Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:3][NH:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1
Reactant: Cc1nc2ccc(N(C)C(=O)C(F)(F)F)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1ccc2nc(C)oc2c1
Yield: 81.2 %

Procedure:
To a solution of crude 2,2,2-trifluoro-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (16.5 g, 63.0 mmol) in MeOH (440 mL) and water (73 mL) was added K2CO3 (35.3 g, 25.5 mmol). The reaction mixture was stirred at reflux for 3 h, then concentrated under vacuum, diluted with water (50 mL), extracted with EtOAc (2×50 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to obtain crude N,2-dimethylbenzo[d]oxazol-6-amine (8.3 g), (MS: ESI +ve, 163.12 [M+H]); 1H NMR: (400 MHz, DMSO) δ: 2.51 (s, 3H), 2.56 (s, 3H), 5.87-5.85 (m, 1H), 6.57-6.53 (m, 1H), 6.65-6.64 (d, J=2.4, 1H), 7.31-7.28 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>ClCCl>[CH2:23]([N:25]([CH2:26][CH3:27])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=1)[CH3:24]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A flask is charged with 3,4-difluorobenzoic acid (2.40 g, 14.88 mmol) and dichloromethane (50 mL) is added. Upon complete dissolution, the mixture is cooled to 0° C. and DMF (0.022 g, 0.298 mmol) and oxalyl chloride (3.85 g, 29.75 mmol) are added. The cooling bath is removed. After 2 h, the mixture is concentrated, taken up in dichloromethane (50 mL) and diethylamine (5.50 g, 74.38 mmol) is added. After 30 min, dichloromethane (500 mL) is added and the mixture is washed with 1M aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford N,N-diethyl-3,4-difluorobenzamide as a brown oil, which is redissolved in anhydrous THF (60 mL). A 2 neck-flask is charged with paraformaldehyde (2.40 g, 76.22 mmol) and connected via a small length of tubing to another two-neck flask fitted with a pipette using an appropriate adapter. The second flask is charged with THF (60 mL) and cooled to −78° C. The paraformaldehyde is cracked with a heatgun and bubbled into the cold THF through the pipette. A clear solution is formed. To the solution of N,N-diethyl-3,4-difluorobenzamide in THF, is added TMEDA (2.98 g, 25.41 mmol) and the flask is cooled to −78° C. sec-BuLi (1.4M in cyclohexane, 18.1 mL, 25.4 mmol) is added and after 30 min, the cold solution of formaldehyde is added via cannula. After 2 h, the cooling bath is removed. Upon reaching room temperature, the reaction is quenched with 1M aqueous sodium bisulfate. After dilution with ethyl acetate, the organic phase is washed with saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 3:7 to 2:3 to 1:1) to yield N,N-diethyl-3,4-difluoro-2-hydroxymethyl-benzamide as an orange oil; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (t, J=7.1 Hz, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 3.26 (q, J=7.1 Hz, 2 H), 3.58 (q, J=7.1 Hz, 2H), 4.62 (br. s., 2 H), 7.00 (ddd, J=8.4, 4.6, 1.6 Hz, 1 H), 7.09-7.19 (m, 1 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[C:34]([O:35][CH3:36])[CH:33]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1OC

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3,4-dimethoxyphenylboronic acid, 5-(3,4-dimethoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=73%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-:25].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]([NH2:21])=[O:25])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: [OH-]
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(N)=O)cc3)ccc21
Yield: 83 %

Procedure:
A mixture of 2.5 g (8 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1), 60 ml of tert.-butanol and 7.5 g of potassium hydroxide powder was refluxed for 4 hours. The mixture was cooled, poured onto saturated sodium chloride solution and extracted twice with ether. The ether phases were washed with sodium chloride solution, dried over Na2SO4 and evaporated down to give 2.2 g (83%) of the pure title compound of melting point 220°-223° C.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH:26]([NH:29][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Product: Cc1cccc(-c2noc(C)c2COc2ccc(C(=O)NC(C)C)cn2)c1
Yield: 74 %

