Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(OCCCOS(C(F)(F)F)(=O)=O)(=O)=O.[F:20][C:21]([F:41])([F:40])[S:22]([O:25][CH:26]1CCCC[CH:27]1[O:32][S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34])(=[O:24])=[O:23]>>[F:38][C:36]([F:37])([F:39])[S:33]([O:32][CH2:27][CH2:26][O:25][S:22]([C:21]([F:41])([F:40])[F:20])(=[O:24])=[O:23])(=[O:34])=[O:35]
Reactant: O=S(=O)(OC1CCCCC1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(OCCCOS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=S(=O)(OCCOS(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
Preparation and handling of organometallic compounds were carried out in the absence of air and moisture under argon (Schlenk technique or glove box). All solvents required were purged with argon and dried over molecular sieves before use. 1,2-Bistrifluoromethylsulfonyloxyethane was synthesized as described by Lindner, Ekkehard; Au, Guenter von; Eberle, Hans-Juergen; Chem.Ber.; 114; 2; 1981; 810-813. The preparations of 1,3-bistrifluoromethylsulfonyloxypropane and 1,2-bistrifluoromethylsulfonyloxycyclohexane were carried out analogously. The indenes used were prepared as described in WO 9840331.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C1C(=O)N([Cl:21])C(=O)C1>C(#N)C>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[NH:8][CH:7]=1
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1ccc2c(=O)[nH]cc(Cl)c2c1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a solution of 6-methoxyisoquinolin-1(2H)-one (2.5 g, 14.27 mmol) in acetonitrile (10 ml) was added NCS (2.54 g, 14.27 mmol) at 80° C. for overnight. The reaction mass was cooled to room temperature and the precipitated solid was filtered to get crude compound (2 g, 55.2%). The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.41 (s, 1H), 8.17-8.15 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.19-7.11 (m, 2H), 3.93 (s, 3H); MS: MS m/z 210.02 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Br)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-bromoaniline to yield 2-[(4-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12]C3C=CC=CC=3)[C:7]=2[C:6](=[O:19])[NH:5][C:4]1=[O:20].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>>[O:25]1[CH2:24][CH:23]1[CH2:21][N:5]1[C:6](=[O:19])[C:7]2[N:8]([CH3:12])[CH:9]=[N:10][C:11]=2[N:3]([CH3:2])[C:4]1=[O:20]
Reactant: ClCC1CO1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: [Na]
Product: Cn1cnc2c1c(=O)n(CC1CO1)c(=O)n2C
Reaction time: 20 h

Procedure:
and R═R1═CH3). A suspension of 3 g (0.148 mole) of the sodium salt of 3,7-dimethylxanthine (III, 1-Na salt; R═R1═CH3) and 20 mL of epichlorhydrin is heated while stirring at 65-70° for 20 hours. After cooling, the precipitate is filtered out and washed with methylene chloride. The derived solution of IX in methylene chloride is stripped and the grease-like residue is kneaded in absolute ether, yielding 2.7 (77%) of 1-(2,3-epoxypropyl)-3,7-dimethylxanthine, melting point 115-119°, M+ 236 (J-C. Pascal et al, J. Med. Chem., 1985, No. 28, No. 5, pp. 647-652, melting point 116-117°).
Reaction SMILES: COC(=O)CN1CC(CNCC2C=CC=CC=2)=CCC(N[C:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:23])C1=O.[Li+].[OH-:37]>C1COCC1.O>[C:24]1([C:22]([OH:23])=[O:37])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing {6-(benzylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 24, (82 mg, 0.14 mmol) in THF/H2O (4 mL of 3:1) is treated with excess LiOH and stirred for 2.5 hours at room temperature. The solution is acidified to pH 7 and concentrated in vacuo. The residue is purified by HPLC to afford the desired product which is used directly for the next step.
Reaction SMILES: [C:1]1([CH2:9][OH:10])([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.N(CCC[Si:54](OC)(OC)OC)=C=O>>[C:1]1([CH2:9][OH:10])([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SiH4:54]
Reactant: CO[Si](CCCN=C=O)(OC)OC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: OCC1(CO)CCCCC1
Product: [SiH4]
Reaction time: 2 h

