Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:21]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCBr
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 2.68g of n-heptyl bromide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate. After concentration by evaporation and purification by chromatography over silica gel in the system ethyl acetate/hexane 2:5, the product is obtained in the form of a solid. Melting point 91°-92°. Rf (ethyl acetate/hexane 4:1)=0.63.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:28]=[C:27]([CH:29]([NH2:31])[CH3:30])[N:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[C:25]=2[CH:39]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:31][CH:29]([C:27]2[N:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[C:25]3[CH:39]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[N:28]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a microwave vessel was added 4-amino-6-chloropyrimidine-5-carbonitrile (B) (0.057 g, 0.366 mmol), DIEA (0.192 mL, 1.098 mmol), and 1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.100 g, 0.366 mmol) in n-butanol (3.66 mL). The solution was stirred at 120° C. under microwave irradiation for 2 h and then purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM as eluent to give a racemic mixture 4-amino-6-((1-(6-fluoro-1-(3-fluorophenyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.65 Hz, 3H) 5.56 (qd, J=6.91, 6.65 Hz, 1H) 6.93 (dd, J=9.00, 2.35 Hz, 1H) 7.08-7.15 (m, 1H) 7.17 (br. s., 2H) 7.31 (td, J=8.41, 2.15 Hz, 1H) 7.35-7.40 (m, 1H) 7.48 (d, J=9.59 Hz, 1H) 7.56 (td, J=8.12, 6.65 Hz, 1H) 7.69 (d, J=7.63 Hz, 1H) 7.73 (dd, J=8.80, 4.89 Hz, 1H) 7.86 (s, 1H); LC-MS (ESI) m/z 392.1 [M+H]+. The racemic mixture (0.085 g) was separated by chiral separation using SFC to give two fractions:
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][CH:2]1[CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH:2]1[O:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1Oc2cccnc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1Oc2cccnc2O1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A solution of intermediate (5) (0.018 mol) and triethyl amine (0.036 mol) in DCM (80 ml) was stirred and cooled with an ice-water bath. Methanesulfonyl chloride (0.027 mol) was added dropwise and the resulting reaction mixture was stirred for one hour while cooling on an ice-bath. The crude reaction mixture was washed with water and brine, then extracted. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 4.2 g of (±)-1,3-dioxolo[4,5-b]pyridine-2-methanol methanesulfonate (ester) (intermediate 6).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.ClCCl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][C:36]([C:38]2[N:47]3[C:41]([CH2:42][NH:43][C:44]4[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=4[CH2:46]3)=[CH:40][CH:39]=2)=[O:37])[CH:29]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:43]2[C:44]3[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=3[CH2:46][N:47]3[C:38]([C:36]([NH:35][CH2:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)=[O:37])=[CH:39][CH:40]=[C:41]3[CH2:42]2)=[O:18])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 2′-acetyl-biphenyl-4-carboxylic acid of Step A (0.340 g, 1.41 mmol) in dry tetrahydrofuran (30 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (1 drop) followed by the dropwise addition of a 2.0 M solution of oxalyl chloride in dichloromethane (1.17 mL, 2.34 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue redissolved in dry dichloromethane (30 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a cream solid. The acid chloride was dissolved in tetrahydrofuran (30 mL); N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 11 (0.300 g, 0.942 mmol) was added, followed by N,N-diisopropylethylamine (0.49 mL, 2.83 mmol) and the reaction mixture stirred at room temperature under nitrogen for 19 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (20 mL), the mixture stirred vigorously for 5 minutes and then partitioned between ethyl acetate (100 mL) and 2 M sodium hydroxide (100 mL). The organic phase was separated, washed with 2 M sodium hydroxide (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 1 to 3.5% methanol in dichloromethane gave a cream foam that was crystallized from ethyl acetate/hexane to afford the title compound (0.45 g, 88%) as a white solid, m.p. 149-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.O1CCOCC1.[Al].CC(C)=O>O=[Mn]=O.CCCCCC>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a 100 mL flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (1.51 g, 3.1 mmol, Intermediate 47: step e) was added 1,4-dioxane (50 mL) followed by activated MnO2 (1.3 g, 15 mmol) and the mixture was heated to reflux in an aluminum heating mantle under N2. After 1 hour, TLC (25% acetone:hexane) indicated that the reaction was complete. The contents were filtered while still hot through Celite® and rinsed with THF. The resulting light yellow solution was concentrated and chromatographed by passing through a silica gel column (10% acetone-hexane increasing to 25% acetone) to give the title compound as a light yellowish amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]B(O)O.