Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=[O:17])[C:9]2=[O:22])=[CH:4][CH:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].[C:29]([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O.[Cu]I>[CH3:29][O:18][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([N:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:23]4[CH2:27][CH2:26][CH2:25][C:24]4=[O:28])=[CH:3][CH:4]=3)[C:9]2=[O:22])[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCN1
Reactant: O=C(O)c1cccc(N2CCN(c3ccc(I)cc3)C2=O)c1
Agent: [Cu]I
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N2CCN(c3ccc(N4CCCC4=O)cc3)C2=O)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
The methyl ester of 3-[3-(4-iodophenyl)-2-oxo-imidazolidin-1-yl]benzoic acid (0.42 g, 1.0 mmol) prepared as in Example 13 was mixed with 2-pyrolidinone (0.10 g, 0.09 mL, 1.2 mmol), CuI (0.02 g, 0.10 mmol), Cs2CO3 (0.65 g, 2.0 mmol), trans-1,2-hexanediamine (0.01 g, 0.01 mL, 0.1 mmol) and dioxane (5 mL). The mixture was heated at 110° C. with stirring for 12 h under nitrogen. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL×3) and the combined extracts were washed with water, brine and dried over anhydrous Na2SO4, and then concentrated. The crude product obtained after the removal of the solvent was chromatographed (silica, dichloromethane:ethyl acetate, 9:1) to provide pure product, 3-{2-oxo-3-[4-(2-oxo-pyrrolidin-1-yl)phenyl]imidazolidin-1-yl}benzoic acid methyl ester, as white solid (0.34 g, 89.5%). MS (ES+) m/z: 380.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Br:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[C:19]([Br:21])[CH:20]=1>C(N(CC)CC)C>[Br:21][C:19]1[CH:18]=[C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:16]=[C:15]([Br:14])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Brc1cc(Br)cc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3cc(Br)cc(Br)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with (3,5-dibromophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(3,5-dibromophenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH:35]=[CH:34][CH:33]=[CH:32]3)[CH2:20][CH:19]2[OH:36])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH:32]=[CH:33][CH:34]=[CH:35]3)[CH2:20][C:19]2=[O:36])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3-n3cccc3)CC2O)CCCCC1)c1ccco1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3-n3cccc3)CC2=O)CCCCC1)c1ccco1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-[4-fluoro-2-(pyrrol-1-yl)phenyl]piperidin-3-ol (1.8 g) obtained in Step 1 in 10 ml of dimethylsulfoxide, was added 2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (1.8 g) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 1.5 g of the titled compound as white color.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[NH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[NH:39])=[CH:36][CH:35]=1)[NH2:33]>CCO>[Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9](=[N:33][NH:32][C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH2:40])=[NH:39])=[CH:41][CH:42]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)c(O)c(C(=O)CCc2ccc([N+](=O)[O-])cc2)c1
Reactant: N=C(N)c1ccc(NN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Br)c(O)c(C(CCc2ccc([N+](=O)[O-])cc2)=NNc2ccc(C(=N)N)cc2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
For example, a solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-phenyl)-propan-1-one 201 (1.48 g, 0.004 mol), EtOH (30 mL), diisopropylethylamine (Hunigs base)(3 mL), and 4-Hydrazino-benzamidine 200 (0.93 g, 0.004 mol) is heated at reflux for 4 hr. (reaction times can vary between 2 h to 18 h). The solution is cooled to ambient temperature, filtered, washed with 6N HCl (2×25 mL), and dried for 12-18 h in a vacuum oven to give a 90% yield of 4-{N′-[1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-phenyl)-propylidene]-hydrazino}-benzamidine 202 as an off-white solid (1.78 g, 0.0036 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH:20]=O.C(O)(=O)C.[O:26]=[C:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH2:20][N:31]1[CH2:30][CH2:29][NH:28][C:27](=[O:26])[CH2:32]1
Reactant: O=C1CNCCN1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C1CN(Cc2c(-c3ccccc3)[nH]c3c([N+](=O)[O-])cc(Cl)cc23)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
5-Chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, 1.66 mmol) obtained in Step 1 was dissolved in dichloromethane (20 mL), and thereto acetic acid (0.10 g, 1.66 mmol), 2-oxopiperazine (0.3 g, 3.32 mmol) and sodium triacetoxy borohydride (0.71 g, 3.32 mmol) were added in drops. The mixture was stirred at room temperature for 4 hours. At the end of reaction, the mixture was diluted with water, and extracted with dichloromethane. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give 5-chloro-7-nitro-3-(2-oxo-piperazin-4-yl)methyl-2-phenyl-1H-indole (0.55 g, Yield 86%).
