Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)c(N3CCCCC3)c2)CC1
Yield: 88.5 %

Procedure:
1-(5-Fluoro-2-nitro-phenyl)-piperidine (100 mg, 0.44 mmol) was treated with N-methylpiperizine (3 mL) and heated to 80° C. overnight. The reaction was diluted with EtOAc (10 mL), washed with water (2×10 mL), dried (Na2SO4) and concentrated in vacuo to afford 118 mg (88%) of 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine as an oil. The 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine (22 mg, 0.07 mmol) was stirred with 13 mg 5% Pd—C in 1 mL of MeOH under H2 for 2 h. The mixture was filtered through SiO2, eluting with 10% MeOH—CHCl3, and the solvent was concentrated in vacuo to give 17 mg (86%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H26N4, 275.22 (M+H), found 275.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CC(C)=O.O>[CH2:18]([O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ncccc1OCc1ccccc1
Reaction time: 8 h
Yield: 62 %

Procedure:
Methyl 3-hydroxypicolinate (2.0 g) was dissolved in 100 ml of acetone. Potassium carbonate (3.4 g) and 3.4 ml of benzyl bromide were added to the solution, and a reaction was allowed to proceed at room temperature overnight. The reaction solution was then refluxed for 4 hr. Water (50 ml) was added thereto, and the mixture was neutralized with 1 N hydrochloric acid, followed by concentration under the reduced pressure. Methylene chloride and water were added to the residue. The organic layer was dried over magnesium sulfate, and was then dried under the reduced pressure. The dried organic layer was then purified by column chromatography (chloroform-methanol) to give 2.1 g (yield 62%) of methyl 3-benzyloxypicolinate.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl.C(=O)([O-])O.[Na+]>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[OH:3][CH:4]([C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)[CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of zinc chloride (8.14 g, 59.8 mmol) in diethyl ether (200 ml) was added sodium borohydride (4.53 g, 120 mmol), and the-mixture was stirred at room temperature for 30 min. The insoluble material was filtered off, and to the filtrate was added ethyl 3-oxo-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (10.5 g, 29.9 mmol) in diethyl ether (50 ml). The mixture was stirred at room temperature for 30 min. and 1N hydrochloric acid was added to the reaction solution under ice-cooling to quench the reaction. Saturated aqueous sodium hydrogen carbonate was added until the pH became 8, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from diisopropyl ether-hexane to give ethyl (2RS,3RS)-3-hydroxy-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (9.52 g, 90%).
Reaction SMILES: [C:1]1([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[BH4-].[Na+]>CO.O>[CH:1]1([C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: N#Cc1ccc(C2=NCCc3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C2NCCc3ccccc32)cc1
Yield: 89.7 %

Procedure:
A solution of 3.48 g of 4-(3,4-dihydro-isoquinolin-1-yl)-benzonitrile in 90 ml of methanol was cooled to 5° C. while stirring and treated with 1.7 g of sodium borohydride within 30 min. After completion of the addition, the mixture was stirred at 5° C. for a further 30 min. Subsequently, 50 ml of water were slowly added dropwise and the mixture was stirred at room temperature for a further 10 min. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. 3.15 g of crystalline (RS)-4-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-benzonitrile were obtained. Recrystallization of a sample from diisopropyl ether gave colorless crystals of m.p. 94°-97° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>N.CO.C1COCC1.[Ni]>[NH2:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]2[NH:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[C:11]=3[CH:18]=2)=[CH:20][CH:21]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(C#N)cc3)cc12)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1

