Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:18]=[CH:17][C:7]3[NH:8][C:9]([CH:11]4[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)=[N:10][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:19][C:20]1[C:25]([N:14]2[CH2:13][CH2:12][CH:11]([C:9]3[NH:8][C:7]4[CH:17]=[CH:18][C:4]([CH:1]5[CH2:2][CH2:3]5)=[CH:5][C:6]=4[N:10]=3)[CH2:16][CH2:15]2)=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: c1cc2[nH]c(C3CCNCC3)nc2cc1C1CC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1nccnc1N1CCC(c2nc3cc(C4CC4)ccc3[nH]2)CC1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
The mixture of 5-cyclopropyl-2-piperidin-4-yl-1H-benzoimidazole (98 mg, 0.41 mmol), 2,3-dichloro-pyrazine (74 mg, 0.5 mmol) and K2CO3 (115 mg, 0.83 mmol) in CH3CN (15 mL) was heated to 80° C. for 10 h. Then it was concentrated and partitioned between DCM and H2O, the organic layer was dried over Na2SO4, and concentrated to give the desired compound 2-[1-(3-chloro-pyrazin-2-yl)-piperidin-4-yl]-5-cyclopropyl-1H-benzo imidazole (88 mg, 65%).
Reaction SMILES: [OH:1][C:2]([C:5]1(C(OCC)=O)[O:9][NH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3].[BH4-].[Na+].O.[CH2:18]([OH:20])C>>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:18][OH:20])[CH:6]=1)([CH3:3])[CH3:4]
Reactant: CCO
Reactant: CCOC(=O)C1(C(C)(C)O)C=CNO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
9.96 g of ethyl 5-(1-hydroxy-1-methylethyl)isoxazole-5-carboxylate was dissolved in 200 ml of ethanol, and 3.78 g of sodium borohydride was then added. The mixture was stirred at room temperature for 10 hours. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced-pressure. The residue was subjected to silica gel column chromatography to obtain 6.17 g of [5-(1-hydroxy-1-methylethyl)isoxazol-3-yl]methanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:19])([CH3:18])[CH2:7][C:8]2([CH2:12][C:13]([O:15]CC)=[O:14])O)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:19])([CH3:18])[CH2:7]/[C:8]/2=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1(O)CC(C)(C)c2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C/C(=C\C(=O)O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 69.7 %

Procedure:
A solution of ethyl 2-(6-fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate (16 g, 0.0601 mol) in 1N sodium hydroxide (60.1 ml, 0.0601 mol) and ethanol (60 ml) was stirred for 20 h. The solution was concentrated to a small volume by spin evaporation in vacuo, diluted with deionized water (100 ml), and acidified to pH 3 with 1N hydrochloric acid This biphasic solution was extracted with dichloromethane (2×100 ml). The extracts were combined, washed with deionized water (20 ml), dried with magnesium sulfate (Mallinckrodt), and concentrated by spin evaporation in vacuo. The residue was dissolved in dichloromethane (30 ml), cooled to 0° C., and diluted with 400 ml of a cold (0° C.) solution of trifluoroacetic acid (45 g, Aldrich) in dichloromethane (400 ml). After 15 min. the solution was concentrated by spin evaporation in vacuo and the residue was crystallized by adding hexanes to give 9.23 g (70%) of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid as a white crystalline solid, m.p., 202°-203.5° C.;
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:37][O:38][CH3:39])[N:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N+:26]([O-:6])=[CH:25][C:24]3[N:30]=[C:31]([CH2:37][O:38][CH3:39])[N:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
3-Chloroperoxybenzoic acid (60% pure, 3.5 g, 12.3 mmol) was added portionwise to a solution of 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline (4.2 g, 11.19 mmol) in 200 mL of dichloromethane. The reaction was stirred at ambient temperature for 2 hours, and then 100 mL of 2% aqueous sodium carbonate was added. The aqueous layer was extracted with two 100 mL portions of dichloromethane and the organic fractions were combined, dried, and concentrated to give 4.3 g of crude 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-5-oxido-1H-imidazo[4,5-c]quinoline as a light brown solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CS(C)=O.Cl[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH2:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)=[CH:22]4)=[N:16][N:17]=2)[N:14]=1>O>[CH3:1][N:2]([CH3:3])[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH2:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)=[CH:22]4)=[N:16][N:17]=2)[N:14]=1
Reactant: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Reactant: CNC
Solvent: O
Solvent: CS(C)=O
Product: CN(C)c1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 130 °C
Yield: 30 %

Procedure:
To a 5 ml microwave vial 1 ml of dimethylamine 40% in water was added followed by 300μ of DMSO to dissolve 25 mg (0.067 mmol) 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoline. The reaction heated in a microwave for 2000 seconds at 130° C. The reaction mixture was filtered then purified via preparatory HPLC to return the title compound (7.7 mg, 30% yield). Analytical data is presented in Table 2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Product: c1cc(N2CCC3(CC2)OCCO3)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 8 and morpholine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1>C(OCC)C.O1CCCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:28]2([OH:31])[CH2:29][CH2:30][CH:25]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[CH2:26][CH2:27]2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCC(N2CCN(c3ccccn3)CC2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCC(N2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.74 