Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([C:7]#[N:8])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: ClCCNCCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
49 g 4-chlorobenzyl cyanide 1 (323 mmol, 1.00 equiv) and 58 g of bis[2-chloroethyl]amine (323 mmol, 1.00 equiv) were dissolved in 325 mL of anhydrous DMF in a 2 L round bottom flask fitted with a magnetic stir bar, reflux condenser, and N2 inlet. The mixture was cooled in an ice water bath, then 52 g of 60% NaH in mineral oil (1293 mmol, 4.00 equiv) was added to the stirring solution at a rate such that the exothermic reaction did not become violent. After the addition was complete, the apparatus was transferred to an oil bath and the mixture heated to 60° C. and stirred for 48 h under N2 atmosphere. The mixture was cooled to room temperature and the remaining hydride carefully quenched under N2 by dropwise addition of a small amount of H2O. The resultant slurry was poured into 2 L of rapidly stirring H2O and the pH adjusted to ˜1 with concentrated HCl. The mixture was transferred to a 4L separatory funnel and extracted with 3×500 mL of hexane. The organic extracts were discarded and the aqueous extracts was adjusted pH to ˜9 by the addition of solid K2CO3. The resultant precipitate was collected by vacuum filtration and washed with small portions of H2O, followed by hexane. The tan solid was dried under vacuum to yield 4-(4-chloro-phenyl)-piperidine-4-carbonitrile: MS (ES) M+H expected=221.7, found=221.1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.[CH3:10][CH2:11][CH2:12][CH2:13]C(O)=O>>[CH2:10]([C:2]1[NH:1][CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=O)O
Reactant: COC(=O)c1c[nH]cn1
Product: CCCCc1nc(C(=O)OC)c[nH]1

Procedure:
The title compound was prepared using the procedure described in Example 55(a) starting from methyl 1H-imidazole-4-carboxylate (5 g, 39.7 mmol) and n-valeric acid (13 ml, 119 mmol). Yield: 1.2 g. 1H-NMR (400 MHz; CDCl3): δ 0.92 (t, 3H), 1.24-1.29 (m, 2H), 1.68-1.76 (m, 2H), 2.76 (t, 2H), 3.87 (s, 3H), 7.62 (s, 1H), 9.92 (bs, 1H).
Reaction SMILES: [CH:1]([CH:4]1[C:9]2[N:10](C(OCC3C=CC=CC=3)=O)[CH:11]=[N:12][C:8]=2[CH2:7][C@@H:6]([C:23]([O:25][CH3:26])=[O:24])[N:5]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([CH3:3])[CH3:2].C(C1C2N=CNC=2C[C@@H](C(OC)=O)N1C(OCC1C=CC=CC=1)=O)(C)C.CN>CN(C=O)C>[CH:1]([C@H:4]1[C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH2:7][C@@H:6]([C:23]([O:25][CH3:26])=[O:24])[N:5]1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1Cc2ncn(C(=O)OCc3ccccc3)c2C(C(C)C)N1C(=O)OCc1ccccc1
Agent: CN
Agent: COC(=O)[C@@H]1Cc2[nH]cnc2C(C(C)C)N1C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1Cc2[nH]cnc2[C@H](C(C)C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 2.7 %

