Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].[ClH:36]>C(#N)C.C(Cl)Cl.C(O)C.C(OCC)C>[ClH:36].[ClH:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
A mixture of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine (3.30 g, 0.0109 mol), benzylbromide (1.86 g, 0.0109 mol), and sodium bicarbonate (1.68 g, 0.02 mol) was stirred 16 h at room temperature in 300 mL of acetonitrile (dried over 4 A molecular sieves) containing sodium iodide (0.2 g). The mixture was then heated at reflux 16 h followed by stirring 72 h at room temperature. The reaction was stripped to dryness and partitioned between chloroform and water. The chloroform layer was extracted with 5% sodium hydroxide and dried (Na2SO4). The chloroform was removed to give a fluffy-brown residue. This material was dissolved in methylene chloride for flash chromatography on a silica gel column. Elution was accomplished using 1% acetone in methylene chloride, 3% acetone in methylene chloride, and 5% acetone in methylene chloride. Fractions of similar purity were combined, and solvents removed to give an oil. This oil was converted to the HCl salt in an ethanol-diethyl ether mixture. The white solid obtained was then recrystallized from methanol-diethyl ether to give a white solid. The solid was dried 16 h at 78° C. in the presence of phosphorus pentoxide. This method provided 1.86 g (36.7%) of white crystalline solid, mp 241°-242° C. (dec.).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:16][CH:4]1[CH2:5][O:6][C:7]1[C:8]([N+]([O-])=O)=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>COCCOC>[CH2:17]([O:24][C:8]1[C:7]([O:6][CH2:5][CH:4]2[O:3][CH2:16]2)=[CH:12][CH:11]=[CH:10][N:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ncccc1OCC1CO1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(COc2ncccc2OCC2CO2)cc1

Procedure:
3.6 g of a sodium hydride suspension (55%) are added in portions, at 0°-5°, to 15.7 g of 3-(2,3-epoxypropoxy)-2-nitro-pyridine and 9.0 g of benzyl alcohol dissolved in 150 ml of 1,2-dimethoxyethane, with stirring and cooling, and the mixture is stirred for a further 3 hours at 0°-5° and for 2 hours at 20°-25°. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, the solution is washed with water and the ethyl acetate solution is evaporated. The residue (20 g) is chromatographed on 400 g of silica gel and eluted with toluene (250 ml fractions). 2-Benzyloxy-3-(2,3-epoxypropoxy)-pyridine is obtained in the form of an oil from fractions 28-36.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:29])=[O:28].[OH-].[NH4+:36]>>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccoc1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (95 mg, 0.177 mmol) and ammonium hydroxide (4 mL), the title compound was obtained as an off-white solid (59 mg, 61% yield). MS (ESI): 519 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]=[CH:3]1.N1C(=O)C2NC=NC=2N[C:14]1=O>>[N:8]1([C:9](=[O:11])[C:10]2[N:2]([CH3:1])[CH:3]=[N:4][C:5]=2[NH:6][C:7]1=[O:12])[CH3:14]
Reactant: Cn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: Cn1c(=O)[nH]c2ncn(C)c2c1=O

Procedure:
N-Demethylation of paraxanthine by Ndm also resulted in production of formaldehyde. After 90 minutes of incubation, 338.5±7.7 μM of paraxanthine was N-demethylated by 7.4 units of Ndm and approximately 540.6±20.9 μM of formaldehyde was produced (FIG. 5). 7-Methylxanthine (126.9±6.40 μM) and xanthine (193.7±4.0 μM) were the N-demethylated products. Tallying up all the products formed from paraxanthine, it was determined that approximately one molecule of formaldehyde was produced per methyl group removed.
Reaction SMILES: [C:1]1([C@H:7]2[NH:12][C:11](=O)[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11][NH:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COC[C@@H](c2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc([C@@H]2COCCN2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of (5R)-5-phenylmorpholin-3-one 5 (2.500 g, 14.11 mmol) in THF (57.02 mL) cooled in an ice bath was added lithium aluminium hydride (2M in THF) (9.170 mL of 2 M, 18.34 mmol) slowly over 5 mins. On complete addition mixture was warmed to 40° C. and stirred for 1 h. The reaction mixture was cooled down to rt then added more LAH (4.9 mL, 0.7 eq) and warmed back to 40° C. for a further 1 h. The reaction mixture was cooled in an ice bath and EtOAc (5 ml) was slowly added and the resulting mixture stirred at rt for 30 mins and then added very small amount of water until no vigorous reaction occurred. The reaction mixture turns thick so methanol (approx 50 mL) was added followed by a small amount of 1M NaOH to make mixture basic, filtered through celite, washing through with methanol. The filtrate was concentrated in vacuo and then loaded onto SCX2 (50 g) washed with methanol and filtrate discarded. The product was then eluted with 2M ammonia in methanol and the filtrate concentrated in vacuo to leave product as an orange oil that solidified on standing; 1H NMR (400.0 MHz, DMSO) d 2.85 (2H, m), 3.14 (1H, m), 3.45 (1H, m), 3.66 (1H, m), 3.78 (3H, m), 7.23 (1H, m) 7.31 (2H, m) and 7.41 (2H, m) ppm; MS (ES+) 164.1
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([N:17]=[C:18]=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1>CN(C=O)C>[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([NH:17][C:18]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(Cl)c(C)c1N=C=O
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C)c1NC(=O)N=C1NC(=O)CN1C
Reaction time: 4 h