Procedure:
As described for example 249f, 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.6 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (160 mg, 74%) which was obtained as a white solid. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH3:30]>C(#N)C>[CH2:29]([O:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])[CH3:30]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of methyl 2-hydroxy-2′-(trifluoromethyl)biphenyl-4-carboxylate (5.03 g), anhydrous potassium carbonate (7.05 g, 51 mmol) and bromoethane (6.35 mL, 85 mmol) was prepared in anhydrous ACN (75 mL) and heated at 50° C. for 15 hours. The reaction mixture was cooled at RT, filtered and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc/heptane), the title was obtained as a colorless oil (4.45 g, 79% over 2 steps). HPLC (Method A), Rt 5.3 min (purity: 99.0%). LC/MS (Method B): 325.0 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][O:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCc1nc2ccccc2s1
Reactant: CCOC(=O)c1ccccc1NO
Product: CCOC(=O)c1ccccc1NOCc1nc2ccccc2s1
Yield: 52 %

Procedure:
The titled compound was prepared using similar procedure as that of Example-1 (step-2) using ethyl 2-(hydroxyamino)benzoate and 2-(chloromethyl)benzo[d]thiazole in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C@H:22]2[CH2:26][O:25]C(C)(C)[O:23]2)=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])[CH:7]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C@H:22]([OH:23])[CH2:26][OH:25])=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])[CH:7]=1
Reactant: CC1(C)OC[C@H](COc2ccc(Cl)cc2NC(=O)c2cnn3cccnc23)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)ccc1OC[C@H](O)CO)c1cnn2cccnc12
Yield: 83.3 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-amide (40 mg) and an aqueous solution of hydrochloric acid (2 M, 5 mL) in tetrahydrofuran (5 mL) was heated at 70° C. for 15 minutes. The resulting mixture was cooled and the solid formed was collected by filtration, washed with a diluted aqueous solution of sodium hydroxide and with water, dried in a vacuum oven to give 30 mg of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-((R)-2,3-dihydroxy-propoxy)-phenyl]-amide as a white solid. MS=362 [M]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:37]1[C:38]2[C:45]([CH3:46])=[CH:44][NH:43][C:39]=2[N:40]=[CH:41][N:42]=1>C(O)(C)C>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:18][N:17]([C:37]3[C:38]4[C:45]([CH3:46])=[CH:44][NH:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 110 °C

Procedure:
To a solution of 3-(4-(2-methoxyethoxy)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D, and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol) in isopropanol (1.0 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (55 mg, 0.322 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 h, during which time the mixture became homogenous. The mixture was concentrated under vacuum and purified by prep HPLC (30×100 mm C18 column, 5-100% acetonitrile:water (10 mM NH4OAc), 15 min, 45 mL/min) to afford the title compound (17.4 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH3:51])[C@@H:3]([C:12]1[NH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]4[NH:37][C:36]([C@@H:38]([NH:43]C(=O)OC(C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[N:35][CH:34]=4)=[CH:29][CH:28]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1)[NH:4]C(OC(C)(C)C)=O.[ClH:53].O1CCOCC1>C(Cl)Cl>[ClH:53].[NH2:4][C@H:3]([C:12]1[NH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]4[NH:37][C:36]([C@@H:38]([NH2:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[N:35][CH:34]=4)=[CH:29][CH:28]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1)[C:2]([CH3:51])([CH3:52])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](N)c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H](N)C(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a reaction mixture of tert-butyl (S)-1-(5-(4-(6-(2-((S)-2,2-dimethyl-1-(tert-butoxycarbonylamino)propyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropylcarbamate (0.2 g, 0.283 mmol) in DCM was added 4M hydrogen chloride in dioxane (2 mL, 8 mmol). The reaction mixture was stirred at rt for 4 h and then concentrated to dryness to yield an HCl salt of (S)-1-(5-(4-(6-(2-((S)-1-amino-2,2-dimethylpropyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine as a yellow solid. LC-MS (Cond. 1): [M+H]+ 507.43, Rt=3.241 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7](OC)[N:6]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:4].[CH2:23]([Si](C)(C)C)[CH:24]=[CH2:25].O>C(Cl)Cl.[Cl-].[Na+].O.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:25][CH:24]=[CH2:23])[N:6]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[O:4]
Reactant: COC(=O)C1CCCC(OC)N1C(=O)OCc1ccccc1
Reactant: C=CC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCC1CCCC(C(=O)OC)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
6-Methoxy-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Compound 233, 1.04 g, 3.39 mmol) was dissolved in CH2Cl2 (10 mL), and the solution was cooled to −78° C. using dry ice-acetone bath. 1M TiCl4 solution in CH2Cl2 (3.7 mL) was added dropwise over a 1-minute period, followed by allyltrimethylsilane (1.61 mL, 10.14 mmol). The bath was changed to water, and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into brine (50 ml) and extracted with CHCl3 (2×50 mL). The combined organic layers were washed with saturated NaHCO3 solution (50 mL) and finally dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography (1:5 EtOAc/hexanes) to give Compound 234 (0.91 g, 84%). Rf=0.78 (1:2 EtOAc/hexanes).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O>O.C(#N)C>[C:34]1(=[O:43])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]12
Reactant: CCCCOc1cc(C(N)CC(=O)OC)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-butoxy-4-methoxyphenyl)propionate hydrochloride (0.95 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 niL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C., <1 mm) to afford 1.1 g (89%) of methyl 3-phthalimido-3-(3-butoxy4-methoxyphenyl)propionate as a white solid: mp 54-55° C.; 1H NMR (CDCl3) δ7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.85-6.76 (m, 1H), 5.76 (dd, J=5.9, 10 Hz, 1H), 4.02 (t, J=6.7 Hz, 2H), 3.86-3.71 (m, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 3.24 (dd, J=5.9, 16.5 Hz, 1H), 1.89-1.73 (m, 2H), 1.59-1.41 (m, 2H), 1.04-0.89 (m, 3H); 13C NMR (CDCl3) δ171.1, 168.1, 149.2, 148.5, 133.9, 131.8, 130.9, 123.3, 120.2, 112.7, 111.4, 68.6, 55.9, 51.9, 50.7, 35.9, 31.1, 19.2, 13.9; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 6.5 min, 100%, Anal. Calcd. for C23H25NO6. Theoretical: C, 67.14; H, 6.12; N, 3.40. Found: C, 66.89; H, 6.15; N, 3.31.
Reaction SMILES: C[O-].[Na+].[CH3:4][C@:5]12[C:13](=[O:14])[CH2:12][C@H:8]([C:9]1([CH3:11])[CH3:10])[CH2:7][CH2:6]2.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=O.O>C1CCCCC1>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[C:12]1[CH:8]2[C:9]([CH3:10])([CH3:11])[C:5]([CH3:4])([CH2:6][CH2:7]2)[C:13]1=[O:14]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: COc1ccc(OC)c(C=C2C(=O)C3(C)CCC2C3(C)C)c1
Temperature: 50 °C