Procedure:
A 2:1 mixture of 3,5-dibenzyl 6-methyl (6S)-4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]-pyridine-3,5,6(4H)-tricarboxylate and 5-benzyl 6-methyl (6S)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5,6-dicarboxylate (mixture of 4S and 4R diastereomers; 600 mg, ˜1.20 mmol) was dissolved in DMF (6 mL) and methylamine (1.22 mL, 2 M in THF, 2.44 mmol) was added. The reaction mixture was split into 3 equal portions. The first reaction mixture was stirred at room temperature for 18 h. The second reaction mixture was heated at 60° C. for 4 h, methylamine (0.20 mL, 2 M in THF, 0.41 mmol) was added and the reaction mixture was heated under reflux at 80° C. for 18 h. The third reaction mixture was heated using a Biotage microwave (100° C., absorption high, pre-stirring 20 sec) for 20 min, methylamine (0.20 mL, 2 M in THF, 0.41 mmol) was added and the reaction mixture was heated using a Biotage microwave (120° C., absorption high, pre-stirring 20 sec) for 20 min. Methylamine (1.00 mL, 2 M in THF, 2.00 mmol) was added and the reaction mixture was heated using a Biotage microwave (160° C., absorption high, pre-stirring 20 sec) for 20 min. The 3 reaction mixtures were combined and the solvents were removed in vacuo. The residue was partitioned between EtOAc (30 mL) and sat aq NaHCO3 solution (30 mL). The organic layer was washed with sat aq NaHCO3 solution (30 mL), brine (30 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4% and 5% MeOH in DCM (200 mL each)) and by reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 40% to 90% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give 5-benzyl 6-methyl (4S,6S)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5,6-dicarboxylate (46.2 mg, 2.7%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:31]([OH:33])=O)[CH:3]=1.F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.N1(O)C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:31]([NH2:41])=[O:33])[CH:3]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C(=O)O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution 4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-trifluorophenyl)methyl]pyridine-2-carboxylic acid (392 mg, 0.800 mmol) in N,N-dimethylformamide (10 ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (624 mg, 1.20 mmol), benzotriazol-1-ol (162 mg, 1.20 mmol), ammonium chloride (85.6 mg, 1.60 mmol), and N-ethyldiisopropylamine (0.557 ml, 3.20 mmol) were added in a nitrogen atmosphere at room temperature. After stirring for 2 hours at the same temperature, the reaction mixture was dissolved in ethyl acetate, and the solution was washed with 1 N hydrochloric acid, 1 N aqueous sodium hydroxide, saturated aqueous ammonium chloride, and then saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and then was collected by filtration, to obtain the title compound (229 mg, 0.468 mmol, 58%) as a white solid. The filtrate was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and then was collected by filtration, to obtain the title compound (66 mg, 0.135 mmol, 17%) as a white solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[C:11]([CH3:18])=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[C:11]([CH2:18][Br:8])=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(Br)c1CBr
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of NBS (3.45 g), dibenzoyl peroxide (100 mg) and 3-bromo-2-methylbenzonitrile (3.47 g) in carbon tetrachloride (40 ml) was heated at reflux under nitrogen for 48 h. The mixture was then cooled to room temperature, filtered and concentrated in vacuo to give a pale yellow solid. Chromatography eluting with dichloromethane gave the title compound as a white solid (4.23 g) m.p. 90°-93° C.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:20]([Cl:26])=[CH:21][N:22]=[CH:23][C:24]=3[Cl:25])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)=[O:3]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: NCc1ccccc1Cl
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccccc1Cl
Yield: 58 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 2-chlorobenzylamine to give Compound 31 (0.15 g, 58%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].C(N(S(F)(F)[F:38])CC)C>ClCCl>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:38])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(F)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (5.0 g, 12.06 mmol) and dichloromethane (100 mL) is stirred at −78° C. Diethylaminosulfur trifluoride (1.8 mL, 13.74 mmol) is added, the cold bath is removed, and the reaction is stirred at room temperature 1 hr. The reaction mixture is diluted with water (100 mL), the layers are separated, and the aqueous layer is extracted with dichloromethane (2×100 mL). The organic layers are combined, washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated to give 5.1 g, 100%, of the title compound as a tan solid. LCMS M+1=418.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([CH3:52])[S:11]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH:23]2[CH2:30][N:29]3[C:31]4[CH:32]=[C:33]([C:44]([O:46]C)=[O:45])[CH:34]=[CH:35][C:36]=4[C:37]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[C:28]3[C:27]3[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=3[O:25][CH2:24]2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([N:10]([CH3:52])[S:11]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH:23]2[CH2:30][N:29]3[C:31]4[CH:32]=[C:33]([C:44]([OH:46])=[O:45])[CH:34]=[CH:35][C:36]=4[C:37]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[C:28]3[C:27]3[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=3[O:25][CH2:24]2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCCN1CCN(S(=O)(=O)N(C)C(=O)OC(C)(C)C)CC1)COc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)S(=O)(=O)N1CCN(CCCC2COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)O)cc4n3C2)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2N NaOH (aq) (30 eq) was added to a solution of methyl 7-[3-(4-{[(tert-butoxycarbonyl)(methyl)amino]sulfonyl}piperazin-1-yl)propyl]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.06 M) in MeOH and the reaction stirred at 70° C. for 3 h. The reaction was allowed to cool to RT before reducing the volume of MeOH in vacuo. The residue was partitioned between 1N HCl (aq) and EtOAc, ensuring the aqueous phase was acidic. The aqueous was extracted a second time with EtOAc and the combined organics washed with brine before being dried (Na2SO4), filtered and concentrated in vacuo. The material was taken on without further purification. (ES+) m/z 681 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]3[C:13](=[O:14])[N:12]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=[O:23])[C:9]3=2)[N:4](CC2C=CC(OC)=CC=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O.C(OCC)(=O)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:15]([N:12]1[C:13](=[O:14])[C:8]2[C:9](=[C:10]3[C:2]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[N:3][NH:4][C:5]3=[N:6][CH:7]=2)[C:11]1=[O:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cn2nc(Br)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2cnc3[nH]nc(-c4ccccc4)c3c2C(=O)N1CCc1ccccc1
Temperature: 180 °C

