Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=2Br)[CH:17]=1)(=[O:15])[CH3:14].BrC1C2C(=CC=CC=2)C=CC=1OC>>[C:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=2)[CH:17]=1)(=[O:15])[CH3:14]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: COc1ccc2ccccc2c1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: COc1ccc2cc(C(C)=O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
80 Ml of anisole and 18 g of anhydrous aluminum chloride are added to the solution of 2-acetyl-5-bromo-6-methoxynaphthalene obtained as in example 1a), while keeping the temperature at -10° C. The reaction mixture is kept for 24 hours under stirring at room temperature and then it is worked as in example 1 obtaining 38.5 g of product with a yield equal to 78.5% calculated on the basis of the starting material 1-bromo-2-methoxynaphthalene.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]1CCN2C(=NCCC2)CC1.CI>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([O:12][CH3:28])=[CH:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Product: COC1=CC(=O)OC(CCc2ccc(C(C)(C)C#N)c(F)c2)(C2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A magnetically stirring solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile (− rotation, 0.15 g, 0.40 mmol) was cooled to 0° C. DBU (0.18 mL, 1.21 mmol) was added followed by MeI (0.076 mL, 1.21 mmol) and reaction was stirred at 0° C. for 1 hour. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers of the resulting reaction mixture were separated and the organic layer was washed with brine (1×10 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (20% EtOAc in Hexanes) to give the desired product as a yellow oil (0.062 g, 41%). 1H NMR (400 MHz, CDCl3): δ 1.18 (d, J=6.5 Hz, 3H), 1.40 (d, J=6.5 Hz, 3H), 1.50-1.78 (m, 8H), 1.94-2.05 (m, 2H), 2.18 (s, 3H), 2.64-2.73 (m, 3H), 3.75 (s, 2H), 5.17 (s, 1H), 6.89-6.97 (m, 2H), 7.35-7.40 (m, 1H). MS (ESI): 386 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.S(Cl)([Cl:16])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:16])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(Cl)cc(CO)n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc(CCl)n1
Reaction time: 0.67 h

Procedure:
To a solution of methyl 4-chloro-6-(hydroxymethyl)-2-pyridinecarboxylate (166 mg, Ref: Kittika et al., Tetrahedron, 44 (10), 2821, (1988)) in dry dichloromethane (3 ml) was added thionyl chloride (66 μl). The solution was stirred for 40 minutes. LC/MS indication reaction completion. Solvent was removed u.r.p. (under reduced pressure) to give a white solid. Toluene (˜2 ml) added then removed u.r.p. The residue was dried in vacuo to give a white solid. (175 mg, 97%). LC/MS [MH+]=220/222, Rt=2.51 min. Title compound obtained as the free base.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[C:12]([NH2:20])=[CH:11][C:10]=1[C:21]([F:24])([F:23])[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](C1NC=CN=1)(C1NC=CN=1)=[O:26]>ClC1C=CC=CC=1Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]2[C:12]([NH:20][C:25](=[O:26])[C:16]3[N:15]2[CH:19]=[CH:18][N:17]=3)=[CH:11][C:10]=1[C:21]([F:24])([F:22])[F:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cc(C(F)(F)F)c(NCc2ccccc2)cc1-n1ccnc1
Solvent: Clc1ccccc1Cl
Product: O=c1[nH]c2cc(C(F)(F)F)c(NCc3ccccc3)cc2n2ccnc12
Yield: 41.7 %

Procedure:
A solution of N-benzyl-5-(1H-imidazol-1-yl)-2-(trifluoromethyl)benzene-1,4-diamine (160 mg; 0.48 mmol; 1 eq) and carbonyl diimidazole (156 mg; 0.96 mmol; 2 eq) in 1,2-dichlorobenzene (20 ml) is stirred under argon at reflux for 3 h. Concentration, filtration over a small silicagel pad with ethyl acetate as eluent and purification by prep CCM on silicagel (ethyl acetate) affords the title product (72 mg; 0.2 mmol; 42%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([Br:8])=[CH:6][S:5][N:4]=1.[N+](C1C=C([N+]([O-])=O)C=C(C(OO)=O)C=1)([O-])=[O:10]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:7]([Br:8])=[CH:6][S:5](=[O:10])[N:4]=1
Reactant: COc1nscc1Br
Reactant: O=C(OO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC1=NS(=O)C=C1Br
Reaction time: 1 h