Procedure:
A suspension of 9.2 g (0.17 mol) of sodium methoxide in 200 ml of cyclohexane is initially introduced into an apparatus rendered inert with nitrogen and the mixture is treated with a solution of 18.2 g (0.12 mol) of DL-camphor in 100 ml of cyclohexane. The mixture is heated to 50° C. with stirring and 25 g (0.15 mol) of molten 2,5-dimethoxybenzaldehyde are then added. The reaction mixture is heated under reflux for 3 hours. After cooling, it is treated with 300 ml of water. The organic phase is separated off, washed with 1N hydrochloric acid and then with saturated sodium chloride solution, and dried over sodium sulfate. After removing cyclohexane in vacuo, 17.1 g of crude product are obtained. Excess DL-camphor is removed by steam distillation. After chromatography on silica gel 60 using toluene/ethyl acetate in the ratio 3:1 as the eluent, an oil is obtained which after some time solidifies to give 9.2 g of crystalline 3-(2',5' -dimethoxybenzylidene)camphor of melting point 70°-72° C.
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Br:12])[C:3]1=[O:13]>O>[Br:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Br:12])[C:3]1=[O:13]
Reactant: O=C1c2cccc(Br)c2CCC1(Br)Br
Solvent: O
Product: O=C1c2cccc(Br)c2CCC1Br
Yield: 98.5 %

