Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CN(P(N(C)C)(N(C)C)=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOCC>[C:23]1([NH:22][CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(Br)C(C)O
Reactant: Nc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCOC(=O)C(Nc1ccccc1)C(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of ethyl 2-bromo-3-hydroxybutanoate (10 g) and 15 ml of HMPT is added 13.2 g of aniline. The reaction is stirred at RT for 3 days and then taken up in ether followed by washing with dilute sulfuric acid, pH 3, and water. The ether phase is dried over magnesium sulfate and evaporated to yield ethyl 2-phenylamino-3-hydroxybutanoate, which is saponified using 1.6 g of sodium hydoxide, 40 ml of methanol and 20 ml of water with stirring overnight at RT. The acid 2-phenylamino-3-hydroxybutanoic acid (3.0 g) is reacted with m-phenoxybenzyl bromide (3.4 g) in HMPT (20 ml) and potassium carbonate (2.12 g) at 35° for a few hours and worked up using ether/water to yield the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoic acid.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=NC=C1.ClC1C=CC=CC=1C(=O)C1C=[C:24]([N+:26]([O-])=O)[CH:23]=CC=1N1C(CN2C(=O)C3=CC=CC=C3C2=O)=NN=C1CN(C)C.O.NN>C(O)C>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:23][CH:24]=[N:26]1
Reactant: C1=CNc2ccccc2C=N1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner [1,4]benzodiazepin. in Example 27, 2'-chloro-5-nitro2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-nitro-1-[(dimethylamino)methyl] -6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]1,4]benzodiazepin.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
4-bromo triphenylamine 7.6 g(23.45 mmol), aniline 21.85 g(0.235 mol), sodium tert-butoxide 6.76 g(70 mmol), Pd2(dba)3[(tris(dibenzilidene acetone)dipalladium(0))] 0.86 g(0.938 mmol) and tri(tert-butyl)phosphine 0.23 g(1.173 mmol) in 500 ml round bottom flask were dissolved with toluene 200 ml, and refluxed for 12 hours. After the reaction was terminated, the reaction solution was cooled to room temperature, and 200 ml of distilled water was added thereto to extract an organic layer. The organic layer was dried over MgSO4, concentrated, and purified by silica gel column chromatography. The eluate was concentrated and dried to give N,N,N′-triphenyl-p-phenylenediamine (6.71 g, 85%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[C:6]([O:13][CH3:14])[CH:5]=1.[CH2:15](I)[CH3:16]>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:15][CH3:16])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: CCI
Reactant: COc1cc(Br)cc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2c(OC)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
NaH (96 mg, 4 mmol) was suspended in 7 mL DMF in a round bottom flask and cooled to 0° C. 6-bromo-4-methoxy-1H-indole (0.75 g, 3.3 mmol) was added dropwise as a solution in DMF (1 mL). Ethyl iodide (0.28 mL, 3.5 mmol) was added dropwise and the reaction mixture was stirred for 10 min. Volatiles were removed under reduced pressure and the residue partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organics layers were dried over MgSO4, filtered, and evaporated to give a red oil. The resulting residue was purified on silica gel column chromatography eluting with hexanes/ethyl acetate (0-10%) to afford pure 36-2 (584 mg, 70%) as a white solid.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([Cl:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:25](Cl)=[O:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:11][C:25]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:22]([Cl:24])=[O:23])[CH:17]=2)[CH:12]=1)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCCCCCCCO
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOC(=O)c1ccc2cc(C(=O)Cl)ccc2c1
Yield: 56.3 %

Procedure:
After a solution of n-decyl alcohol (0.5 g), naphthalene-2,6-dicarboxylic acid dichloride (0.6 g), and triethylamine (0.27 g) and a very small amount of dimethylaminopyridine in methylene chloride (50 ml) was stirred at room temperature overnight, the solution was distilled to remove the solvent, until the titled compound (about 0.5 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][OH:14])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NO)c1ccc(Cl)cc1
Yield: 54.5 %

Procedure:
1-(4-Chlorophenyl)propan-1-one (8.4 g, 50 mmol) was combined with hydroxylamine hydrochloride (4.0 g, 58 mmol), pyridine (4.6 g, 58 mmol), and ethanol (75 mL). The mixture was refluxed for 3 h. Solvent was evaporated and the residue diluted with water and extracted into diethyl ether/hexane (1:1). The organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. Crystallization from cold hexane gave 5.0 g of 1-(4-chlorophenyl)propan-1-one oxime.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]Br)=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:16].[Ca+2].O1CCOCC1.O.Cl>O1CCOCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:16])=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)n1ncc(Cl)c(CBr)c1=O
Agent: Cl
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)n1ncc(Cl)c(CO)c1=O