Procedure:
To a solution of 3-methoxy-4-bromoisothiazole (2.9 g, 15 mmol) in methylene chloride (15 ml) there can be was added, in portions, 3,5-dinitroperbenzoic acid (3.4 g, 15 mmol) with ice bath cooling. After about one hour, the precipitated 3,5-dinitrobenzoic acid can be filtered off and the solvent evaporated in vacuo. By triturating the residue with diethyl ether, a crystalline product, 3-methoxy-4-bromoisothiazole-1-oxide, can be obtained. Additional material can be obtained by chromatographing the mother liquors on silica gel, eluting with chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(Cn2cncn2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1 g of 4-bromobenzyl bromide, 0.41 g of 1,2,4-triazole, 0.55 g of potassium carbonate and 33 mg of potassium iodide in 30 ml of acetone is stirred at 50° for 20 hours. The solid is removed by filtration and the solution is concentrated by evaporation. The resulting crude precursor (1) is purified by column chromatography (SiO2, hexane/ethyl acetate 1:1) and crystallised from ether; m.p. 77°-79°;1H-NMR (CDCl3):δ=5.3 (2H,s), 7.15 and 7.5 (4H,m), 7.95 (1H,s), 8.08 (1H,m).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[C:27]([CH2:28]Cl)=[C:26]([NH:30][C:31]([NH2:33])=[O:32])[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][CH2:28][C:27]3[C:22]([CH3:21])=[CH:23][CH:24]=[CH:25][C:26]=3[NH:30][C:31]([NH2:33])=[O:32])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH2:12][C:13]#[CH:14]
Reactant: Cc1cccc(NC(N)=O)c1CCl
Reactant: C#CCc1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(N)=O)cccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
A mixture of 8-hydroxy-2-methyl-3-(2-propynyl) imidazo-[1,2-a]pyridine (0.571 g) and potassium carbonate (0.424 g) in N,N-dimethylformamide (11.5 ml) was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then 6-methyl-2-ureidobenzyl chloride (0.6 g) was added. After being stirred for 2.5 hours. The mixture was poured into water and the resulting precipitates were collected by filtration. The crude product was purified by column chromatography on silica gel (25 g) with a mixture of chloroform and methanol (100:1 to 100:4) as eluents to give 2-methyl-8-(6-methyl-2-ureidobenzyloxy)-3-(2-propynyl)imidazo[1,2-a]pyridine (0.13 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1.[H][H]>C(O)C.Cl.[Pd]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1
Reactant: [H][H]
Reactant: O=C(NCc1cccnc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(NCC1CCCNC1)c1ccccc1
Yield: 82.6 %

Procedure:
Ba) A solution of 42.5 g of N-(3-pyridinylmethyl)-benzamide in 220 ml of ethanol and 220 ml of 1N hydrochloric acid is treated with 4.2 g of palladium on charcoal and hydrogenated at room temperature for 24 hours over 100 bar of hydrogen. Then, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylene chloride and shaken with 11N sodium hydroxide solution. The organic phase is washed with water, dried and evaporated. There are obtained 36.1 g of (RS)-N-piperidin-3-ylmethyl-benzamide, MS (FAB): 218 M+.
Reaction SMILES: [CH2:1]1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.C=C>C1(C)C=CC=CC=1>[CH2:1]=[CH2:2].[CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: C=C
Solvent: Cc1ccccc1
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 70 °C

