Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3cnccc3c21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)CCNC3
Yield: 0.1 %

Procedure:
A catalytic amount of platinum oxide was added to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.4 g, 1.66 mol)) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted five times with dichloromethane (100 mL). The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 0.34 g of 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 220-223° C. Analysis: Calculated for C13H19N5+¼H2O: % C, 62.50% H, 7.87; % N, 28.03; Found: % C, 62.50; % H, 7.72; % N, 27.46.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:30])=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:24])=[C:17](F)[C:18]=3[N+:20]([O-:22])=[O:21])[C:13](=[O:25])[C:12]([C:26]([OH:28])=[O:27])=[CH:11]2)[CH:9]=1>CS(C)=O.N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:30])=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:24])=[C:17]([NH:2][CH3:1])[C:18]=3[N+:20]([O-:22])=[O:21])[C:13](=[O:25])[C:12]([C:26]([OH:28])=[O:27])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Cc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c([N+](=O)[O-])c1F
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CNc1c(C)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Pyridine (500 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-6-methyl-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (70 mg), and the mixture was heated and stirred overnight at 40° C. Dimethyl sulfoxide (10 drops) was added to the reaction mixture, followed by stirring at 40° C. for 5 hours. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Solids deposited were collected by filtration aid washed with ethanol and diethyl ether to obtain the title compound (53 mg) as a yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:14]3[N:15]=[C:16]([NH2:25])[N:17]=[C:18]([C:19]4[O:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[C:13]=3[N:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=1.[CH2:26]([OH:31])[C:27]([F:30])([F:29])[F:28]>>[CH3:24][C:21]1[O:20][C:19]([C:18]2[C:13]3[N:12]=[N:11][N:10]([CH2:9][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][O:31][CH2:26][C:27]([F:30])([F:29])[F:28])[N:8]=4)[C:14]=3[N:15]=[C:16]([NH2:25])[N:17]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1
Reactant: OCC(F)(F)F
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COCC(F)(F)F)n2)o1

Procedure:
Prepared from 3-(6-bromomethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and trifluoroethanol by the method described in Example 32.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1>O.CC(O)=O>[N:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCCCc2ccccc21
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of sodium nitrite (1.35 g, 19.6 mmol) in water (4.0 mL) was added dropwise to a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g, 16.3 mmol) in AcOH (10 mL) at 0-10° C. The mixture was stirred at 5° C. for 10 min, room temperature for 1 h and extracted with CH2Cl2 (3×20 mL). The organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:9) gave 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 91%) as a brown liquid. 1H NMR (CDCl3, 300 MHz) δ 1.70-1.85 (m, 4H), 2.70-2.82 (m, 2H), 3.92 (br, 2H), 7.25-7.32 (m, 1H), 7.32-7.40 (m, 2H), 7.40-7.48 (m, 1H) ppm.
Reaction SMILES: O[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].C([CH2:14][C:15]([OH:17])=[O:16])#N>>[OH:11][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH2:14][C:15]([OH:17])=[O:16])=[CH:2]1
Reactant: O=C1c2ccccc2CC1O
Reactant: N#CCC(=O)O
Product: O=C(O)CC1=CC(O)c2ccccc21

Procedure:
In an alternative preparation scheme, the intermediate hydroxy-indanone can be reacted with cyanoacetic acid to give the corresponding hydroxyindene-3-acetic acid, which is then esterified before introduction of the R5 -methylene grouping in order to facilitate the purification of desired intermediates. Since introduction of the R5 -methylene grouping is accompanied by ester hydrolysis, the intermediate free acid is re-esterified to facilitate purification followed by reaction with an appropriate halo-alkyl-A group to yield the desired final product ##STR15## can be prepared by reacting a halo-indene-3-acetic acid with a A(CH2)n -containing benzaldehyde prepared from the corresponding individual components ##STR16##
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([OH:5])=[O:4].[CH3:9][C:10](O)([CH3:12])[CH3:11].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([O:5][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:4]
Reactant: CC(C)(C)O
Reactant: O=C(O)C(Br)CCBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Br)CCBr
Temperature: 27.5 °C
Yield: 39 %