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.Br[CH2:15][C:16]([C:18]1C=CC=[CH:20][CH:19]=1)=O.C(O)C>[Pt](=O)=O.CO>[C:2]1([C:3]2[N:4]=[C:5]3[CH2:10][NH:9][CH2:8][CH2:7][N:6]3[CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: c1ccc(-c2cn3c(n2)CNCC3)cc1

Procedure:
2-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 2-bromo-1-phenylethanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]#[N:12])[CH2:3]1.C(N(CC)CC)C.Cl.CN(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O.C(#N)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:9][CH2:8][C:7]([N:5]2[CH2:6][C@@H:2]([F:1])[CH2:3][C@H:4]2[C:11]#[N:12])=[O:10])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 49.1 %

Procedure:
(2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboni trile (259 mg), triethylamine (0.42 mL), trimethylamine hydrochloride (143 mg) and acetonitrile (5 mL) were mixed together. While this mixture was cooled in a salt-ice bath, 4-chlorobenzenesulfonyl chloride (350 mg) was added in portions and the mixture was further stirred for 1 hour. Subsequently, water (5 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were combined, washed with saturated brine (2×5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate) to give (2S,4S)-1-[2-[(4-chlorophenyl)sulfonyloxy]acetyl]-4-fluoropyrr olidine-2-carbonitrile as a white solid (256 mg, 49% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].[CH2:29](I)[CH3:30]>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:29][CH3:30])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.5 g of approximately 55 % sodium hydride, and the solution was stirred for 30 minutes. To this was further added 4.7 g of ethyl iodide and stirring was further continued for 1.5 hours at room temperature. After the reaction was complete, the solvent was distilled off from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product, which was then recrystallized from methanol to give 2.7 g of 1-(m-nitrophenyl)-3-ethylquinazoline-2,4 (1H, 3H)-dione as light brown prisms, melting at 193°-194° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.CCN(C(C)C)C(C)C.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][N:35]([C:12]([C:3]3[S:4][C:5]4[N:6]=[CH:7][NH:8][C:9](=[O:11])[C:10]=4[C:2]=3[CH3:1])=[O:14])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCN(c3cccc(Cl)c3)CC2)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (2 g, 9.5 mmol) in DMF (20 mL) was added DIEA (5 mL, 28.5 mmol), 1-(3-chlorophenyl)piperazine hydrochloride (2.2 g, 9.5 mmol), and HATU (4.7 g, 12.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (60 mL) and the organic layer was washed successively with sat. NaHCO3 aq. (50 mL) and brine (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated to give crude product as a gummy solid. Purification by flash column chromatography using EtOAc as the eluent afforded the 3 g of pure 6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one, (yield: 81%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].[CH2:16]([C:18]([CH2:23]O)([CH2:21]O)[CH2:19][CH3:20])O.C1OC1>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].[CH3:16][C:18]([CH3:23])([CH3:21])[CH2:19][CH3:20]
Reactant: CCC(CO)(CO)CO
Agent: C=CC(=O)O
Solvent: C1CO1
Product: CCC(C)(C)C

Procedure:
4.88 g polyoxyethylated trimethylol propane triacrylate, molecular weight=1162 20 moles ethylene oxide
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13](=[O:50])[N:14]([CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([CH:48]=O)[CH:39]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36].[C:51]([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:50])[N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[CH2:37][C:38]1[CH:39]=[C:40]([CH:48]=[CH2:51])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1
Reactant: O=C([O-])O
Reactant: COC(=O)N(Cc1cc(C=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)C(=O)OC)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A suspension of Ph3PCH3Br (53.4 mg, 0.15 mmol) in THF (500 μL) was cooled to 0° C. potassium bis(trimethylsilyl)amide (256 μL of a 0.5 M solution in toluene, 0.128 mmol) was added slowly and the reaction was kept at 0° C. After fifteen minutes, methyl[3-formyl-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (24.2 mg, 0.043 mmol) (Example 40) was dissolved in THF (1 mL) and was added via cannula to the reaction which was then slowly warmed to room temperature. After fifteen minutes at room temperature, the reaction was diluted with EtOAc (30 mL), and poured into NaHCO3 (10 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 25% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(trifluoromethyl)-5-vinylbenzyl]carbamate. Rf=0.42 (25% EtOAc/hexanes) LCMS=566.2 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.68 (broad singlet, 1H), 7.36 (s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.15 (broad singlet, 1H), 7.10 (d, J=10.