[F-].[K+].O1CCCC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 78.2 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (25 g), methylboronic acid (8.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (1:1)(2.9 g) and potassium fluoride (16 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g). 4-(3,5-Dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g) was dissolved in chloroform (100 mL), 4N hydrogen chloride/ethyl acetate (50 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, and the mixture was filtered to give the title compound (10 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]=[CH:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH:3]=[O:4].[CH:12]([Mg]Cl)=[CH2:13].O>O1CCCC1>[CH3:1][CH:2]([CH2:5][CH:6]=[CH:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH:3]([OH:4])[CH:12]=[CH2:13]
Reactant: C=C[Mg]Cl
Reactant: CCC(C)C=CCC(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)C(C)CC=CC(C)CC
Yield: 94 %

Procedure:
54 g (0.35 mole) of 2,6-dimethyl-oct-4-en-1-al are added in the course of 15 minutes to a solution of 0.4 mole of vinyl-magnesium chloride in 2 liters of tetrahydrofuran, whilst cooling with ice. After a reaction time of 30 minutes, the mixture is hydrolyzed with 40 ml of water, the organic phase is isolated and the solvent is distilled off. The reaction product is fractionated, giving 60 g of the above allyl alcohol (yield, 94% of theory). B.p. = 48°-52° C at 0.02 mm Hg; nD25 = 1.4591.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3C(=O)C4[C:17](=CC=CC=4)[C:16]3=[O:25])[O:11][C:10]2=[O:26])=[CH:5][C:4]=1[F:27])#[CH:2].C1COCC1.C(O)C.O.NN>C1COCC1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:25])[CH3:17])[O:11][C:10]2=[O:26])=[CH:5][C:4]=1[F:27])#[CH:2]
Reactant: C#Cc1ccc(N2CC(CN3C(=O)c4ccccc4C3=O)OC2=O)cc1F
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: C#Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 50° C. suspension of Example 3A (1.65 g) in 1:1 THF/ethanol (34 mL) was treated with hydrazine monohydrate (3×240 μL) at 1 hour intervals. One hour after the final addition the mixture was cooled to 25° C. and filtered. The filtrate was concentrated in vacuo. The resultant material was dissolved in a mixture of pyridine (17 mL) and dichloromethane (17 mL), cooled to −5° C., and treated with acetic anhydride (854 μL). The reaction mixture was warmed to room temperature, stirred for 5 minutes, and concentrated to provide crude product. The crude product was dissolved in 4:1 THF/dichloromethane (75 mL) and washed with 1:1 brine/water. The aqueous wash was extracted with dichloromethane (25 mL), and the combined extracts were dried over MgSO4. Next the mixture was filtered and concentrated. The residue was dissolved in acetone (20 mL) and filtered. The filtrate was concentrated and the residue triturated with hexanes to provide the desired product. MS (ESI(+)) m/e 277 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.5-7.4 (m, 2H), 7.16-7.19 (dd, J=2.4, 8.4 Hz, 1H), 5.93 (bt, 1H), 4.8 (m, 1H), 4.05 (t, J=9 Hz, 1H), 3.8-3.6 (m, 3H), 3.28 (s, 1H), 2.02 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][C:20]=1[F:28]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: N#Cc1cc(-c2ccc(Cl)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (64 mg, 75%), MS (ISP) m/z=340.3 [(M+H)+], mp 309° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)(=[O:7])[CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:16])[CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCCC(C(=O)O)C1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCCC(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (2.12 ml, 32.1 mmol) was added to fluorobenzene solution (20 ml) of 1-acetyl-3-piperidinecarboxylic acid (5.00 g, 29.2 mmol) under ice-cooling, which was stirred at room temperature for 30 minutes. Aluminum chloride (9.74 g, 73.0 mmol) was added to the solution, which was stirred at 90° C. for 1 hour. The reaction mixture was poured in ice, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, saturated sodium hydrogencarbonate solution, and again saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give (1-acetyl-3-piperidinyl)(4-fluorophenyl)methanone (4.93 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:14]
Reactant: CCI
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(F)cc1C(C)=O

Procedure:
5'-Fluoro-2'-hydroxyacetophenone (9.38 g, 61 mmole), iodoethane (7.3 ml, 91 mmole) and K2CO3 (12.6 g, 91 mmole) in acetone (100 ml) was stirred at 60° C. overnight. The mixture was filtered, evaporated, dissolved in hexane/ethyl acetate, washed with 2M NaOH (2×20 ml) and water, dried (MgSO4) and evaporated to give 2'-ethoxy-5'-fluoroacetophenone. A solution of mCPBA )19.3 g, 112 mmole) in CH2Cl2 (500 ml) was dried with MgSO4. 2'-Ethoxy-5'-fluoro-acetophenone (10.2 g, 56 mmole) was added and the mixture was stirred for 3 days. More mCPBA (5 g, 29 mmole) and MgSO4 was added and stirring was continued for 2 days. The mixture was filtered, diluted with ethyl acetate, washed with 2M NaOH (2×70 ml), NH4 Cl (sat, 50 ml), dried (MgSO4) and evaporated. The residue (10.45 g,) was dissolved in ethanol (100 ml). KOH (8.9 g, 160 mmole) was dissolved in water (50 ml). The solutions were combined and stirred for 1 h. The mixture was washed with diethyl ether/hexane 2×(50+25 ml), acidified with HCl (konc), extracted with ethyl acetate (3×100 ml), dried (MgSO4) and evaporated. The residue (8.22 g) was dissolved in CH2Cl2 (100 ml). Triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and the solution was refluxed for 2 hrs. More triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and refluxing was continued overnight. The solution was evaporated, CH2Cl2 (200 ml) was added and the solution was washed with water, 2M NaOH and NH4Cl. Drying (MgSO4) and evaporation provided 4.0 g of 1-ethoxy-4-fluoro-2-methoxymethoxybenzene. This compound was reacted in a manner analogous to Example 39 to give (+,-)-N-(cis-2-(3-ethoxy-6-fluoro-2-methoxymethoxyphenyl)-cyclopropyl)-N'-(5-chloropyrid-2-yl)-urea. Finally deprotection with 2M HCl in dioxane gave the titled compound. 1H NMR (250 MHz, DMSO-D6) δ 1.04-1.14 (m, 1H), 1.41-1.56 (m+t, 4H), 1.96-2.06 (m, 1H), 3.05-3.15 (m, 1H), 4.06-4.19 (m, 2H), 6.64 (t, 1H), 6.94 (dd, 1H), 7.19 (d, 1H), 7.82(dd, 1H), 8.10(d, 1H), 8.61 (br.s, 1H), 9.08 (br.s, 1H), 9.57 (br.s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O=C1NC(CN2CCNCC2)=CC(=O)N1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc([N+](=O)[O-])cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: O=c1cc(CN2CCNCC2)[nH]c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Yield: 91.7 %

Procedure:
1-Acetyl-N-(3,4-dichlorophenyl)-N-{3-[4-(4-nitrobenzyl)-1-piperidinyl]propyl}-4-piperidinecarboxamide (Example 302) (70 mg, 0.12 mmol) was dissolved in ethanol (0.4 mL). To the mixture was added stannic chloride 2 hydrate (135 mg, 0.61 mmol), and the mixture was heated for 30 minutes under reflux. The mixture was cooled, and to the mixture were added aqueous solution of 1N-sodium hydroxide (10 mL) and ethyl acetate (10 mL). The resulting white precipitates were filtered off with Celite. The filtrate was subjected to extraction procedure. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (alumina 10 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (63 mg, 0.11 mmol, Yield 92%) as pale yellow oily substance.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:20](Cl)[N:21]=[CH:22][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:20]([C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)CC(O)c1c(Cl)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CC(O)c1c(-c2ccc(Cl)cc2)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 25 °C
Yield: 25.9 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.212 mmol), 4-chlorophenyl boronic acid (66 mg, 0.424 mmol), NaHCO3 (53 mg, 1.06 mmol), aq. 2M K3PO4 (0.53 ml, 1.06 mmol) in dioxane (1 mL) and water (0.2 mL) was added Pd(dppf)Cl2 (5 mg, 0.0068 mmol). The reaction was degassed with nitrogen (3×), heated at 120° C. (MW) for 1.5 h, cooled to RT then diluted with EA (10 mL) water (2 mL). The reaction was filtered and the filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-chlorophenyl)-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 26% yield) as a colorless oil. LCMS: MH+ 546 and TR=2.602 min.
Reaction SMILES: [OH-].[Na+].CS(C)=O.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[OH:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A stirred solution of sodium hydroxide (16.8 g) in water (32 mL) at 20° C. is treated with dimethyl sulfoxide (560 mL). It is then treated with 3,4-dihydroxy-benzaldehyde (56.9 g), portionwise during 5 minutes, while keeping the temperature at 20° C. It is then treated with benzyl bromide (49.7 mL), portionwise, at 20° C. The solution is then heated at 80° C. for 6 hours and then allowed to stand at room temperature overnight. After dilution with ice-water (2240 mL) the solution is extracted with diethyl ether (1×1000 mL, 2×250 mL). The combined ether extracts are washed with water, dried over magnesium sulfate and concentrated, to give an oily solid, which is recrystallized from a mixture of ethyl acetate and isopropanol, to give 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g), in the form of pale yellow crystals, m.p. 118-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][C:10]1[O:12][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2c(F)cccc2F)n1
Yield: 34 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2,6-difluorophenyl)acetic acid (0.651 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.345 g (34%) of ethyl 5-(2,6-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.