at 0° C. over 30 min. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The mixture was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×40 mL of sodium chloride (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). Purification afforded 2.0 g (53%) of benzyl 3-hydroxyazetidine-1-carboxylate (50.2) as a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:26][CH2:22][CH2:23][CH2:24][CH3:25])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1cc2c(cc1Cl)C=C(C(=O)OCC)C(C(F)(F)F)O2
Temperature: 90 °C
Yield: 79.1 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and butylamine (0.15 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The solution was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give a light yellow oil (0.46g, 79%): GCMS m/z 377.00 (M+). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 7.08 (s, 1H), 6.23 (s, 1H), 5.63 (q, 1H, J=7.0 Hz), 4.70 (brs, 1H), 4.27 (m, 2H), 3.17 (m, 2H), 1.63 (m, 2H), 1.43 (m, 2H), 1.31 (m, 3H), 0.98 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 7 g of 5-aminopyridine-2-carboxylic acid methyl ester, 8.9 g of 3,4-dichlorobenzaldehyde, and 40 ml benzene are refluxed for 29 hours on a water-separating trap. The initial suspension becomes a clear solution, which is evaporated. The solid residue is triturated with diethyl ether and recrystallized from acetonitrile, to yield the 5-(3,4-dichlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 202°-207°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][C:20](Cl)=[N:21][CH:22]=1.C(=O)([O-])[O-:25].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:6](=[O:7])([OH:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][C:20]([NH:15][CH2:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([OH:5])=[O:7])=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: O=C([O-])[O-]
Reactant: Clc1ncc(Br)cn1
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)O
Product: O=C(O)N1CCCC[C@H]1CNc1ncc(Br)cn1
Temperature: 25 °C
Yield: 141.5 %

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 g), 5-bromo-2-chloropyrimidine (0.9 g) were combined in xylene (20 ml) containing potassium carbonate (1.29 g) and diisopropylethylamine (2.43 g) and warmed to reflux for 48 h. The mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, pentane-25% ethyl acetate/pentane). The appropriate fractions were collected, solvent removed at reduced pressure to give the title compound (1.43 g) as a colourless gum
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+].[Fe]>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(I)cc(N2CCOCC2)c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc(I)cc(N2CCOCC2)c1
Yield: 81 %

Procedure:
4-(3-Iodo-5-nitrophenyl)morpholine (200 mg, 0.60 mmol, prepared according to WO 2008104754 A1 20080904) and powdered iron (142 mg, 2.54 mmol) were suspended in ethanol (2 ml) and acetic acid (240 μl, 4.20 mmol) and heated 3 h to 95° C. The reaction mixture was diluted with water, neutralised to pH=6 with sodium carbonate and extracted with ethyl acetate (×3). The organic phase was washed successively with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 179 mg (81% yield, 82% purity) of the title compound were obtained and used in the next synthetic step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:16](=[O:18])[CH3:17])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:19][CH2:17][C:16]([C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([CH:10]([CH3:11])[CH3:12])=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])=[O:18]
Reactant: [Br-]
Reactant: CC(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)c1cc(C(C)C)c(C(=O)CBr)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1 (2,4,6-triisopropylphenyl)ethanone (10.0 g, 65.3 mmol) in acetonitrile (81 mL) was added tetrabutylammoniumtribromide (TBABr3, 19.6 g, 40.6 mmol). The reaction was stirred at room temperature for 3.0 h. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(2,4,6-triisopropylphenyl)ethanone (13.2 g), which was used directly for the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:7]([S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:6]=1)=O.[NH2:25][C:26]([NH2:28])=[S:27]>CO>[BrH:1].[NH2:28][C:26]1[S:27][CH:2]=[C:3]([C:5]2[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:7]([S:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH:6]=2)[N:25]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1Sc1ccc(F)cc1F
Reactant: NC(N)=S
Solvent: CO
Product: Br
Product: CS(=O)(=O)Nc1ccc(-c2csc(N)n2)cc1Sc1ccc(F)cc1F

Procedure:
A mixture of 4'-bromoacetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide and thiourea (0.58 g) in methanol (15 ml) was refluxed for 1 hour, and then cooled. The precipitates were filtered, washed with ethanol and dried to give crystals of 4'-(2-amino-4-thiazolyl)-2'-(2,4-difluorophenylthio)methanesulfonanilide hydrobromide (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH:12]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][C:14](O)=[O:15]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14](=[O:15])[CH2:13][NH:12][C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:6][CH:5]=1)=[O:11]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(=O)CNC(=O)OCc2ccccc2)cc1
Yield: 70 %

Procedure:
p-Hydroxybenzoic methyl ester and Z-Gly.OH were treated in the same manner as in Example 78 to obtain N-benzyloxycarbonyl glycine p-methoxycarbonylphenyl ester (hereinafter represented by ##STR11## COOCH3 ") in a yield of 70%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][N:15]=2)[C:11]=1O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[N:10]2[N:13]=[CH:14][N:15]=[C:9]2[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ncnn2c1O
Product: CCOC(=O)c1cnc2ncnn2c1Cl

