Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:37][C:36]([OH:38])=[C:35]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)[C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47]
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile from Example A(147) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.17–1.59 (m, 8H), 1.56–1.6 (m, 2H)), 1.82 (s, 6H), 1.88–2.01 (m, 2H), 2.31–2.79 (m, 3H), 3.79 (d, J=16 Hz, 1H), 3.89 (d, J=16 Hz, 1H), 7.34–7.52 (m, 3H), 8.91 (d, J=2.5 Hz, 1H), 9.63 (d, J=2.5 Hz, 1H), 10.9 (s, 1H). C28H29Cl2N5O3: C, 60.65; H, 5.27; N, 12.63. Found: C, 60.45; H, 5.19; N, 12.40. MS (ESI): 555.2(M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[N:6]=[N:5]1.[CH3:12][C:13]1[O:17][C:16]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:15][CH:14]=1.[C:35](=[O:38])([O-:37])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[C:8]([OH:9])(=[O:17])[C:35]([OH:37])=[O:38].[CH2:10]([N:7]1[C:8](=[O:9])[N:4]([CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][CH:29]([NH:28][C:20]3[N:19]([CH2:18][C:16]4[O:17][C:13]([CH3:12])=[CH:14][CH:15]=4)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:30][CH2:31]2)[N:5]=[N:6]1)[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Reactant: CCn1nnn(CCBr)c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1nnn(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(C)o3)CC2)c1=O
Product: O=C(O)C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 3.32 parts of 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 4.65 parts of 1-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 1.6 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 80° C. The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in methanol. The salt was filtered off and dried, yielding 5.2 parts (55%) of 1-ethyl-1,4-dihydro-4-[2-[4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-5H-tetrazol-5-one ethanedioate(1:2); mp. 190.5° C. (compound 22).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Alternative method) A 2.00 g portion of 2,4-dimethoxybenzoic acid was dissolved in 30 ml of sulfuric acid, and 0.49 ml of concentrated nitric acid was added under ice-cooling. After 3 hours of stirring at room temperature, this was poured into 100 g of ice water, and the thus formed crystals were collected by filtration, washed with water-methanol and then dried under a reduced pressure to give 1.41 g of 2,4-dimethoxy-5-nitrobenzoic acid. The physicochemical properties were identical to those of the compound obtained by the former method.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[H-].[Na+].[H][H].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=1>C(#N)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:9]2[CH2:8][CH2:7][S:6][C:5]2=[CH:4][N+:1]([O-:3])=[O:2])[CH:15]=1
Reactant: ClCc1cccnc1
Reactant: O=[N+]([O-])C=C1NCCS1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])C=C1SCCN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.6 %

Procedure:
2-Nitromethylenethiazolidine (2.9 g) was suspended in dry acetonitrile (30 ml), and 60% sodium hydride (0.9 g) was added under a nitrogen stream. Then, the mixture was stirred at room temperature until the generation of hydrogen ceased. A solution of 3-picolyl chloride (3.2 g) in dry acetonitrile (5 ml) was added, and the mixture was stirred at room temperature for 3 hours. Acetonitrile was distilled off under reduced pressure. Dichloromethane was added to the residue, and the mixture was washed with water. Dichloromethane was then distilled off from the dichloromethane layer. The remaining oily product was purified by column chromatography to give the desired 3-(3-pyridylmethyl)2-nitromethylenethiazolidine (0.5 g).
Reaction SMILES: CO[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[H-].[Na+].[CH3:14]I.O.C1C[O:20][CH2:19]C1>>[CH3:19][O:20][C:10]1[CH:11]=[C:6]([CH:3]([CH3:14])[C:4]#[N:5])[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: COC(C#N)c1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(C(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
To a solution of methoxyphenyl acetonitrile (4.0 g, 27 mmol) in THF at room temperature was added NaH (1.19 g, 30 mmol). After 20 min, MeI (1.68 mL, 27 mmol) was added. The reaction was stirred at room temperature overnight. H2O was added to quench the reaction. It was concentrated and diluted with Ether. The ether was washed with 1N HCl, saturated NaCl, dried and concentrated to give a crude mixture which was purified by column chromatography on ISCO (120 g) with 0-30% hexanes in ethyl acetate over 28 min to yield 2-(3-methoxyphenyl)-propanenitrile (1.9 g, 44% yield) as a light brownish oil. HPLC retention time (Method C)=2.47 min. LC/MS (ESI) (M+H)+=162.16. 1H NMR (CDCl3, 400 MHz) δ ppm 1.64 (d, J=7.34 Hz, 3H), 3.82 (s, 3H), 3.85-3.92 (m, 1H), 6.83-6.96 (m, 2H), 7.24-7.34 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.N[C:16]1[CH:22]=[CH:21][C:20](N2CCN(C)CC2)=[CH:19][C:17]=1N.[N:30]1C=CC=CC=1>C(Cl)Cl>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[C:9]([S:11]([NH2:30])(=[O:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:17]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2ccc(-c3ccccc3)nc12
Yield: 47.8 %