Procedure:
Melt cyclohexanedimethanol in laboratory oven. When melted, take 294.7 g of cyclohexanedimethanol along with 0.11 g dibutyl tin dilaurate and place in a flask at about 35° C. Add 419.5 g of isocyanatopropyltrimethoxysilane over 75 minutes. Then hold for two hours. Cool and empty.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].ClC1C=C(Cl)C=C(Cl)C=1[O:19][C:20](=O)[CH2:21][C:22](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:23]>C1(C)C(C)=CC=CC=1>[OH:23][C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[S:6][CH2:7][CH2:8][N:9]2[C:20](=[O:19])[CH:21]=1
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])C=C1NCCS1
Solvent: Cc1ccccc1C
Product: O=c1cc(O)c([N+](=O)[O-])c2n1CCS2
Yield: 31.5 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Intermediate (I-19b), 2-nitromethylene-thiazolidine (0.65 g, 4.45 mmol) was reacted with malonic acid bis-(2,4,6-trichloro-phenyl) ester (1.5 g, 4.45 mmol) in Xylene (10 mL) to afford the crude product. Purification by column chromatography on silica gel (100% ethylacetate) afforded 0.3 g of the product (33% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:30])[CH:16]([NH:25][C:26](=[O:29])[CH2:27][OH:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:13][O:14][C:15](=[O:30])[CH:16]([NH:25][C:26](=[O:29])[CH2:27][O:28][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CO
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3(4-hydroxy phenyl) propionic acid (10 grams, 60.17 mmol) and 2-(2-hydroxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester 3 (15.2 grams, 60.07 mmol) in anhydrous dichloromethane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide (31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 6, which can be purified in an appropriate solvent.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH2:14][C@H:10]([C:11]([OH:13])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][N:18]([CH3:17])[C:11]([C@H:10]1[CH2:14][CH2:15][CH2:16][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: CNCCOCCOCCOCCOCCOCCOCCOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCCOCCOCCN(C)C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 212.5 %

Procedure:
To a solution of Boc-(S)-nipecotic acid (137 mg, 0.60 mmol), N-methyl-2,5,8,11,14,17,20-heptaoxadocosan-22-amine 135c.1 (310 mg, 0.88 mmol) and DIPEA (335 mg, 2.6 mmol) in DMF (3 mL) was added HATU (285 mg, 0.75 mmol). The reaction was stirred for 1 hour and then the DMF was removed under vacuum. The residue was added to saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated to give (S)-tert-butyl 3-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl(methyl)carbamoyl)piperidine-1-carboxylate (720 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5](I)=[C:4]([CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([B:18]([OH:21])[OH:19])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: COB(OC)OC
Reactant: CCc1cc(Br)cc(CC)c1I
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Br)cc(CC)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-bromo-2,6-diethyl-1-iodobenzene (10 g, 0.029 mol) in tetrahydrofuran (100 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 22.2 ml, 0.035 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (17.98 g, 0.17 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×300 ml) and the organic fractions are combined, washed with brine, dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-diethylphenylboronic acid (5 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH:5]([OH:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH:5]([OH:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(C)C(O)c1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)C(C)C(O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 18 h
Yield: 84.5 %

Procedure:
The 3-hydroxy-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methyl ester (0.24 g, 1.14 mmol) was combined with the 4-chloromethyl-2-methyl-quinoline (0.313 g, 1.37 mmol) and cesium carbonate (1.1 g, 3.42 mmol) in DMSO (5 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred for 18 h, filtered to remove the solids, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give a mixture of diasteromers. The product was purified by FCC on silica gel eluting with ethyl acetate:hexane (60:40, v: v) to give 3-hydroxy-2-methyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionic acid methyl ester (0.352 g, 84%) as a glass. MS found: (M+H)+=366.
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.S(=O)(=O)(O)O.C(OCC)(=O)C>COCC(O)C>[CH:11]#[C:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Solvent: COCC(C)O
Solvent: CCOC(C)=O
Product: C#Cc1ccc(O)cc1
Reaction time: 8 h