Procedure:
2,4-Dibromobutanoic acid (the crude product from above) dissolved in DCM (10 L) in a 50 L-reactor. 2-Methylpropan-2-ol (12000 g, 162.16 mol) and boron anhydride (8000 g, 114.29 mol) were added to the above solution. 1680 g of H2SO4 was added dropwise to the above solution under N2 (gas) while maintaining the temperature at room temperature (25-30° C.). The mixture was allowed to react for 24 h at room temperature. Then 15 L aqueous Na2CO3 (sat.) was added to quench the reaction. The organic phase was separated and dried over Na2SO4. The solvent was removed under vacuum to give the crude product, which was purified by silica gel column chromatography to give tert-butyl 2,4-dibromobutanoate as a brown oil (3800 g, 12.58 mol, 39%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(CC#N)ccc1O
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1OCCCCCCCCCCCO
Temperature: 80 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
11.0 g (67 mmol) of [4-hydroxy-3-methoxy-phenyl]acetonitrile and 20.4 g (81 mmol) of 11-bromoundecan-1-ol were dissolved in 100 mL of N,N-dimethylformamide. 18.7 g (135 mmol) of potassium carbonate and 2.2.0 g (13 mmol) of potassium iodide were added and the suspension was heated to 80° C. After 48 h, the reaction mixture was cooled to room temperature and poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 16.6 g of {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile are obtained as a yellow solid (74% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[N+:16]([O-])([OH:18])=[O:17].Cl>CC(OC(C)=O)=O.CC(O)=O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C1(c2ccc(OC)c([N+](=O)[O-])c2)CC1
Yield: 98.1 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) in Ac2O (300 mL) was added a solution of HNO3 (14.1 g, 146 mmol, 65%) in AcOH (75 mL) at 0° C. The reaction mixture was stirred at 0˜5° C. for 3 h before aq. HCl (20%) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (200 mL×3). The organic layer was washed with sat. aq. NaHCO3 then brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (36.0 g, 98%), which was directly used in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, J=2.1 Hz, 1H), 7.54 (dd, J=2.1, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 3.65 (s, 3H), 1.68-1.64 (m, 2H), 1.22-1.18 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([O:1][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:3][CH2:4]2)=[O:19])=[CH:16][CH:15]=1
Reactant: COc1ccc(/C=C/C(=O)N2CCC(O)CC2)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCN(C(=O)/C=C/c2ccc(OC)cc2)CC1

Procedure:
A solution of 6.65 g of 4-hydroxy-(E)-1-[3-(4-methoxy-phenyl)acryloyl]-piperidine in 50 ml of methylene chloride was treated with 4 ml of triethylamine at 0° C. while gassing with argon. 2.7 ml of methacryloyl chloride were added dropwise within 15 minutes. Subsequently, the reaction mixture was concentrated to dryness in a vacuum. Chromatographic purification of the residue on silica gel with ether/hexane (vol. 4:1) gave 4.21 g of 2-methyl-acrylic acid (E)-I-[3-(4-methoxy-phenyl)-acryloyl]-piperidin-4-yl ester as a colourless oil. λmax (methylene chloride)=292.5 nm (ε=22775 l mol-1 cm-1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[Se:4][C:3]=1[C:11]#[N:12].C([OH:15])C>[OH-].[Na+]>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:9])([CH3:8])[CH3:10])[Se:4][C:3]=1[C:11]([NH2:12])=[O:15]
Reactant: CC(C)(C)c1cc(N)c(C#N)[se]1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Temperature: 7.5 °C
Yield: 84 %

Procedure:
To a suspension of 3-amino-5-(tert-butyl)selenophene-2-carbonitrile (5.0 g) in aqueous sodium hydroxide solution (80 mL, 10%) was added ethanol (50 mL) and the mixture refluxed for 1 h. Ethanol was distilled off under vacuum (appr. 25 mL) and the mixture was allowed to cool to 5-10° C. The separated crystals were filtered off, washed with cold water and dried to give the product as a off-white color solid (4.5 g, 84%), mp 160-162° C. 1H NMR (400 MHz, CDCl3): δ 6.58 (1H, s, H-4), 5.75 (2H, br s, —CONH2), 5.13 (2H, br s, —NH2), 1.34 (9H, s, tert-butyl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)=[N:9][C:8]=1[CH3:20].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[N:9][C:8]=1[CH3:20]
Reactant: COC(=O)CCCc1oc(-c2ccccc2OC)nc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCc1oc(-c2ccccc2O)nc1C