Procedure:
2-tert-butyl-4-bromomethyl-5-chloro 3(2H)-pyridazinone (2 g, 7.19 mmol) and calcium carbonate (3.5 gm) are added to a 1:1 mixture of dioxane-water (40 ml). The mixture is refluxed for 6 hours after which 30 ml of 3N HCl solution is added to it. The solution is stirred for 10 minutes after which dioxane is removed under reduced pressure. The resulting solution is then extracted with dichloromethane and the dichloromethane layer is washed and dried. The crude obtained after concentration is purified by flash chromatography (ethyl acetate/hexanes: 1:2).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO>O>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzothiazole, 0.28 g of potassium carbonate and 3 ml of methanol was refluxed with heating for 1.5 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzothiazole (hereinafter, referred to as the present compound 4).
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]2=[C:15]([C:18]([O:20]CC)=O)[N:16]=[CH:17][N:8]2[C:7]2[CH:23]=[CH:24][S:25][C:6]1=2>C(O)C>[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]2=[C:15]([C:18]([NH:2][NH2:3])=[O:20])[N:16]=[CH:17][N:8]2[C:7]2[CH:23]=[CH:24][S:25][C:6]1=2
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Yield: 94 %

Procedure:
8 ml of hydrazine hydrate were added to a suspension of 4.0 g (12.6 mmol) of ethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate in 40 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 3.6 g (94%) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide as colourless needles of m.p. >260°.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[NH:3][CH2:2]1.Br[C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:20])[C:16]([OH:30])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2.C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>[Cu].CN(C=O)C>[O:5]=[S:4]1(=[O:6])[CH2:7][CH2:1][CH2:2][N:3]1[C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:20])[C:16]([OH:30])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: O=S1(=O)CCCN1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCCS2(=O)=O)c2cccnc2c1O
Temperature: 25 °C

Procedure:
A mixture of 1,3 propanesultam (prepared as in White et al, J. Org Chem. 1987, 52: 2162) (0.081 g, 0.66 mmol), 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.10 g, 0.27 mmol), potassium carbonate (0.092 g, 0.66 mmol) and copper powder (0.017 g, 0.27 mmol) under an atmosphere of argon was stirred at 160C for 16 hr. The reaction was allowed to cool to room temperature and the residue was treated with DMF (5 mL) and TFA (1.5 mL) and filtered through a pad of celite to remove the solids. The filtrate was purified by reverse phase HPLC. (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:32])[C:15]=2[C@H:16]2[O:22][CH2:21][C@@H:20]([F:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:33].[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1B(O)O>>[NH2:24][C@H:19]1[C@H:20]([F:23])[CH2:21][O:22][C@H:16]([C:15]2[N:14]([CH3:32])[N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:33])=[C:2]([C:39]3[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=3[F:41])[N:7]=2)[CH2:17][CH2:18]1
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cc(F)ccc1F
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3cc(F)ccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 103), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,5-difluorophenyl)boronic acid gave 222. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.21 (dd, J=8.6, 3.7 Hz, 1H), 8.09 (dd, J=11.0, 8.6 Hz, 1H), 7.85-7.75 (m, 3H), 7.43 (tt, J=9.2, 2.4 Hz, 1H), 4.83 (dd, J=10.3, 3.8 Hz, 1H), 4.46-4.21 (m, 1H), 4.20-3.89 (m, 2H), 3.80 (s, 3H), 3.18-3.04 (m, 1H), 2.16-2.04 (m, 1H), 1.94-1.79 (m, 1H), 1.75-1.55 (m, 4H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[N:16]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:21]([C:20]2[C:15]([Cl:14])=[N:16][C:17]([C:24]([F:27])([F:25])[F:26])=[CH:18][CH:19]=2)=[O:22])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CNc1ncc(C(F)(F)F)cc1NC(=O)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.5 %