Procedure:
In 80 g of propylene glycol monomethyl ether was dissolved 88 g of p-t-butoxystyrene, and then, 2 g of azobisisobutyronitrile was added to the solution, after which they were subjected to polymerization for 10 hours under a nitrogen atmosphere while the reaction temperature was kept at 80° C. After the polymerization, an aqueous sulfuric acid solution was added to the reaction mixture and the resulting mixture was subjected to hydrolysis at 80° C. for 8 hours. Subsequently, ethyl acetate was added to the reaction mixture and the resulting mixture was washed with water, after which the solvent was replaced by acetone. The resulting resin solution was dropped into a large amount of water to coagulate a resin. The resin was recovered and dried in a vacuum drier kept at 50° C. overnight to obtain 48 g of a white fine powder of poly(p-hydroxystyrene).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[I:11]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[C:7]=1[I:11]
Reactant: Cn1nc(Cl)cc(N)c1=O
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cn1nc(Cl)c(I)c(N)c1=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of Example 74a (2.12 g, 13.3 mmol) and N-iodosuccinimide (5.38 g, 23.9 mmol) in acetonitrile (30 mL) was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-40% ethyl acetate in hexanes to afford 3.27 g (86%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[CH:4][CH:3]=1>Cl.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C=C2c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in (4) described above (2.8 g) and 2M hydrochloric acid-dichloromethane solution (100 mL) was stirred at room temperature overnight. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by flush chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=25/1) to give the titled compound (1.9 g) as a yellow powder.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:23]1[C:28]2[NH:29][C:30]3[CH:38]=[CH:37][N:36]=[CH:35][C:31]=3[CH2:32][CH:33]([OH:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1.S(=O)(=O)(O)[O-].[Na+]>ClCCl.O.C(=O)(O)[O-].[Na+]>[N:23]1[C:28]2[NH:29][C:30]3[CH:38]=[CH:37][N:36]=[CH:35][C:31]=3[CH2:32][C:33](=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: OC1Cc2cnccc2Nc2ncccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: O=C1Cc2cnccc2Nc2ncccc21
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Dess-Martin periodinane (0.810 g, 1.91 mmol) was added to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:3′,4′-f]azepin-5-ol (0.370 g, 1.74 mmol, Intermediate D-5) in dichloromethane (30 mL) under an atmosphere of nitrogen and stirred for 1 h. The yellow mixture was poured into a solution of sodium bisulfate in water and stirred for 5 minutes. The mixture was then diluted with dichloromethane and sodium bicarbonate was added to adjust the pH to 8-9. The mixture was extracted three times with dichloromethane and the combined extracts were dried over sodium sulfate, filtered, and concentrated. The crude product residue was adsorbed onto silica gel and chromatographed on a silica gel column eluting with 10% methanol/dichloromethane to provide the desired product as a light tan solid (330 mg, 90%). 1H NMR (DMSO-d6): δ 10.55 (s, 1H), 8.51 (dd, 1H), 8.42 (s, 1H), 8.35 (d, 1H), 8.18 (dd, 1H), 7.33 (d, 1H), 7.06 (dd, 1H), 3.82 (s, 2H). LC/MS: 212 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]=[C:11]=[O:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[CH2:25][C:24](=[O:26])[CH:23]=[CH:22][NH:21]2)=[CH:16][CH:15]=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]([N:21]2[CH:22]=[CH:23][C:24](=[O:26])[CH2:25][C@H:20]2[C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[O:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Reactant: COc1ccc(Br)c(N=C=O)n1
Product: COc1ccc(Br)c(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)n1