Procedure:
Dissolve 4-[2-(2-methoxy-phenyl)-4-methyl-oxazol-5-yl]-butyric acid methyl ester (2.1 g, 7.3 mmol) in CH2Cl2 (20 mL) under nitrogen at room temperature. Add boron tribromide (1M in CH2Cl2, 21.8 mL) and stir at room temperature until the reaction is complete. Quench the mixture with methanol, add water and extract with CH2Cl2. Dry the combined extracts over Na2SO4 and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to allow for isolation of 4-[2-(2-hydroxy-phenyl)-4-methyl-oxazol-5-yl]-butyric acid-methyl ester (1.55 g, 77%). MS (ES): (M+1)+ 276.1, 277.2 m/z.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of 4-bromo-2-nitroaniline 17 (1.0 g, 4.67 mmol), tributylphenyl tin (2.2 g, 6.07 mmol), bis(triphenylphosphine)palladium (II) chloride (164 mg, 0.234 mmol), and triphenylphosphine (613 mg, 2.34 mmol) in DMF (15 ml) was heated under N2 at 120° C. overnight. After the solution was cooled to room temperature, the reaction mixture was directly chromatographed on silica gel eluting with 2-5% EtOAc/Hexane to give 752 mg (75%) of 5 as a yellow solid: mp 169°-171° C.; IR (CHCl3) 3517, 3398, 3022, 1635, 1525, 1250; 1H NMR δ8.38 (1H, d, J=2.2), 7.66 (1H, dd, J=8.7, 2.2), 7.59-7.54 (2H, m), 7.49-7.34 (3H, m), 6.90 (1H, d, J=8.8), 6.13 (NH, brs); 13C NMR δ144.2, 139.3, 135.0, 130.9, 129.5, 127.8, 126.8, 124.4, 119.8, 112.8; Anal. Calcd for C12H10N2O2 : C, 67.28; H, 4.70; N, 13.08. Found: C, 67.38, H, 4.76; N, 13.01.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Reactant: OB(O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC1Oc2ccc(-c3cccs3)cc2NC1=O
Temperature: 100 °C
Yield: 33 %

Procedure:
315 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is mixed in 4 ml of DME with 0.2 g of 2-thiopheneboronic acid and 150 mg of tetrakis-triphenylphosphine-palladium (O) and 340 mg of sodium bicarbonate (dissolved in 4 ml of water). It is stirred for some time at 100° C. The product is diluted with ethyl acetate, extracted 3 times with water, and dried with magnesium sulfate. It is concentrated by evaporation. The crude product is purified by column chromatography with a hexane/ethyl acetate mixture and yields pure 33% product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1>CC#N>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)[C:10]=1[Br:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2cc(NC(=O)OC(C)(C)C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1ccc2c(Br)c(NC(=O)OC(C)(C)C)ccc2c1
Yield: 90.9 %

Procedure:
A mixture of ester 147 (977 mg, 3.24 mmol) and NBS (664 mg, 3.73 mmol) in CH3CN (25 mL) was stirred at reflux for 45 min, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was washed with 10% aqueous Na2SO3 and water (×2), dried, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give methyl 2-[(tert-butoxycarbonyl)amino]-1-bromo-6-naphthoate (148) (1.12 g, 91%) as a white solid: mp (petroleum ether) 130-131° C.; 1H NMR [(CD3)2SO] δ 8.93 (s, 1H), 8.65 (d, J=1.6 Hz, 1H), 8.64 (d, J=8.9 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H), 8.11 (dd, J=8.9, 1.7 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 3.93 (s, 3H), 1.50 (s, 9H). Anal. (C17H18BrNO4) C, H, N, Br.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:22][O:23][C:24](=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[N:34]O)Cl)=[C:28]([Cl:36])[CH:27]=1>CCOCC.CC#N>[C:8]([O:7][C:1]([C:2]1[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])=[CH:27][C:28]=2[Cl:36])=[N:34][O:4][C:3]=1[CH3:5])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(C(Cl)=NO)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)Cc1ccc(-c2noc(C)c2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C

Procedure:
tert-Butyl acetoacetate (5.0 g, 32 mmol) is dissolved in ether (100 mL). Potassium bis(trimethylsilyl)amide (5.7 g, 29 mmol) is added slowly while stirring at room temperature. Then the mixture is concentrated and triturated with hexane. The precipitate is filtered and dried to yield crude potassium enolate 23 (4.6 g, 23 mmol, 81%). Enolate 23 (1.0 g, 5.0 mmol) is dissolved in MeCN (50 mL) and cooled to 0° C. Intermediate 16 (1.1 g, 4.2 mmol) dissolved in MeCN (10 mL) is added dropwise and the solution is stirred at 0° C. for 2 hours. The solvent is evaporated and the remainder is purified by column chromatography using a hexanes/EtOAc gradient to afford 3-(2-chloro-4-methoxycarbonylmethyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid tert-butyl ester 24 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.41 (d, J=1.5 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.25 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 3.69 (s, 3H), 3.65 (s, 2H), 2.73 (s, 3H), 1.28 (s, 9H). MS calculated for C18H21ClNO5 (M+H+) 366.1, found 366.4.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2O)[N:11]=1)(=[O:8])[CH3:7].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:6]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[Cl:3])[N:11]=1)(=[O:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2c(O)ccnc2n1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc2c(Cl)ccnc2n1
Yield: 18 %