g (30 mmol) of 3-bromopyridine in 100 ml of diethyl ether is cooled to --78° C. under a nitrogen atmosphere. n-Butyllithium (18.75 ml, 30 mmol) is added dropwise. The resulting suspension is stirred for 30 minutes. To this solution is added a solution of 5.19 g of 4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanone in 175 ml of tetrahydrofuran dropwise. The cold bath is removed and the mixture is allowed to warm to room temperature and quenched with 50 ml of saturated ammonium chloride solution. The tetrahydrofuran is evaporated under vacuum and the residue is partitioned into water/dichloromethane. The organic phase is separated and dried over magnesium sulfate and evaporated in vacuo to give the title compound as a mixture of cis and trans isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][C:23](=[O:25])[CH3:24])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(Oc1ccnc(O)c1)C(O)C(C)(C)O2
Reaction time: 16 h

Procedure:
A mixture of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° for 16 hours. The mixture is evaporated, purified chromatographically and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-acetamido-3-chromanol is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][N:12]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[CH3:13])[CH:3]=1)=[O:6])[CH3:9]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCOC(=O)c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(-c2ccc(F)cc2C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
In a mixed solvent of 250 ml of toluene and 50 ml of ethanol were dissolved 20 g of ethyl 2-chloroisonicotinate and 20 g of 2-methyl-4-fluorophenylboronic acid, and 5.8 g of palladium tetrakistriphenylphosphine and 250 ml of a 2M aqueous sodium carbonate solution, and the mixture was stirred at 50 to 70° C. for 2 hours. The solution was cooled down to room temperature and extracted by adding ethyl acetate and water. The organic layer was further washed with water, and dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1), to give 24.8 g of 4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)pyridine as shown in Table 132 below.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH3:18]O>>[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:7][C:8]([O:10][CH3:18])=[O:9]
Reactant: NC(CC(=O)O)c1cccc(Cl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (110 ml) is cooled to −10° C. and slowly admixed with thionyl chloride (12.0 g, 101.2 mmol). 3-Amino-3-(3-chlorophenyl)propionic acid (10.1 g, 50.6 mmol) is added and the mixture is stirred at room temperature overnight. The solution is concentrated to a high extent, under reduced pressure, and partitioned between ethyl acetate (100 ml) and saturated sodium hydrogen carbonate solution (200 ml). The pH of the aqueous phase is above 7. The aqueous phase is again extracted twice with ethyl acetate (100 ml). The combined ethyl acetate phases are dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[C:11](=[O:17])[N:10]([CH3:18])[CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:7][C:6]=1[C:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[C:11](=[O:17])[N:10]([CH3:18])[CH:9]=1
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)n2cncc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)n2cncc2c1=O
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of the title compound from Example 129, Step 2 (140 mg, 0.38 mmol) in THF (20 ml) was added pyridine (152 mg, 1.90 mmol). Then methanesulfonyl chloride (48 mg, 0.46 mmol) was added to the solution at 0° C. The solution was allowed to warm up to room temperature and heated to reflux for overnight. The reaction mixture was concentrated under reduced pressure to yield the crude product that was purified by prep-HPLC to give the title compound (75.26 mg, 44%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.15 (s, 1H), 7.50 (d, J=2.8 Hz, 1H), 7.30 (dd, J=8.8, 2.4 Hz, 1H), 7.18 (td, J=8.8, 5.3 Hz, 1H), 7.00-6.88 (m, 2H), 6.83 (s, 1H), 6.78 (d, J=8.8 Hz, 1), 3.60 (s, 3H), 3.03 (s, 3H). LCMS: 447.0 (M+1)+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][N+:11]#[C-:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:14]I.[OH-].[Na+].O>ClCCl>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([S:7]([CH:10]([N+:11]#[C-:12])[CH3:14])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: CI
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of toluene-4-sulfonylmethylisocyanide (15 g), methyl iodide (109 g) benzyl trimethyl ammonium chloride (3.5 g) in dichloromethane (300 mL) was added 5 mol/L aqueous sodium hydroxide solution (307 mL) under ice cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water and this mixture was extracted with diethyl ether. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (16 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:4]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[C:5](=O)[NH:6][N:7]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:5]1[N:6]=[N:7][C:2]([CH3:1])=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:4]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: Cc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