Procedure:
A suspension of 6-ethoxycarbonyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine (7 g) in phosphorus oxychloride (20 ml) was refluxed for 30 minutes, the resultant orange solution was further refluxed for one hour, and excess phosphorus oxychloride was removed by distillation under reduced pressure. Benzene (50 ml) was added to the residue, and remaining phosphorus oxychloride was completely removed by azeotropic distillation under reduced pressure. Chloroform (80 ml) was added to the residue, the insoluble matters were filtered off, and the solvent was removed in vacuo from the filtrate. Purification of the brown residue by silica gel column chromatography gave 3.9 g of the objective compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].CC(=CC)C.O.P([O-])(O)(O)=[O:36].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.C1COCC1.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[C:4]([OH:36])=[O:5]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(C(=O)O)c3)nc(OC)n2)cc1
Reaction time: 15 h

Procedure:
A solution of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [120 mg, 0.31 mmol, Example 35(j)] and 2-methyl-2-butene (2.93 mL, 28 mmol) in t-butanol (4 mL) and THF (2 mL), is treated with a solution of sodium dihydrogen phosphate monohydrate (303 mg, 2.2 mmol) and sodium chlorite (0.28 g, 3.2 mmol) in water (2 mL) at room temperature. After 15 hours at 20° C., the mixture is concentrated and diluted with water. The mixture is adjusted to pH 3 and the resulting solid is filtered and dried to afford 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid. [118 mg, 96%, Example 20(a)]. LCMS: RT=2.38 minutes, MS: 398 (M+H). IC50=0.4 nM
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].[H][H]>[Pd].C(O)C>[NH:4]=[C:3]([C:7]1[C:8](=[O:19])[N:9]([CH3:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:6]=1[OH:5])[CH2:1][CH3:2]
Reactant: [H][H]
Reactant: CCc1noc2cc(-c3ccccc3)n(C)c(=O)c12
Agent: [Pd]
Solvent: CCO
Product: CCC(=N)c1c(O)cc(-c2ccccc2)n(C)c1=O

Procedure:
A mixture of 7.2 g. (0.0314 mole) of 3-ethyl-5-methyl-6-phenyl-isoxazolo[4,5-c]pyridin-4(5H)-one, 160 ml. ethanol and 0.800 g. 10% palladium on carbon is hydrogenated at 50 psi and room temperature. The hydrogenation is ceased after 1 equivalent of hydrogen is absorbed (ca 4 hours). The mixture is filtered to remove the catalyst and the solvent removed in vacuo. The residue is crystallized from ether to give 3-(1-iminopropyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone, m.p. 145° to 147° C.
Reaction SMILES: [CH2:1]([O:3][P:4](F)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C[Si](C)(C)[O-:12].[K+:15]>CCOCC>[CH2:1]([O:3][P:4]([O-:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[K+:15]
Reactant: C[Si](C)(C)[O-]
Reactant: CCOP(=O)(F)OCC
Agent: [K+]
Solvent: CCOCC
Product: CCOP(=O)([O-])OCC
Yield: 54.5 %

Procedure:
The procedure of Example 1 was followed except that diethylfluorophosphate (0.9 mL, 6.4 mmol) was added by syringe to a slurry of potassium trimethylsilanolate (0.82 g, 6.4 mmol) in dry ether (25 mL) and a 5 h reaction time was used. Potassium diethylphosphate (0.67 g, 54% yield) was isolated as a tan solid: 1H NMR (D2O, DSS) δ 1.2 (t, J=6.9 Hz, CH3, 6H), 3.9 (q, J=6.9 Hz, CH2, 4H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[O:10]1[CH2:11][CH2:12][CH2:13][CH:14]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][O:10]2)[C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1c(F)cn(C2CCCO2)c(=O)n1C1CCCO1
Temperature: 160 °C

Procedure:
In 20.8 ml of pyridine were dissolved 5.2 g (40 m mol) of 5-fluorouracil and 9.8 g (140 m mol) of 2,3-dihydrofuran. The solution was heated at about 160° C. in a closed tubular reactor under agitation for 5 hours. The resultant reaction mixture was treated similarly to Example 7 to give the above mentioned-compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[CH2:23]([O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1)[CH3:24]>>[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])[CH:29]=[CH:28][N:27]=1)[CH3:24]
Reactant: CCOc1cc(B(O)O)ccn1
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Product: CCOc1cc(-c2cnn(-c3ccc(C(=O)NCCCOC)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 213 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and (2-ethoxypyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.1 Hz, 3H) 1.71 (quin, J=6.7 Hz, 2H) 3.18 (s, 3H) 3.21-3.29 (m, 2H) 3.32 (t, J=6.3 Hz, 2H) 4.22 (q, J=7.1 Hz, 2H) 7.31 (s, 1H) 7.40 (d, J=5.3 Hz, 1H) 7.94 (d, J=5.6 Hz, 1H) 8.26-8.34 (m, 1H) 8.34-8.42 (m, 1H) 8.47 (br. s., 1H) 8.61 (t, J=5.6 Hz, 1H) 8.82 (d, J=1.5 Hz, 1H) 13.42 (br. s., 1H). MS m/z 398 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:41][CH:42]([CH3:47])[C:43]([CH3:46])([OH:45])[CH3:44]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16]([NH:41][CH:42]([CH3:47])[C:43]([OH:45])([CH3:46])[CH3:44])[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Reactant: CC(N)C(C)(C)O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1)C(C)(C)O
Temperature: 120 °C