Procedure:
(S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (3-bromo-6-methoxy-pyridin-2-yl)-amide was prepared by reaction of 3-bromo-2-isocyanato-6-methoxy-pyridine with (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one using the procedure of step 3 of Example 1. MS (M+H) 421.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.[N:13]#[C:14][C:15]#[N:16].N1C=CC=CC=1>CN(C)C=O>[C:14]([C:15]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:16]=1)#[N:13]
Reactant: N#CC#N
Reactant: Cc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
2.0 g (11 mmol) of 2-amino-4'-methylacetophenone hydrochloride was measured out in a 100-ml round bottom flask. To the material was then added 40 ml (40 mmol) of a 1 mol/l N,N-dimethylformamide solution of cyanogen at a temperature of 0° C. To the mixture was then added 1.7 g (22 mmol) of pyridine. The mixture was then heated at a temperature of 60° C. with stirring for 18 hours. The reaction mixture was then allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography to obtain 1.55 g (yield: 77 %) of 2-cyano-4- (p-tolyl)imidazole.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[NH:25][NH2:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:29]([O:28][C:24]([N:25]([C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1)[NH2:26])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Ic1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(N)c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 38A (420 mg, 1.0 mmol) was coupled with tert-butyl carbazate (Aldrich, 158 mg, 1.2 mmol) under the catalysis of Cul (Strem Chemicals, 9.5 mg, 0.05 mmol) with Cs2CO3 (Strem Chemicals, 489 mg, 1.4 mmol) in DMF (anhydrous, Aldrich, 5 mL) at 80° C. overnight. The mixture was diluted with EtOAc (50 mL) and washed with water (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as an oil (190 mg, yield, 45%). 1H NMR (MeOH-d4, 300 MHz) δ 1.46 (s, 9H), 1.76–2.16 (m, 3H), 2.20–2.39 (m, 1H), 2.41–2.54 (m, 1H), 3.16–3.47 (m, 5H), 3.66–3.86 (m, 1H), 4.70–4.84 (m, 1H), 6.77–6.93 (m, 2H), 6.94–7.04 (m, 4H), 7.25–7.48 (m, 2H) ppm. MS (DCl/NH3) m/z 426 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH3:19][C:20]1([CH3:32])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)[O:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:19][C:20]1([CH3:32])[C:24]([CH3:25])([CH3:26])[O:23][B:22]([C:27]2[CH:31]=[N:30][N:29]([CH:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[CH:28]=2)[O:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
A mixture of tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (7.33 g, 26.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.09 g, 26.2 mmol), and Cs2CO3 (12.8 g, 39.3 mmol) in DMF (50 mL) was heated at 100° C. for 24 h. The mixture was cooled to RT and diluted with water (100 mL) and extracted with EtOAc (3×60 mL). The combined organic phases were washed with water (3×50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography (20 to 40% ethyl acetate:hexanes) to afford 3.84 g (39%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.74 (s, 1H), 4.17-4.35 (m, 3H), 2.89 (m, J=11.12 Hz, 2H), 2.14 (d, J=14.65 Hz, 2H), 1.90 (qd, J=12.25, 4.42 Hz, 3H), 1.48 (s, 9H), 1.33 (s, 12H); MS (ESI): 379.15 [M+H]+; HPLC tR=3.17 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([OH:24])[C:10]1[N:15]2[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].P(CC1C2N(C=C(C(O)=O)N=2)C=CC=1)(O)(O)=O.O1CCOCC1.[Cl:48]Cl>>[ClH:48].[CH2:1]([O:3][P:4]([CH:9]([OH:24])[C:10]1[N:15]2[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: ClCl
Agent: CCOC(=O)c1cn2c(C(O)P(=O)(OCC)OCC)cccc2n1
Agent: O=C(O)c1cn2cccc(CP(=O)(O)O)c2n1
Solvent: C1COCCO1
Product: Cl

Procedure:
The product from Example 55 (1.2 g, 3.37 mmol) was dissolved in CH2 Cl2 (15 mL) and treated with 6N HCl in dioxane (0.56 mL, 3.37 mmol). The resulting salt was precipitated with Et2O, filtered, washed with Et2O, and dried in vacuo to give 1.3 g (99%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O>[NH2:29][C:24]1[N:25]=[C:26]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:22]([Cl:21])[N:23]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12

Procedure:
49.0 mg (0.18 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 33.0 mg (0.20 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 0.12 ml (0.24 mmol) of 2N hydrochloric acid is added, and the mixture is heated at reflux overnight. Using concentrated aqueous sodium hydroxide solution, the mixture is made alkaline, and the product is purified by preparative HPLC.