19.77 g of 6-methyl-5-(4-methylphenyl)-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 100 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added chloroform and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 19.90 g of 3-chloro-6-methyl-5-(4-methylphenyl)-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxii) of the present invention).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:38]([O:41][CH3:42])[O:39][CH3:40])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2C(OCC1C=CC=CC=1)=O)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:38]([O:39][CH3:40])[O:41][CH3:42])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(OC(C)=O)(O1)C2COC(N)=O
Agent: [Pd]
Solvent: CO
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
11-Benzyloxycarbonyl-8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (270 mg) was dissolved in methanol (10 ml). To the solution was added 10% palladium on carbon (300 mg) and the mixture was stirred for 1 hour under hydrogen atmosphere (20 psi) at room temperature. The reaction mixture was filtered through cellulose powder and the filtrate was evaporated in vacuo. The residue was subjected to preparative thin layer chromatography and development was carried out with a mixture of chloroform and methanol to afford 8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (80 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH:30]([F:32])[F:31])=[CH:23][C:22]=1[CH2:33][C:34](Cl)=[O:35].[Cl-].[NH4+]>C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH:30]([F:32])[F:31])=[CH:23][C:22]=1[CH2:33][C:34]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:35]
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Reactant: COc1cc(Br)c(CC(=O)Cl)cc1OC(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(CC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)cc1OC(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
To 108 mg of (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one in 8 ml THF (anhydrous, inhibitor free) at −78° C. under argon was added 0.18 ml of 2.5 M n-butyl lithium in hexanes. The mixture was stirred at −78° C. for 10 minutes and then 118 mg of (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid chloride dissolved in 2 ml THF was added. The solution was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 30 minutes with stirring. To this mixture was then added 10 ml saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo. Chromatography (20% Ethyl acetate in hexanes) gave 30 mg (S)-1-[2-(2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one. MS (M+1) 485.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH:22][C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]1>ClCCl>[O:22]=[C:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 131 %

Procedure:
To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) in dichloromethane (60 mL) at rt was added (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5 g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additional dichloromethane (50 mL×3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ˜6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120 g column, EtOAc in Hexane, 0 to 100% gradiant, 85 mL/min) afforded 4.18 g (84%) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) −ve. 1H NMR (400 MHz, CDCl3) δ ppm 4.64-4.89 (1 H, m), 3.84-3.96 (2 H, m), 3.77 (3 H, s), 2.81-3.10 (1 H, m), 2.59 (1 H, dd, J=18.93, 1.76 Hz), 1.52 (9 H, s).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:3]([C:6]1[CH:11]=[CH:10][C:9]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCN(CC)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an oven dried flask fitted with a magnetic stir bar and condenser, Pd(PPh3)4 (207 mg, 0.18 mmol) and cuprous iodide (115 mg, 0.6 mmol) was added and the system was evacuated and back flushed with N2. Dry THF (25 mL) was added, subsequently N,N-diethyl-(4-iodophenyl)amine (1 g, 3.6 mmol in 3 mL THF) and dry degassed diisopropylethylamine (2.5 mL, 14.5 mmol) stirred for 10 min. Trimethylsilylacetylene (0.85 mL, 6 mmol) was added and the mixture was stirred at room temperature for 4 h and then at 80° C. for 30 min. The reaction mixture was cooled to room temperature, poured into ice water and stirred at rt for 1 h. The mixture was extracted with ethyl acetate (50×3), the combined organic layer was washed with saturated ammonium chloride solution and was dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by silica gel column chromatography using hexane/EAC (0-5%) as eluent. Yield: 0.54 g. (61%). IR (neat) 2958, 2857, 2145, 1605, 1515, 1468, 1401 cm−1; 1H NMR (400 MHz, CDCl3) 7.37 (d, J=8.8 Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 3.37 (q, 7.2 Hz, 4H), 1.19 (t, 6.8 Hz, 6H), 0.32 (s, 9H); 13CNMR (100 MHz, CDCl3) δ 147.41, 133.14, 110.81, 108.66, 106.77, 90.43, 44.09, 12.35.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([N:36]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]1[NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:46]([N:36]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:37]1[N:41]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3[nH]2)cc1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N(Cc4ccccc4)Cc4ccccc4)nc4ccccc43)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.35 g) was reacted with N,N-dibenzyl-1H-benzo[d]imidazol-2-amine.via General Procedure J for Buchwald coupling to give 255 mg of 2-(1-((2-(2-(dibenzylamino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol following flash chromatography.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[CH:3][C:4]=2[CH3:24])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C)CC2)c(C)c1
Yield: 28.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (775 mg) described in Preparation Example 6 and oxazolidin-2-one (174 mg), the title compound (224 mg) was obtained.