Procedure:
The following polymerization procedure was utilized in all of the examples. First, varying amounts of 86 to 98 wt % DCPD in toluene were charged to a dry, 1 gallon reactor, which was then heated to 70° C. The specific amounts of DCPD used are specified in Table 1. In Examples 1-10, 200 milliliters of polymerization grade toluene were charged to the reactor; however in Examples 11-12, the 200 milliliters of toluene were not added. Then, the reactor was pressured to 150 psig with ethylene and then depressured. This pressure/depressure cycle was completed three times. Ethylene was then charged to maintain a pressure of 100 psig in the reactor. Then, the ethylene pressure was increased to 300 psig and maintained for 15 minutes while the reactor was stirred. The ethylene flow was then stopped, and the reactor was vented to 50 or 100 psig. 10-30 milliliters of 10 wt % methylaluminoxane (MAO) in toluene and 0.01 to 0.04 grams of a titanium complex were then charged to the reactor. The ethylene flow to the reactor was re-established at between 50 and 300 psig and maintained for between 60 to 90 minutes to produce an ethylene/dicyclopentadiene polymer mixture comprising ethylene/dicyclopentadiene polymer, toluene, and unreacted ethylene and DCPD. The ethylene flow was then stopped by adding 5 milliliters of methanol, and the reactor was allowed to cool. The ethylene/dicyclopentadiene polymer mixture was then washed and dried in a vacuum oven at 50° C. In some examples, 5 milliliters of an antioxidant solution were also added to the ethylene/dicyclopentadiene polymer mixture prior to drying. The antioxidant solution contained 10 weight percent tris(p-nonylphenyl) phosphite (TNPP) and 40 weight percent tetrakis(methylene(3,5-di-tert-butyl-4-hydroxyhydrocinnamate in cyclohexane. The TNPP was obtained from GE Specialty Chemicals in Parkersburg, W.Va. The tetrakis(methylene(3,5-di-tert-butyl-4-hydroxyhydrocinnamate was obtained as Irganox® 1076 from Ciba-Geigy Corporation in Hawthorne, N.Y.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:30][CH:27]4[CH2:29][CH2:28]4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=CC1CC1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(CC3CC3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with cyclopropanecarboxaldehyde to provide 30 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:28]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:29][CH3:30])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([OH:27])=O)[CH:19]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C(Cl)(=O)C(Cl)=O.[CH3:52][N:53](C=O)[CH3:54]>C(Cl)Cl>[CH3:52][N:53]([CH3:54])[C:25]([C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:15]([CH2:14][N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:45])([F:44])[F:1])[CH:39]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:37]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:16]([N:28]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:29][CH3:30])=[N:17]2)=[CH:22][CH:21]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: CCN(CC1CCCC1)c1nc2cc(C(=O)O)ccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN(CC1CCCC1)c1nc2cc(C(=O)N(C)C)ccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-2-[N′-(cyclopentylmethyl)-N′-ethylamino]quinoline-7-carboxilic acid (30 mg, 0.047 mmol), oxalyl chloride (10 ul), and catalytic amount of DMF in CH2Cl2 (2 mL) is stirred at room temperature for 3 hours and concentrated in vacuo. The residue is dissolved with THF and treated with 2M dimethylamine in THF, and the resulting THF mixture is stirred at room temperature for 3 hours. The mixture is quenched by 1N HCl and extracted with EtOAc. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give 3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-2-[N′-(cyclopentylmethyl)-N′-ethylamino]quinoline-7-carboxylic acid dimethylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 95.1 %

Procedure:
Preparation of example 150 from the title compound of Example 7 (hydrochloride) (44 mg, 0.144 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-hydroxyphenyl)propanoic acid (46 mg, 0.173 mmol), triethylamine (0.060 mL, 0.43 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (66 mg, 0.173 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (74 mg, 0.137 mmol) as a yellow powder in 95% yield.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[C:10]([CH3:11])=[C:9]([I:12])[C:8]([CH3:13])=[CH:7][N:6]=1>CO.C1COCC1>[I:12][C:9]1[C:8]([CH3:13])=[CH:7][N:6]=[C:5]([O:2][CH3:1])[C:10]=1[CH3:11]
Reactant: Cc1cnc(F)c(C)c1I
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(C)c(I)c1C
Reaction time: 2 h