Procedure:
Phosphorous oxychloride (6.0 ml) was added to a stirred mixture of 2-acetamido-5-hydroxy-1,8-naphthyridine (2.4 g, 11.8 mmol) and N,N-dimethylaniline (6.0 ml) in toluene (100 ml). The mixture was then heated at reflux for 1 hour. The mixture was allowed to cool, the tolulene was removed by evaporation and the residue was partitioned between methylene chloride and aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried (MgSO4) and the solvent was removed by evaporation to give 2-acetamido-5-chloro-1,8-naphthyridine (470 mg, 18%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][C:17]#[N:18])[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(Cl)(Cl)Cl.[Pt]=O>[NH2:18][CH2:17][CH2:16][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10]
Reactant: COC(=O)[C@@H](C)N(CCC#N)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](C)N(CCCN)C(=O)OC(C)(C)C

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-alaninate (1.5 g) in ethanol (80 mL) and chloroform (1.4 mL) was added platinum oxide (350 mg), and the reaction mixture was stirred over an atmosphere of hydrogen for 16 h. The mixture was filtered through Celite, and the Celite washed with methanol and dichloromethane. The filtrate was concentrated to give methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate as an oily residue.
Reaction SMILES: [NH:1]1[C:5]([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[N:8]=[N:7]2)=[CH:4][CH:3]=[N:2]1.Br[CH2:16][CH2:17][F:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:18][CH2:17][CH2:16][N:2]1[CH:3]=[CH:4][C:5]([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[N:8]=[N:7]2)=[N:1]1
Reactant: FCCBr
Reactant: c1cc2c(cn1)nnn2-c1ccn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FCCn1ccc(-n2nnc3cnccc32)n1
Yield: 99.3 %

Procedure:
To a solution of Intermediate 48 (50 mg, 0.269 mmol) in DMF (1 mL) was added 1-bromo-2-fluoroethane (41 mg, 0.322 mmol) and Cs2CO3 (263 mg, 0.806 mmol). The reaction was irradiated in a microwave apparatus for 10 min at 120° C. The resulting mixture was filtered, concentrated and purified by chromatography on silica gel eluted with 100% EtOAc to obtain the title compound (62 mg, 88%). MS (ESI) mass calcd. C10H9FN6, 232.1. m/z found, 233.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[NH:10])OC)[CH:2]=1.Cl.C([O:14][C:15](=O)[C@H:16]([CH3:18])[NH2:17])C.C(N(CC)CC)C>O1CCCC1>[CH3:18][CH:16]1[C:15](=[O:14])[NH:10][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:17]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: COC(=N)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1N=C(c2cccnc2)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A stirred mixture of methyl pyridine-3-carboximidate (10.6 g), alanine ethyl ester monohydrochloride (10 g), triethylamine (8.4 ml) and tetrahydrofuran (250 ml) was heated under reflux under nitrogen for 5 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and the solvent removed in vacuo. The residue was triturated with a 1:1 mixture of ether and ethyl acetate, and the resulting solid was collected by filtration and washed with ether. The two crops of solid were combined, suspended in water (130 ml), and the mixture was stirred at ambient temperature for 1 hour. The resulting solid was collected by filtration and dried in vacuo to give 4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as a yellow solid (4.9 g), m.p. 238-241° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[NH:18]1[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[N:4]=[C:3]([CH2:2][N:18]3[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]3)[CH:8]=[N:7][C:6]=2[O:9][CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ncc(CBr)nc1-c1cccc(Cl)c1
Reactant: COC(=O)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine (Intermediate 3, 200.00 mg, 0.64 mmol), in acetone (3.19 mL), was added methyl 1H-1,2,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) and potassium carbonate (264.44 mg, 1.91 mmol). The reaction was stirred at room temperature for 2 h. The LCMS showed two peaks with [M+H] values consistent with the two major regioproducts. The mixture was diluted with DCM (5 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, SiO2, 20-100% EtOAc/hexanes) afforded the title compound (100 mg; 44%). 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.01 (td, J=1.1, 2.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.45-7.36 (m, 2H), 5.64 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H). [M+H]=360.24.