Procedure:
To a solution of 2-(2-chloro-phenyl)-1-[7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone, 31, (0.036 g, 0.080 mmol) in N-methylpyrrolidinone (2 mL) is added diisopropylethylamine (0.071 mL, 0.410 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.035 g, 0.240 mmol). The mixture is heated to 120° C. for 4 hours. The reaction crude product is then purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.54 (s, 1H), 7.42-7.38 (m, 1H), 7.32-7.10 (m, 7H), 4.36 (s, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI+ MS: m/z (rel intensity) 467.0 (100, M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[OH-].[Li+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[OH:9])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(C)cc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cc2c(C)cc(C)cc2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 3,5-dimethylphenol (12 g) were added lithium hydroxide monohydrate (4.2 g) and 4-methoxybenzyl chloride (14 mL) at 85° C., and the mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and purified by column chromatography on silica gel (eluent: dichloromethene) to give 2-(4-methoxybenzyl)-3,5-dimethylphenol (5.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N1C=CC=CC=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O>[CH3:22][C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:28])=[CH:30][CH:31]=1)([CH3:20])[CH3:21]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 16.8 g. (0.1 mol) 4-methoxy-2-nitroaniline in 150 ml. anhydrous pyridine are added dropwise, while cooling with ice, 19.7 g. (0.1 mol) 4-tert.-butylbenzoic acid chloride. The reaction mixture is stirred for 1 hour at ambient temperature, poured into 1 liter of cold water and the precipitate obtained is filtered off with suction. There are obtained 32.3 g. (98% of theory) of the title compound in the form of yellow crystals; m.p. 103°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19](O)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=O.CN(C)CCN>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([NH:26][CH2:27][CH2:28][N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2 hours with nitrogen bubbling through it. The reaction mixture was then heated at 55° C. for 2 hours under nitrogen and cooled to room temperature. A solution of N,N-dimethylethylenediamine (4.41 g, 0.050 mole) in tetrahydrofuran (5.5 ml) was added and the reaction mixture was stirred at room temperature under nitrogen over the weekend. The reaction mixture was evaporated to a white solid and triturated with water (100 ml). The solid was collected by filtration, rinsed once with a 5% potassium hydroxide solution, and washed twice more with water to give 4.9 g of a white solid (79%). A second crop of white solid was obtained from the mother liquor of the above solid. The second crop was dried under high vacuum at 70° C. to give a white solid, mp 141.5°-143° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([O:11]C)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].C(Cl)(=O)C(Cl)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CO.ClCCl>[N:1]1([CH2:7][CH2:8][C:9]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NCc1ccccn1
Reactant: COC(=O)CCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCN1CCOCC1)NCc1ccccn1
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of methyl 4-morpholinepropionate (5.0 g, 28.9 mmol) in MeOH (25 mL) was added 2N NaOH (17.3 mL, 34.6 mmol). The mixture was stirred for 1 h then concentrated in vacuo. The residue was suspended in dichloromethane (125 mL) and DMF (30 μL) was added followed by oxalylchloride (10 mL, 115.6 mmol). The mixture was allowed to stir for 2 h. then concentrated in vacuo. The resulting solid was added portion-wise to a solution of 2-(aminomethyl)pyridine (2.88 mL, 28.2 mmol) and triethylamine (9.0 mL, 64.86 mmol) in dichloromethane (200 mL). The mixture was stirred at ambient temperature for 1 h. then washed with water (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield 3-morpholin-4-yl-N-pyridin-2-ylmethyl-propionamide (5.56 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:21][OH:22])=[C:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:21]=[O:22])=[C:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2c(CO)ccc3ccc(OC)cc23)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cccc(-c2c(C=O)ccc3ccc(OC)cc23)c1
Yield: 92.1 %

Procedure:
7-Methoxy-1-(3-methoxyphenyl)-2-naphthalenemethanol (1.75 g) was oxidized using the reagent prepared as in Example 136 from oxalyl chloride (0.62 mL) and dimethylsulfoxide (0.9 mL) in dichloromethane (14 mL). The usual work up furnished 1.6 g of 7-methoxy-1-(3-methoxyphenyl)-2-naphthalenecarboxaldehyde.