Procedure:
A 28% solution of sodium methoxide in methanol (185 mL) was added to 2-fluoro-4-iodo-3,5-dimethylpyridine (97.4 g) in THF (954 mL) at 20° C. The mixture was stirred at 55° C. to 65° C. for two hours. The reaction mixture was cooled and then partitioned by adding MTBE (1 L) and water (1 L). The organic layer was washed with brine. The combined aqueous layers were extracted with MTBE (500 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. n-heptane (50 mL) was added to the residue, and the mixture was stirred at 0° C. for one hour. The precipitated solid was collected by filtration. The solid was washed with cooled n-heptane (10 mL). The title compound (42.6 g) was obtained. The filtrate was concentrated under reduced pressure. n-heptane (5 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 minutes. The precipitated solid was collected by filtration. The solid was washed with cooled n-heptane (2 mL) The title compound (20.2 g) was obtained. The filtrate was concentrated under reduced pressure. n-heptane (5 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 minutes. The precipitated solid was collected by filtration. The solid was washed with cooled n-heptane (2 mL). The title compound (10.7 g) was obtained. The combined title compound (73.5 g) was obtained.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C:10](=[O:11])[O:9][C:7](=O)[CH2:6]1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CC(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:18]2[C:7](=[O:9])[CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:10]2=[O:11])=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)N[C@@H]1CC(=O)OC1=O
Solvent: CC(C)=O
Product: CC(=O)N[C@@H]1CC(=O)N(Cc2ccc(F)cc2)C1=O
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the method of Witiak et al. (J. Med. Chem., 1971, 14(1), 24-30), N-acetyl-D-aspartic acid anhydride (2.19 g, 13.9 mmol) and para-fluorobenzylamine (1.74 g, 13.9 mmol) in acetone (12 mL) were heated together in a sealed tube at 100° C. for 1 h. The solvent was then removed under reduced pressure. Acetic anhydride (15 mL) was added to the residue and the mixture heated 50 min. at 100° C. The solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, 10% methanol in dichloromethane) to give the product as a foam (3.16 g, 85%). HPLC retention time 1.94 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH:10]([C:18]([O:20]CC)=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O>[CH2:1]([N:8]1[CH2:17][CH2:16][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH:10]([C:18]([OH:20])=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC12OCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CN(Cc2ccccc2)CCC12OCCO2
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a flask, etrahydrofuran (0.890 mL) was added to ethyl 8-benzyl-1,4-dioxa-8-azaspiro[4.5]decane-6-carboxylate (0.0813 g, 0.267 mmol). Potassium hydroxide (0.2157 g, 3.9 mmol) in water (0.445 mL) was added to the solution, and the reaction was allowed to stir for 3 hrs at 40° C. The reaction was neutralized to pH 7 using 1N hydrochloric acid. The reaction was concentrated under vacuo and purified using prep LC/MS. LC-MS: 278.65 [M+H]. LC/MS RT=1.66 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:27]=[CH:28]/[C:29]([O:31]C)=[O:30])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc3ccc(/C=C/C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 55.4 %

Procedure:
A solution of (E)-methyl 3-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)acrylate (150 mg, 0.35 mmol, 1.00 equiv) and sodium hydroxide (70.4 mg, 1.76 mmol, 5.00 equiv) in methanol (10 mL) and H2O (2 ml) was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 20 mL of water. The pH value of the solution was adjusted to 3 with 1N hydrochloric acid. The solids were collected by filtration, and purified by re-crystallization from methanol, affording 80 mg (55%) of (E)-3-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)acrylic acid as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=4[CH:21]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1cc3cc([N+](=O)[O-])ccc3o1)CC2

Procedure:
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.7 g), 2-bromomethyl-5-nitrobenzofuran (0.93 g) and potassium carbonate (0.5 g) in acetonitrile were heated under reflux for 8 hours. After cooling the solvent was removed in vacuo, the residue dissolved in methylene chloride and washed three times with aqueous sodium carbonate and three times with brine. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an oil methylene chloride. The product-containing fractions were combined and evaporated in vacuo to give an oil which was triturated with hexane and the evaporated in vacuo to give the title compound as a foam, yield 0.76 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH2:8][CH:9]=O)[CH3:2].[C:22]1([C@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH2:8][CH:9]=[N:30][C@@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:29])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)CN(CCC=O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN(CCC=N[C@H](C)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
2[(Benzyloxycarbonyl)-(3-oxo-propyl)-amino]-acetic acid ethyl ester (0.32 g; 1.09 mmol)) is dissolved in dichloromethane (10 ml). Molecular sieves (2 g; 3 Angström) are added. The reaction mixture is cooled to 0° C. and (R)-(+)-1-phenylethylamine (0.132 g; 1.09 mmol) is added and the mixture is stirred at 0° C. for 4 hours. The solids are filtered off and the solvent is removed under reduced pressure. 0.35 g of a light yellow oil (yield 93%) is obtained. The obtained imine is directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2ccc([N+](=O)[O-])n2)cc1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2ccc(N)n2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3,4-dimethylphenyl)-3-nitro-1H-pyrazole (900 mg, 4.15 mmol, 1.00 equiv) in methanol/ethyl acetate (20/10 mL). The solution was treated with Pd/C (500 mg) and stirred under an atmosphere of hydrogen overnight at room temperature. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 750 mg (97%) of 1-(3,4-dimethylphenyl)-1H-pyrazol-3-amine as a yellow solid.