Procedure:
Raney-Nickel (0.1 9) catalyzed hydrogenation of 0.206 g (0.6 mmol) 4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzonitrile in a mixture of 5% ammonia in methanol (20 ml) and THF (4 ml) for 6 h at atmospheric pressure followed by filtration and evaporation of the solvent gives the title compound; m.p. 253-256° C.; MS-ES+: (M+H)+=344.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].Cl[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25].C(N(CC)CC)C.CC#N>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:26][C:24](=[O:25])[NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCCCOC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol), hexyl chloroformate (0.51 g, 3.1 mmol), and triethylamine (0.63 g, 6.2 mmol) in THF (35 mL) was stirred at 40° C. under nitrogen for 3 hours. The mixture was cooled and diluted with ethyl acetate (100 mL), washed with water (3×100 mL), and evaporated. The residue was chromatographed in methylene chloride-methanol gradient, eluting the product at 19:1 methylene chloride-methanol. This material was further purified by preparative HPLC, using a 50-50 acetonitrile-water isocrat, and providing 0.40 g as a white solid, in 31% yield; mp 111-113° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 5.08 (99.11%); 1H NMR (DMSO-d6) δ 1.11-1.57 (m, 11H), 2.02-2.07 (m, 1H), 2.46-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.97 (t, J=8.3 Hz, 2H), 4.35 (d, J=6.0 Hz, 2H), 5.15 (dd, J=12.9 Hz, J=5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.84-7.90 (m, 2H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 13.8, 22.0, 25.0, 28.6, 30.8, 30.9, 43.5, 49.0, 64.0, 121.6, 123.5, 129.8, 131.6, 133.2, 147.9, 156.6, 167.0, 167.1, 169.8, 172.7; Anal. Calcd for C21H15N3O6: C, 60.71; H, 6.07; N, 10.11. Found: C, 60.49; H, 6.13; N, 9.91.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH2:7]([O:14][CH2:15][CH:16]1[CH2:21]CC(=O)C[CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:2]1[CH2:5][CH2:17][CH:16]([CH2:15][O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC(COCc2ccccc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC(COCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of methyltriphenylphosphonium bromide (12.27 g) and anhydrous tetrahydrofuran (60.0 mL) was cooled to −78° C. A suspension of potassium t-butoxide (4.37 g) in tetrahydrofuran (60.0 mL) was added dropwise. The mixture was stirred at 0° C. for 1 hour and then for 1 hour as the reaction warmed to ambient temperature. The reaction mixture was cooled to −40° C. and a solution of EXAMPLE 341D (5 g,) in tetrahydrofuran (35 mL) was added dropwise. After stirring 18 hours at ambient temperature, the reaction was quenched by the careful addition of 33% brine (150 mL) and diluted with ether (150 mL). The layers were separated and the aqueous layer was extracted with ether (2×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel and eluted with a 0, 10, 15, 25% ethyl acetate in hexane step gradient to provide the title compound.
Reaction SMILES: [N:1]1[C:9]2[C:8](=O)[C:7](=[N:11]O)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C.[Pd]>[N:1]1[C:9]2[CH2:8][CH:7]([NH:11][C:13](=[O:15])[CH3:14])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C(=NO)Cc2cccnc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)NC1Cc2cccnc2C1

Procedure:
18 g (0.11 mol) of the compound of step c were dissolved in 500 ml of acetic acid and 500 ml of acetic acid anhydride and hydrogenated for 20 h at a pressure of 2 bar over 5 g of palladium on barium sulfate. The reaction mixture was filtered and evaporated. The residue was dissolved in 1000 ml of ethanol, treated with 10.8 ml of perchloric acid and hydrogenated for 10 h at 50° C. and a pressure of 3.5 bar over 5 g of palladium on charcoal (10%). The resulting mixture was evaporated, the residue taken up in dilute NaOH solution and extracted with ethyl acetate. Evaporation of the combined organic phases and subsequent chromatography of the residue yielded racemic N-(6,7-dihydro-5H-[1]pyrindin-6-yl)acetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN.O.Cl>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Yield: 69.6 %