Procedure:
8-Quinolinesulfonyl chloride (0.185 g, 0.81 mmol) was added to a solution of 2-amino-5-(4-methyl-1-piperazinyl)aniline (0.168 g, 0.81 mmol) and pyridine (514 mL, 6.39 mmol) in CH2Cl2. After 1 h at room temperature the mixture was washed with aq NaHCO3 (10%), dried (MgSO4) and the solvent was removed. Purification by chromatography (SiO2, CH2Cl2/MeOH/heptane, 4:1:5) gave N-2-amino-4-(4-methyl-1-piperazinyl)-]-phenyl-8-quinolinesulfonamide (0.110 g , 35%). MS (posES-FIA) m/z=found: 384.2. calcd 383.48. %); Anal. (C19H22ClN5O2S.3H2O ) C, H, N, S and a small amount of the bis-sulfonylated N-{4-(4-methyl-1-piperazinyl)-2-[(8-quinolinylsulfonyl)amino]phenyl}-8-quinolinesulfonamide (0.070 g, 15%). The product was converted to HCl salt before analysis; MS (posES-FIA) m/z=found: 589.6. calcd: 588.16. Anal. (C29H29ClN6O4S2.2H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH:10](O)=[O:11]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=CO
Product: O=CNc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL) was heated to reflux for 4 h. The mixture was poured into ice-water and stirred for 0.5 h. The white solid was collected by filtration, and dried under vacuum to give 4.8 g (79%) of crude N-(3,5-difluorophenyl)formamide. To the solution of LiAlH4 (3.0 g, 78.9 mmol) in dry THF (50 mL) was added a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol) in dry THF (50 mL) at r.t. The mixture was stirred overnight and then quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml). The reaction mixture was filtered and extracted with EtOAc. Organics were dried (Na2SO4), and concentrated to give 3.8 g (86%) of the title compound as a pale brown oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCBr
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 52.6 %

Procedure:
A mixture of 4,5-diphenyl-2-imidazolethiol (2.5 g), 8-bromooctane (3.8 g), anhydrous potassium carbonate (13.7 g) and dry butanone (60 ml) was stirred at reflux for 2 h. The cooled reaction mixture was filtered to remove solid and the flitrate was evaporated to dryness. The residue was mixed with hexane and the resulting precipitate was collected by filtration. Recrystallisation from ethanol and water gave 2-octylthio-4,5-diphenylimidazole (1.9 g, 53%) as a white solid, m.p. 133°-4°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH2:10][C:11](O)([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(COc3ccc(Cl)cc3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(COc3ccc(Cl)cc3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(4-chlorophenoxy)methyl]-4,5-dihydro-1H-imidazole from Step 3 (750 mg, 1.5 mmol) and p-toluenesulfonic acid monohydrate (135 mg) in toluene (100 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate (1/1) to give 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[(4-chlorophenoxy)methyl]-1H-imidazole as a white solid: mp (DSC) 173° C. Anal. Calc'd for C23H18N2Cl2SO3.0.25 H2O: C, 57.81; H, 3.90; N, 5.86; Cl, 14.84. Found: C, 57.67; H, 3.83; N, 5.52; Cl, 15.17.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([Cl:15])[CH:3]=1.Cl.C(O)C.O=[C:21]([C:27](OCC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CO.[C].[Pd]>[NH2:14][S:11]([C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[Cl:15])[N:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27](=[O:28])[NH:8]2)(=[O:13])=[O:12]
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a solution of 4-amino-2-chloro-5-nitrobenzenesulfonamide (2.00 g, 7.95 mmol) in methanol (40 ml) were added 10% palladium-carbon (400 mg) and successively 10% hydrochloric acid (6 ml) at room temperature, and catalytic hydrogenation was conducted for 2 hours at ambient temperature under ambient pressure. Catalyst was filtered off using celite and the filtrate was distilled off under reduced pressure. After dissolved this into ethanol (16 ml), diethyl ketomalonate (1.21 ml, 7.95 mmol) was added, which was stirred for 5 hours at room temperature. The precipitate was collected by filtration, washed with ethanol and then purified by means of silica gel column chromatography [hexane-ethyl acetate=1:2] to obtain 288 mg of the title compound. Yield 11%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1.[Br:37]N1C(=O)CCC1=O>ClCCl.CCOCC>[Br:37][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
8.68 g (33.08 mmol) of triphenylphosphine are added, under an argon atmosphere, to a solution of 7.85 g (33.08 mmol) of tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate in 85 mL of dichloromethane. The mixture is cooled to 0° C. and 5.95 g (33.08 mmol) of N-bromosuccinimide are added portionwise over 25 minutes. Stirring is continued for 3 hours at 0° C. The solvent is then evaporated off, the oil obtained is taken up in ether and the precipitate formed is filtered off and discarded. The filtrate is evaporated and the residue is purified by chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give 6.90 g of tert-butyl [4-(2-bromoethyl)phenyl]carbamate, the characteristics of which are as follows:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=4)[N:16](S(C4C=CC(C)=CC=4)(=O)=O)[CH:15]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH:43]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44]1.N1CCOCC1>ClCCl>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([C:9]3[N:8]=[C:7]([NH:6][CH:4]4[CH2:5][N:2]([S:49]([CH2:48][CH:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)(=[O:51])=[O:50])[CH2:3]4)[C:12]([F:13])=[CH:11][N:10]=3)=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: O=S(=O)(Cl)CC1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=S(=O)(CC1CCCC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of N-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.03 g, 0.06 mmol) in dichloromethane (1 mL) was added iPr2NEt (0.33 μL, 1.90 mmol) followed by cyclopentylmethanesulfonyl chloride (0.01 g, 0.06 mmol). The resulting mixture was stirred 30 minutes at room temperature at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube for 10 minutes. The solution was quenched with aqueous saturated NH4Cl solution (0.5 mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 27.4 mg (88% yield) of the desired product, 469, as a solid. LCMS RT=3.1 min, ES+465.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 121.2 %