Procedure:
A mixture of 0.42 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.50 g of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid, 0.64 g of EDCI hydrochloride, 30 mg of HOBt and 2.5 ml of pyridine was stirred at room temperature for 7 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane, and then dried to obtain 0.81 g of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 2-Chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2cccc3c(N4CCCC4)c(Br)cc(c23)C(=O)N1OCc1ccccc1
Yield: 90.1 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.25 g, 0.59 mmol, from Example S1-A) in DMF (5 mL) was added pyrrolidine (0.05 g, 0.70 mmol) and triethyl amine (0.18 g, 1.8 mmol). The reaction was reacted at 85° C. for 24 hours, cooled, and concentrated under vacuum. The residue was triturated with methanol to give 0.24 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:29])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(C)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (4Hydroxy-phenyl)-p-tolyl-methanone from Srep A under the Standar Procedure J. The compound thus obtained was allowed to react under Standar hydrolysis procedure C (NaOH) to give the title compound. Ms(ES) for C27H28O6 [M+NH4]+: 471 [M+H]+: 449.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)c1
Yield: 88 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 88%). MS(ESI) m/z 438 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4]
Reactant: C[Si](C)(C)CCl
Reactant: Cc1cc(O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OC[Si](C)(C)C)cc(C)c1O
Temperature: 25 °C

Procedure:
Mix 2,6-dimethylhydroquinone (1.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), chloromethyltrimethylsilane (1.9 g, 10 mmol) and dimethylformamide (50 mL). Stir at room temperature under inert atmosphere until the reaction is complete. Dilute the mixture with ice-water and extract with ethyl ether. Wash the ethereal layer with water, then brine and filter through fluorosil-Na2SO4. Evaporate to give the title compound and purify by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: C#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 40.9 %

Procedure:
4-Chloro-2-fluoro-5-(2-propynyloxy)aniline (1.9 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.52 g) were dissolved in acetic acid (20 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 1.3 g of N-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]3,4,5,6-tetrahydrophthalimide (Compound No. 3). M.P. 136.4° C.
Reaction SMILES: [N:1]1[N:2]([CH2:10][CH2:11][C:12]#[C:13][C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](O)=[O:22]>>[N:1]1[N:2]([CH2:10][CH2:11][C:12]#[C:13][C:14]2[N:19]=[C:18]([NH:20][CH:21]=[O:22])[CH:17]=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Nc1cccc(C#CCCn2nc3ccccc3n2)n1
Reactant: O=CO
Product: O=CNc1cccc(C#CCCn2nc3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
A solution of anhydride acetic (0.75 mL) and formic acid (0.32 mL) was heated at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (70 mg, 0.27 mmol, 169(A)) was added over 15 min. and the reaction mixture was stirred at room temperature for 1 day. After evaporation of the solvent, the crude residue was triturated with diisopropyl ether, filtered and dried to yield 25 mg (86 μmol, 32%) of N-(6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)formamide as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:9](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccnc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86.7 %

Procedure:
To a solution of 2-nitro-1H-imidazole (500 mg, 4.4 mmol) in DMF (50 mL) is added cesium carbonate (1.7 g, 5.3 mmol) and the mixture is heated to 50° C. for 30 minutes. The resulting suspension is cooled to room temperature and MeI (0.33 mL, 5.3 mmol) is added. The reaction is heated to 50° C. for 2 hours is then cooled to room temperature and filtered through a bed of Celite. The filtrate is poured over ice water and extracted ethyl acetate. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (485 mg, 86%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[O:19][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(3-phenylpropoxy)acetophenone (1.28 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139°-142° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 2 H), 2.84 (m, 4 H), 2.98 (t, 2 H), 4.40 (t, 2 H), 6.68 (s, 1 H), 7.18 (m, 12 H), 7.75 (d, 2 H), 11.86 (bs, 1 H).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11](N2CCCCC2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[OH-:22].[K+].CO.Cl>O>[CH2:20]1[O:19][C:4]2[CH:5]=[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:12])=[O:22])[CH:1]=[CH:2][C:3]=2[O:21]1
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2

Procedure:
To piperine (1) (2 g, 0.7 mmol, 1 eq), 20% of methanolic KOH (100 ml) was added and refluxed for 2 days. After completion of the hydrolysis, methanol was removed under reduced pressure and a yellow coloured oily solid was obtained. This residue was dissolved in water (50 ml) and acidified with 6N HCl to pH<1 yielding a yellowish precipitate of piperinic acid. Recrystallization from methanol gave yellow needles (0.9 g, 60% yield). m.p. 206° C.-208° C. (Lit m.p. 217° C.-218° C.)1