Procedure:
5-(4-Nitrophenyl)-2-(1H)-pyrazinone (0.1 g) was warmed with hydrazine hydrate (1 ml) in 50% aqueous ethanol (2.5 ml). Water (about 3 ml) was added sufficient to provide a clear solution. The mixture was allowed to cool slightly and 10% Palladium on charcoal (0.01 g) added as a slurry in a small amount of water. The well-stirred mixture was re-heated for 2 minutes, stirred without heating for 2 minutes, cooled and filtered. The filtrate was evaporated under reduced pressure to give a residue which was suspended in a little water. Dilute hydrochloric acid was added to pH6; the pale yellow solid was collected and washed with water to afford 5-(4-aminophenyl)-2(1H)-pyrazinone (0.06 g).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]([C:12]3[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>CS(C)=O>[NH:1]1[C:5]([CH2:6][C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:28]4[CH:29]=[CH:30][N:31]=[C:27]4[CH3:26])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1
Reactant: Cc1ncc[nH]1
Reactant: Oc1ccc(-n2c(Cc3nnn[nH]3)ccc2-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(-c2ccc(Cc3nnn[nH]3)n2-c2ccc(O)cc2)cc1
Yield: 14.3 %

Procedure:
To a mixture of 4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)phenol (1.0 g, 2.52 mmol) and 2-methyl-1H-imidazole (2.07 g, 25.2 mmol) in DMSO (10.0 mL) was added 8-HQ (54 mg, 0.38 mmol), Cu2O (0.29 g, 2.52 mmol), Cs2CO3 (0.986 g, 3.03 mmol) and PEG-2000 (0.29 g). The resultant mixture was heated at 150° C. for 3 h under microwave irradiation. The mixture was treated with EA (60 mL), the resultant precipitate was filtered and purified by Biotage-flash (Solid phase: C18; Mobile phase: A: CH3CN, B: H2O (0.05% CF3COOH); gradient: 12%→24% B in A; flow rate: 40 mL/min) to afford an off white solid (143 mg, yield 14%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>O.O1CCOCC1>[OH:10][C:9]1[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=1[C:2](=[N:13][OH:14])[CH3:1]
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=NO)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.6 %

Procedure:
A mixture of 2,4-dihydroxyacetophenone (25 g, 0.16 mol), hydroxylamine hydrochloride (14.8 g, 0.21 mol), sodium acetate (20 g, 0.24 mol) and water/dioxane (300 mL, 1:1) was stirred at room temperature for three days before the mixture was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (11.67 g): 1H NMR (CD3OD, 200 MHz): δ=7.26 (m, 1H), 6.28 (m, 2H), 4.88 (s, 2H), 3.29 (m, 1H), 2.24 (s, 3H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)(=O)=O.COC1(C(=O)NC2(C)CCC2)CCN(C2CC3N(C(OCC)=O)C(CC3)C2)CC1.[NH:50]1[CH2:60][CH2:59][CH:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:52][CH2:51]1>>[CH2:57]([O:56][C:54]([CH:53]1[CH2:59][CH2:60][N:50]([CH:6]2[CH2:9][C:8]3([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)[CH2:7]2)[CH2:51][CH2:52]1)=[O:55])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Reactant: CCOC(=O)C1CCNCC1
Agent: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)NC3(C)CCC3)CC1)C2
Product: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Yield: 12.5 %

Procedure:
tert-Butyl 2-[(methylsulfonyl)oxy]-6-azaspiro[3.4]octane-6-carboxylate isomer 1 (1.79 g, 5.73 mmol) and ethyl isonipecotate (4.49 g, 28.62 mmol) were heated together to 65° C. for 5 days. The reaction mixture was reduced in volume in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 100 g, 40-63 μm, 60 A, 50 mL per min, gradient 1% to 4.5% MeOH in DCM]) to give tert-butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.264 g, 12.5%) as a yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C[C@@H:20]1[C:24]2[NH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:23]=2[C:22](=[O:37])[NH:21]1>>[C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:26]3[NH:25][C:24]4[CH2:20][NH:21][C:22](=[O:37])[C:23]=4[CH:27]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)CNC4=O)cccc2c1=O
Yield: 19 %