Procedure:
To a stirred and cooled (0° C.) solution of tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) (0.35 g, 0.77 mmol) in dichloromethane (2.6 mL) was added trifluoroacetic acid (0.060 mL, 0.78 mmol), and the solution was allowed to warm slowly to ambient temperature. After 18 hours, an additional amount of trifluoroacetic acid (0.060 mL, 0.78 mmol) was added. After 24 hours a third aliquot of trifluoroacetic acid (0.060 mL, 0.78 mmol) was added. After an additional 24 hours, the solution was concentrated to give the title compound as a tan solid (0.325 g, 88%): 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.08 (dd, J=8.8, 2.6 Hz, 4H), 7.87 (s, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 3.17-3.06 (m, 2H), 2.99-2.89 (m, 2H); ESIMS m/z 349 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22].O>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:3]=1[C:4]#[N:5])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCN(CC)c1cccc(N)c1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCN(CC)c1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(diethylamino)benzonitrile (3 g) in methylene chloride (50 ml) is added pyridine (1.4 ml), and thereto is added dropwise acetoxyacetyl chloride (1.8 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is recrystallized from hexane to give the title compound (1.1 g) having the following physical properties.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2([C:25]3[CH:26]=[CH:27][C:28]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCOc1ccc(C2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COCCOc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole following the procedure set out in Example 1, substituting tetrakis triphenylphosphine palladium (0) as catalyst, the title compound was obtained. LC/MS: (PS-A2) Rt 3.27 [M+H]+ 478.
Reaction SMILES: [O:1]([CH3:11])[C@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[CH2:4][CH2:3]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH2:23]>N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:6][C@@H:5]2[C@@H:7]([CH2:9][O:10][S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:19])=[O:23])[O:8][C@H:2]([O:1][CH3:11])[CH2:3][CH2:4]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@H]1CC[C@H](O)[C@@H](CO)O1
Reactant: O
Solvent: c1ccncc1
Product: CO[C@@H]1CC[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Reaction time: 12 h

Procedure:
Methyl 2,3-dideoxy-α-D-erythro-hexopyranoside (6 g, 37 mmol) in dry pyridine (50 ml) was treated with toluene-p-sulphonyl chloride (15.2 g, 80 mmol) at 0° with stirring. The reaction mixture was stored at 22° for 12 h, and after the addition of water (1 ml) it was concentrated. The syrupy residue was poured into ice-water, the oil which separated was extracted with CHCl3, and the extracts were washed with water, dried and evaporated. The solid thus obtained (12 g, 70%) was recrystallized from methanol to give pure methyl 2,3-dideoxy-4,6-di-O-toluene-p-sulphonyl-α-D-erythro-hexopyranoside. M.p.: 110°-111.5°. [α]D22 +80.8° (c 1, chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][C:10]=1[C:11]([NH:42][C:41]1[CH:43]=[CH:44][CH:45]=[C:39]([Cl:38])[CH:40]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-(benzyloxy)-4-(morpholinomethyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in description 50, 270 mg, 0.683 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added DIPEA (0.239 mL, 1.366 mmol), 3-chloroaniline (72.0 μl, 0.683 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.819 mmol) and EDC (262 mg, 1.366 mmol). The solution was stirred for 3 hours then partitioned between EtOAc (20 ml) and water (15 ml). The organic layer was separated, washed further with water (2×20 ml), dried (MgSO4) and the solvent removed. Purification by column (SiO2, Isolute, 3:1-1:1 Cyclohexane/EtOAc) gave the product as a white solid. 205 mg.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][N:37]2COCC[Si](C)(C)C.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)=[O:5])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)(=[O:17])=[O:18])=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: C[Si](C)(C)CCOCn1cnc2c(I)ncnc21
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]cnc12

Procedure:
Prepared from 256 mg (0.51 mmol) of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 191 mg (0.51 mmol) of 6-iodo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-purine dissolved in 2 mL THF with 0.25 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 1 mL methanol and 1 mL 6N hydrochloric acid mixture to give after purification 2.05 mg of the final product as a yellow solid.