Procedure:
To a stirring suspension of 7.92 g (0.07 mole) of creatinine in 50 ml of dry DMF is added 9.08 g (0.05 mole) of 3-chloro-2,6-dimethylphenyl isocyanate. After stirring for four hours, the reaction mixture is filtered through a diatomaceous earth pad to remove unreacted creatinine. Addition of a large excess of ice water precipitates a gummy semisolid mass which eventually crystallizes. After blowing the product to dry it for about eighteen hours, it is recrystallized from acetone-ether. Finally the product is taken up in dichloromethane and the resulting solution is filtered through diatomaceous earth. Concentration and dilution with ether gives pure product, 1-(3-chloro-2,6-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea; m.p. 140°-141.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[C:21]2[CH:35]=[CH:36][CH:37]=[CH:38][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared. The reaction was monitored by tlc (Rf=0.30, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:22])=[O:12])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1
Agent: CC(=O)[O-]
Product: NC(=O)c1ccncc1Nc1ccc(I)cc1

Procedure:
3-(4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-(4-iodophenyl)amino-isonicotinic acid and 0.4 mmol of ammonium acetate. LC/MS [5.03 min; 340 (M+1)]
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>O1CCCC1.CCCCCC.CN1CCCN(C)C1=O>[CH2:15]([CH:14]([C:25]([C:24]([CH3:29])([CH3:28])[CH3:23])=[O:26])[C:13]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCC(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: CCCCC(C(=O)OCC)C(=O)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
A solution of diisopropylamine (22.5 mL) in anhydrous tetrahydrofuran (THF, 100 mL) was treated dropwise with 1.6 M solution of butyl lithium in hexane (100 mL) at 20° C. under nitrogen atmosphere, stirred at this temperature for additional 30 min, then cooled down to −70° C., and treated dropwise during 30 min with a solution of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 18.6 g) and ethyl hexanoate (21.1 g) in THF (100 mL). Upon completion of the addition, the reaction mixture was stirred for 45 min at −70° C. and after that treated dropwise at the same temperature with a solution of 2,2-dimethyl-propionyl chloride (19.3 g) in THF (50 mL). The mixture was allowed to slowly warm-up to room temperature and stirred at this temperature overnight. Finally the reaction mixture was quenched by pouring onto a mixture of ice and 10% aqueous hydrochloric acid. The formed organic phase was separated and the aqueous phase was extracted with chloroform. The combined organic phases were thoroughly washed with brine to remove DMPU, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and distilled in vacuum to give 21.0 g (63%) of the title compound.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([OH:34])=O.[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][NH2:41]>ClCCl>[O:13]=[C:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([NH:41][CH2:40][C:36]1[S:35][CH:39]=[CH:38][N:37]=1)=[O:34]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1nccs1
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and thiazol-2-ylmethanamine (0.021 g, 0.186 mmol) were combined and stirred together in dichloromethane (0.5 mL) at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.69 (d, J=3.3 Hz, 1H), 7.19-7.38 (m, 11H), 6.77 (t, J=5.8 Hz, 1H), 4.67 (d, J=5.8 Hz, 2H), 4.09 (s, 2H), 3.53 (t, J=6.5 Hz, 2H), 2.84 (t, J=6.5 Hz, 2H); MS (ESI+) m/z 392 (M+H)+.
Reaction SMILES: O=C1[NH:6][CH:5]([CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[C:4](=[O:24])N1.[OH2:25].[OH-].[Ba+2].[OH-]>O>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][C@@H:5]([C:4]([OH:24])=[O:25])[NH2:6])[CH:9]=3)[NH:13][CH:12]=2)[CH2:18][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(CC4NC(=O)NC4=O)cc23)CC1
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: CN1CCC(c2c[nH]c3ccc(C[C@H](N)C(=O)O)cc23)CC1

Procedure:
A solution of the product from step (d) (2.4 g) and barium hydroxide hydrate (8.4 g) in water (50 ml) was refluxed for 72 hours, then cooled and evaporated in vacuo. The residue was taken up in hot methanol and filtered to remove barium salts.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC1C(F)=CC=CC=1OC1C=CC(C2C3C(=NC=NC=3N)N(C[C@H]3CCCN3)N=2)=CC=1>ClCCl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Agent: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2C[C@H]1CCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Into a 100 mL, round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (200 mg, 0.40 mmol, 1.00 equiv) in dichloromethane (20 mL), and trifluoroacetic acid (10 g, 87.70 mmol, 221.25 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The pH value of the solution was adjusted to 8-10 with 10% aqueous sodium carbonate. The solution was extracted with dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.1 g (62%) of 3-[4-(2-fluorophenoxy)phenyl]-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 73.3 %