Procedure:
A mixture of 1-bromo-3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (25 mg, 50 umol), cesium carbonate (32 mg, 100 umol), phenyl boronic acid (12 mg, 100 umol) and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (2 mg) in anhydrous N,N-dimethylformamide (2 ml) was heated to 180° C. under microwave conditions for 5 minutes. The mixture was diluted with ethyl acetate (50 ml) and washed with dilute brine (4×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure then treated with trifluoroacetic acid (1 ml) and heated to 70° C. for 7 hours. The mixture was concentrated under reduced pressure and purified by reverse phase column chromatography to yield 7-phenethyl-1-phenylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione. LCMS: [M+H] 369.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17](CO)([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O-])(O)=[O:25].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:19][CH2:18][C:17]([CH:16]=[O:15])([CH2:20][CH2:21]2)[O:25][CH2:24]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: O=C([O-])O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a mixture of (4-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-1-yl)methanol (5A; 182 mg, 0.586 mmol) and NaHCO3 (59 mg, 0.704 mmol) in CH2Cl2 (5 mL) at 0° C. was added Dess-Martin periodinane (298 mg, 0.70 mmol). The solution was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc, washed successively with sat'd aq NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 100% EtOAc:hexanes) to afford the title compound (123 mg, 68% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 7.41-7.28 (m, 3H), 7.12-7.16 (m, 1H), 7.06-6.89 (m, 4H), 6.88 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 4.12-4.09 (m, 2H), 2.17-1.90 (m, 8H).
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.C(C1NC(=O)N(CC2C=CC(OC)=CC=2)C1=O)C.[CH3:42][C:43]1[C:44]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:59]=[CH:60][C:61]([N:64]4[CH:68]([CH2:69][CH3:70])[C:67](=[O:71])[N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:81])=[N:62][CH:63]=3)=[O:57])[CH2:52][CH2:51]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1>>[CH3:42][C:43]1[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:56]([C:58]3[CH:59]=[CH:60][C:61]([N:64]4[CH:68]([CH2:69][CH3:70])[C:67](=[O:71])[NH:66][C:65]4=[O:81])=[N:62][CH:63]=3)=[O:57])[CH2:54][CH2:55]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1
Reactant: CCC1C(=O)N(Cc2ccc(OC)cc2)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1
Agent: CCC1NC(=O)N(Cc2ccc(OC)cc2)C1=O
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCC1C(=O)NC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (300 mg) described in Preparation Example 127 and 5-ethyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione (176 mg) described in Preparation Example 207 and by the reaction and treatment in the same manner as in Example 508, the title compound (153 mg) was obtained via 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-5-ethyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2ccccc2)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Prepare a solution of 5-methyl-2-phenyloxazole (790 mg, 4.97 mmol) in CCl4 (70 mL) under nitrogen. Add N-bromosuccinimide (884 mg, 4.97 mmol) and a catalytic amount of benzoyl peroxide. Reflux the mixture for 2 hours, cool to room temperature, and stir overnight. Wash the reaction mixture with a saturated solution of Na2SO3 (75 mL) followed by saturated sodium hydrogencarbonate (100 mL). Dry the organic phase (magnesium sulfate), filter, and concentrate to afford 1.17 g of 5-bromomethyl-2-phenyloxazole as a white solid. MS: m/e=238 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:14]1CCN2C(=NCCC2)CC1.IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:13])[C:10]([O:12][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(=O)Cc1ccc(Br)cc1
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=O)Cc1ccc(Br)cc1
Reaction time: 2.5 h
Yield: 68 %