Procedure:
This compound (54 mg, 0.15 mmol, 19% yield) as a tan solid was prepared according to the procedures described for Example 287, using 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701; 281 mg, 0.79 mmol), and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (706; 477 mg, 1.35 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 7.84-7.93 (m, 1H), 7.51 (s, 1H), 7.18 (t, J=7.73 Hz, 1H), 6.80 (d, J=1.56 Hz, 1H), 5.96 (s, 1H), 4.25 (d, J=0.59 Hz, 2H), 3.48 (s, 3H), 1.51 (s, 9H). m/z (ESI, +ve) 325.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])[N:7]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2c(C)noc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)noc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To a solution of ethyl 4-{4-chloro-2-[(3,5-dimethylisoxazol-4-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}butanoate (400 mg, 0.90 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (62 mg, 2.68 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. Additional lithium borohydride (62 mg, 2.68 mmol) was added and the mixture was warmed to 50° C. for 4 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to give the title compound (193 mg, 0.47 mmol, 53%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[N:5]=[C:4]([C:12](OC)=[O:13])[CH:3]=1.[BH4-].[Na+].CC(C)=O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: OCc1cc(Cl)cc(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dimethyl 4-chloro-2,6-pyridine dicarboxylate, prepared as in Example 4, (85.0 g, 370 mmol) was dissolved in MeOH (2.3 L). The solution was cooled to 0° C. To the cooled solution was added NaBH4 (63.0 g, 167 mmol) in small portions. The reaction mixture stirred at 0° C. for 1 hour, then at room temperature for 2-3 hours. After about 3 hours, the mixture was allowed to reflux overnight. Acetone (425 mL) was added to the reaction mixture. The solution was heated to reflux for 1 hour, then was concentrated in vacuo. Saturated Na2CO3 solution (650 mL) was added to the concentrate and refluxed for 45 minutes. The flask was allowed to reach room temperature and left at room temperature for 16 h. The flask contained a white precipitate which was filtered and washed with chloroform (30 mL). The white solid was dissolved in hot THF (300 mL), dried over magnesium sulfate and filtered, then concentrated in vacuo to afford 32.1 g 4-chloro-2,6-dihydroxymethyl pyridine as a white solid. The filtrate was concentrated. The resulting white solid was heated in THF (500 mL), dried over magnesium sulfate and filtered. This process was repeated then the solid was stirred in 200 mL of CHCl3 and filtered to afford an additional 23.6 g (87% overall yield) of pure 4-chloro-2,6-dihydroxymethyl pyridine as a white solid: 1H NMR (CD3OD, 400 MHz) δ 7.62 (s, 2H), 5.02 (s, 2H), 4.83 (s, 4H). 13C NMR (CD3OD, 100 MHz) δ 162.57, 145.75, 118.76, 63.74.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:24]([NH:26][O:27][P:28]([CH3:31])(=[O:30])[OH:29])=[O:25])[CH:21]([CH3:23])[CH3:22])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:24]([NH:26][O:27][P:28]([CH3:31])(=[O:29])[OH:30])=[O:25])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NOP(C)(=O)O
Solvent: NCc1ccccc1
Product: CC(C)[C@H](N)C(=O)NOP(C)(=O)O

Procedure:
In a manner analogous to Example 1 b), starting from the benzylamine salt of [(N-benzyloxycarbonyl-L-valyl)amino]-methylphosphonic acid there was obtained (L-valylamino)-methyl-phosphonic acid of melting point 290°-292° C (decomposition); [α]D20 = +67.9° (c = 0.85% in water).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C.CO.[Pd]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[CH:18][CH:17]=1
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)n(C)c(=O)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 3,5-dimethyl-2-[2-[4-(4-trifluoromethylbenzoyl)phenyl]vinyl]-4(3H)-quinazolinone (897 mg) in THF: ethyl acetate: methanol (1:1:1) (60 ml) was added 10% Pd/C (50% hydrous) (179 mg) and the mixture was stirred under hydrogen at room temperature for 2 hours. The catalyst was then filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate =2:1) and recrystallized from ethyl acetate-methanol to provide 307 mg of white powder.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH3:13]>CN(C)C=O.O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH2:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 2-chloro-6-methoxy-3-nitropyridine (25.3 g, 0.134 mol) and a concentrated aqueous ammonia solution (70 ml) in N,N-dimethylformamide (200 ml) was stirred at 70° C. for 4 hours and 15 minutes. The reaction mixture was cooled to room temperature and then diluted with water. The resulted precipitate was collected by filtration to yield the title compound (16.8 g, 99.2 mmol, 74.0%) as a yellow solid.