Procedure:
The product was made by procedures which are well known in the art, that is, by alkylation of 4-nitrophenol (29.2 g, 0.21 mol) with ethyl chloroacetate (24.5 g, 0.20 mole) in the presence of potassium carbonate (30.4 g, 0.22 mol), potassium iodide (0.5 g) and acetonitrile (150 mL) to afford ethyl 4-nitrophenoxyacetate (33 g, 73.3%), m.p. 75°-76° C. after recrystallization from tert-butylmethyl ether; hydrogenation of the latter (22.5 g) at 50 psi in ethyl acetate (200 mL) in the presence of 10% palladium on Carbon (0.3 g) to afford 22.5 g (97%) of ethyl 4-aminophenoxyacetate, m.p. 157°-158° C.; and treatment of the latter (18.52 g, 0.08 mol) with methanesulfonyl chloride (12.6 g, 0.11 mol) in CH2Cl2 (250 mL) in the presence of pyridine (35 mL) to afford N-[4-(ethoxycarbonylmethoxy)phenyl]methanesulfonamide, 20.06 g (92%), m.p. 77.3°-78.5° C. after recrystallization from ethanol.
Reaction SMILES: C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[C:52](=[O:61])[C:53]([C:58]([OH:60])=O)=[CH:54][N:55]([CH3:57])[CH:56]=2)=[CH:47][CH:46]=1.[NH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]2[C:70]([NH2:85])=[N:71][CH:72]=[C:73]([C:75]3[CH:80]=[CH:79][C:78]([O:81][CH3:82])=[C:77]([O:83][CH3:84])[CH:76]=3)[CH:74]=2)=[CH:65][CH:64]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:85][C:70]1[C:69]([C:66]2[CH:65]=[CH:64][C:63]([NH:62][C:58]([C:53]3[C:52](=[O:61])[C:51]([C:48]4[CH:47]=[CH:46][C:45]([F:44])=[CH:50][CH:49]=4)=[CH:56][N:55]([CH3:57])[CH:54]=3)=[O:60])=[CH:68][CH:67]=2)=[CH:74][C:73]([C:75]2[CH:80]=[CH:79][C:78]([O:81][CH3:82])=[C:77]([O:83][CH3:84])[CH:76]=2)=[CH:72][N:71]=1
Reactant: Cn1cc(C(=O)O)c(=O)c(-c2ccc(F)cc2)c1
Reactant: COc1ccc(-c2cnc(N)c(-c3ccc(N)cc3)c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(C)cc(-c5ccc(F)cc5)c4=O)cc3)c2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
HOAt (23 mg), HATU (97 mg), DMAP (10 mg) and DIPEA (50 μl) were added to a solution of 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (46 mg) in DMF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for three hours. The compound obtained in Step 2 of Example 1 (55 mg) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified by PLC [ethyl acetate:methanol=20:1 (v/v)] to give 19 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[NH2:37][C:38]1[C:48]([F:49])=[CH:47][C:46](I)=[CH:45][C:39]=1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41].C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C>[NH2:37][C:38]1[C:48]([F:49])=[CH:47][C:46]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:12]3=[N:13][CH:14]=2)=[CH:45][C:39]=1[C:40]([N:42]([CH3:43])[CH3:44])=[O:41]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1N
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Yield: 80.5 %

Procedure:
548 mg (1.09 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 89 mg (0.109 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct and 368 mg (1.19 mmol) of 2-amino-3-fluoro-5-iodo-N,N-dimethyl-benzamide were placed in a microwave vial. To the vial were added 6 mL of acetonitrile and 5 mL of a saturated aqueous solution of sodium bicarbonate. The vial was sealed and purged with nitrogen and evacuated with vacuum (3×). The vial was irradiated in a microwave at 80° C. for 500 seconds. The resulting mixture was diluted with ethyl acetate and washed with water and brine. The layers were separated and the organic layer was dried over sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes. The clean fractions were concentrated to afford 490 mg (0.877 mmol, 81% yield) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a peach foam. MS: m/z 559.2 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[CH2:31]([C@@H:38]1[CH2:42][O:41][C:40](=[O:43])[NH:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(Cl)Cl>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([N:39]2[C@H:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][O:41][C:40]2=[O:43])=[O:10])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=C(O)CCc1csc2ccccc12
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCc1csc2ccccc12)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-benzo[b]thiophen-3-yl-propionic acid (2.1 g, 0.010 mol), triethylamine (4.12 g, 0.040 mol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added pivaloyl chloride (1.38 mL, 0.011 mol). After stirring for 1.5 h at 0° C., lithium chloride (0.475 g, 0.011 mol) and (R)-4-benzyl-2-oxazolidinone (1.988 g, 0.011 mol) were added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. Then the mixture was washed with water (3×150 mL). The organic layer was separated, dried, and evaporated to give the crude product. The title product was obtained as a brown oil (90%) by flash chromatography on silica gel eluting with 100% methylene chloride. This compound was used immediately in the following procedure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccc(F)c(C(F)(F)F)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 98 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate and 0.24 g of 4-fluoro-3-trifluoromethylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.35 g of 4-(2-butynyloxy)-6-(4-fluoro-3-trifluoromethylphenoxy)pyrimidine (the present compound (48)), m.p.: 90.1° C.