Procedure:
To a solution of 3-(4-bromophenyl)-2-oxopropionic acid (70.0 mg, 0.288 mmol) in DMF (2 mL) at 0° C. was added DBU (72.2 mg, 0.288 mmol) and iodomethane (204 mg, 1.440 mmol). The reaction mixture was stirred for 2.5 hours at the same temperature. The reaction was acidified with 1 M HCl and extraction with ether (3×25 mL), drying (MgSO4), concentrated under reduced pressure and dried on vacuum to get the light brown oily compound B18 in 68% yield and used as such in next step.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.O[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: OCCN1CCCC1
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCCN1CCCC1

Procedure:
2-[N-Pyrollidinyl]ethyl Tributylstannyl Ether is prepared from 65.0 gm (.109 mole) bis(tributyltin) oxide and 25.0 gm (.217 mole) N-(β-hydroxyethyl)pyrolidine in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After refluxing 20 hours, a total of 2.0 ml of water (theory 1.96 ml) had collected in the Dean-Starke tube. The solvent is stripped off on a rotating evaporator to provide 94.0 gm of yellow liquid. This is fractionated at reduced pressure with collection at 150°-154° C. at 0.3 mm of water-white liquid (Percent yield - 63). Infrared spectral analysis shows this liquid to be the desired ether.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=S)[NH:9][C:8]=2[C:7]([C:17]#[N:18])=[C:6]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(O)(=O)C.O.OO>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[CH:10]=[N:9][C:8]=2[C:7]([C:17]#[N:18])=[C:6]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1
Reactant: Cn1c(=S)[nH]c2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cn1cnc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.3 %

Procedure:
Sodium tungstate dihydrate (0.91 g) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.51 g) in a mixture of methanol (9 ml), acetic acid (3 ml) and water (1 ml), and a 30% aqueous hydrogen peroxide solution (0.29 ml) was added dropwise thereto at room temperature and stirred for 2 hours. After the reaction mixture was allowed to cool, the methanol was distilled off under reduced pressure and the residue was adjusted to pH 9 with an aqueous potassium carbonate solution. A 10% aqueous sodium hydrogensulfite solution was added thereto and stirred for 30 minutes, followed by extraction with ethyl acetate (200 mL). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was dried under reduced pressure to obtain the title compound (1.61 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.N#N.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.[CH3:38][N:39](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:38]([C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1)#[N:39]
Reactant: Cc1cc(Br)cnc1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: N#N
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 62.1 %

Procedure:
A mixture of tert-butyl 5-bromo-3-methylpicolinate (7.47 g, 27.4 mmol), zinc cyanide (2.26 g, 19.21 mmol) and zinc dust (0.179 g, 2.74 mmol) was suspended in DMF (55 ml). The suspension was purged with N2 and finally tri-tert-butylphosphine, 1.0M in toluene (2.196 ml, 2.196 mmol) was added under N2 gas. The reaction mixture was heated to 80° C. for 2.5 h. Then 0.8 g of tri-tert-butylphosphine was added to reaction mixture and it was heated to 80° C. for another 5.5 h. The mixture was then cooled to RT and the grey suspension was filtered out. Then 175 ml of MTBE and 40 ml of water were added. The aqueous layer was washed with 75 ml of MTBE. The organic layer was then washed with 100 ml of water and brine. It was dried on MgSO4 and concentrated. The crude material was concentrated to yield a yellow oil which was purified by chromatography through a Redi-Sep pre-packed silica gel column (330 g), eluting with a gradient of 20% to 30% to 40% (40% EtOAc in heptane) in heptane, to provide tert-butyl 5-cyano-3-methylpicolinate (3.72 g, 17.04 mmol, 62.1% yield) as white solid. MS m/z=241.2 (M+Na).