Procedure:
A clear yellow solution of 5-bromo-3,4-dihydro-1(2H)-Naphthalenone(12.09 g, 53.7 mmol) in freshly opened Et2O (220 mL) under an N2 atmosphere was chilled to −5° C. HCl was bubbled in subsurface for 1 min, causing no visible change. The dropwise addition of a solution of Br2 (8.58 g, 53.7 mmol) in CH2Cl2 (20 mL) and Et2O (2 mL) to the vigorously stirring solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each drop was allowed to fully decolorize before adding the next) produced a product mixture that assayed by HPLC. Peak area showed 79.4% title compound, 9.5% unreacted 5-bromo-3,4-dihydro-1(2H)-naphthalenone, 0.6% unidentified, and 9.4% 2,2,5-tribromo-1-tetralone. The addition of H2O produced a top light brown organic phase, and a clear, colorless bottom aqueous phase which was separated. After drying with MgSO4, the organic layer was concentrated in vacuo at room temperature to give the crude intermediate title compound as a light brown oil (16.08 g, 98.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: [H][H]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CC(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 2,4-dinitrophenylacetic acid (1.2 gm) in methanol (60 mL), added Pd/C (80 mg, 10 wt %). H2 gas environment was maintained with pressure using hydrogen gas balloon and solution stirred for 6 hours at RT. The catalyst was removed by filtration, over celite. The filtrate was concentrated in vacuo to give 2,4-diaminophenylacetic acid without further purification, immediately refluxed with 16 ml of 1N HCl for 6 hrs. Reaction was monitored with TLC. The solution was neutralized with 1% sodium hydroxide, extracted with three portions of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate or magnesium sulfate, evaporated in vacuo to get the title compound D4: YD: 67.85%: mp: 193-195° C.; Rf: 0.358 (EA:Hx: 7.0:3.0). 1H NMR (DMSO-d6) 200 MHz, δ: 3.227 (s, 2H), 5.004 (s, 2H) —NH2, 6.094 (dd, J=2.2 & 6.2 Hz, 1H), 6.098 (d, J=2.0 Hz, 1H), 6.786 (d, J=8.4 Hz, 1H), 10.088 (s, 1H). MS (ESI): m/z 146.8 [M−H]−.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:29])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][C:16]2[CH:21]=[C:20]([O:22]C)[C:19]([O:24]C)=[C:18]([O:26]C)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:4].B(Br)(Br)Br.O>C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:29])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][C:16]2[CH:21]=[C:20]([OH:22])[C:19]([OH:24])=[C:18]([OH:26])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:4]
Reactant: CCOC(=O)CN1CCN(C(=O)Cc2cc(OC)c(OC)c(OC)c2)CC1
Agent: BrB(Br)Br
Agent: N#N
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(C(=O)Cc2cc(O)c(O)c(O)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve {4-[2-(3,4,5-Trimethoxy-phenyl)-acetyl]-piperazin-1-yl}-acetic acid ethyl ester (64) (99 mg, 0.26 mmol) in anhydrous DCM (6.0 mL), cool the solution to −78° C. and add dropwise a 1 M BBr3 solution in DCM (2.30 mL, 2.30=101). Stir the reaction mixture for 30 min at −78° C. and after slowly warming up for additional 4 h at −20° C. Add dropwise water and extract the mixture with EtOAc (3 times). Wash the combined organic layer with brine and dry it dry with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain {4-[2-(3,4,5-Trihydroxy-phenyl)-acetyl]-piperazin-1-yl}-acetic acid ethyl ester (65) (34 mg, 40%) as a sticky brownish solid. 1H NMR (400 MHz, CD3OD): 1.35 (t, 3H, J=7.1 Hz); 3.14-3.24 (br.m, 2H); ca. 3.32 (br.m, 2H); 3.65 (s, 2H); 3.78-4.00 (br.m, 4H); 4.12 (s, 2H); 4.34 (q, 2H, J=7.1 Hz); 6.29 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: COc1ccc(Br)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 65 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (150 g, 649 mmol) in Methanol (1500 mL) stirred under nitrogen at 0° C. was added sulfurous dichloride (69.4 mL, 974 mmol) dropwise during 30 min. The reaction mixture was stirred at 65° C. for 12 hr. The solvents were evaporated off, then water (750 mL) and EtOAc (750 mL) was poured into the residue. The mixture was partitiononed. The aqueous layer was extracted with EtOAc (250 mL*3). Combined organic phase was washed with water (200 mL*2), dried over anhydrous Na2SO4 and concentrated to give 150 g (90%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]#[N:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: N#Cc1ccc2ccoc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc2ccoc2c1
Temperature: 50 °C
Yield: 82.9 %

Procedure:
Dissolve benzofuran-6-carbonitrile (0.5 g, 3.28 mmol) in anhydrous THF (10 mL) and add slowly to 1M lithium aluminum hydride in THF (6.56 mL, 6.56 mmol) at ambient temperature. Heat the reaction mixture at 50° C. for 17 h and cool to ambient temperature. Quench the reaction mixture with water until a granular precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.4 g, 79%).