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.54 (d, J=8.5 Hz, 1H), 6.32-6.27 (m, 1H), 5.40 (d, J=18 Hz, 1H), 4.97 (d, J=11 Hz, 1H), 4.37 (broad singlet, 2H), 4.04 (broad singlet, 2H), 3.34 (s, 3H), 3.20 (s, 3H), 2.69 (m, 1H), 1.12 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH:14]1([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C:27](=[O:37])[CH2:28][C:29]3[C:34]([Cl:35])=[CH:33][N:32]=[CH:31][C:30]=3[Cl:36])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][O:18][C:19]2[CH:20]=[C:21](/[C:27](/[O:37][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:28]/[C:29]3[C:30]([Cl:36])=[CH:31][N:32]=[CH:33][C:34]=3[Cl:35])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:16][CH2:15]1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OCC1CC1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OCC3CC3)c2)cc1OC

Procedure:
The compound was obtained starting from 3,4-dimethoxy-benzoyl chloride and 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-(3,5-dichloro -pyridin-4-yl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.O[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
A solution of 116 mg (0.5 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoic acid, 58 mg (0.5 mmol) of ethyl 4-hydroxybenzoate, 117 mg (0.56 mmol) of 1,3-dicyclohexylcarbodiimide and 30 mg (0.25 mmol) of 4-dimethylaminopyridine in 15 ml of methylene chloride was stirred at room temperature for 12 hours. The reaction mixture was then filtered and the filtrate concentrated in-vacuo. The resultant residue was purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as white crystals. PMR (CDCl3): δ 1.32 (6H, s), 1.36 (6H, s), 1.42 (3H, t, J~7.0 Hz), 1.73 (4H, s), 4.40 (2H, q, J~7.0 Hz), 7.28 (2H, d, J~8.1 Hz), 7.45 (1H, d, J~8.8 Hz), 7.93 (1H, dd, J~8.8 Hz, 1.8 Hz), 8.13 (2H, d, J~8.1 Hz), 8.14 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27].C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([O:24][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCCC4)n3)c2n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1(c2cccc(Cn3nnc4c(Cl)nc(N)nc43)n2)CCCC1
Temperature: 35 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 7-chloro-3-{6-[1-hydroxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine (0.5 g, 1.5 mmol) in dry THF (15 mL) at room temperature was treated with trimethylsilyl chloride (0.38 mL, 3.0 mmol) then triethylamine (0.42 mL, 3.0 mmol); stirred at 35° C. overnight, treated with additional quantities of trimethylsilyl chloride (0.19 mL, 1.5 mmol) then triethylamine (0.21 mL, 1.5 mmol) and stirred at 35° C. for 24 h. The mixture was poured into water (60 mL), extracted with EtOAc (×2), concentrated in vacuo and purified by chromatography (SiO2:isohexane-EtOAc (3:1)) to give the title compound (0.55 g, 88%); NMR δH (400 MHz, DMSO) 7.78 (1H, t, J 7.8 Hz), 7.59 (2H, br s), 7.43 (1H, d, J 7.8 Hz), 7.19 (1H, d, J 7.8 Hz), 5.79 (2H, s), 1.68 (7H, m), 1.40 (2H, m), −0.11 (9H, s); (M+H)+ 418.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][OH:24])[CH:3]=1)=[O:17]
Reactant: C#CCCCO
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CCCCO)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with pent-4-yn-1-ol gave 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(5-hydroxypent-1-ynyl)phenyl)propyl)acetamide as brown oil. Yield (1.46 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.22-7.34 (m, 3H), 4.86 (d, J=8.0 Hz, 1H), 3.83 (t, J=5.2 Hz, 2H), 3.65-3.69 (m, 1H), 3.38-3.42 (m, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.38 (bs, 1H) 1.93-1.99 (m, 2H), 1.83-1.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][C:13](O)=[O:14])[CH3:11])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H].C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pt]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][CH2:9][N:10]([CH3:11])[CH2:12][C:13](=[O:14])[NH:16][C:4]=2[CH:3]=1
Reactant: CN(CCc1ccc(Cl)cc1[N+](=O)[O-])CC(=O)O
Reactant: [H][H]
Agent: [Pt]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CN1CCc2ccc(Cl)cc2NC(=O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
{[2-(4-Chloro-2-nitro-phenyl)-ethyl]-methyl-amino}-acetic acid (18.5 g, approximately 0.068 mole, not quite pure) in methanol (250 mL) containing platinum on sulfided carbon (5 wt. %, 12.0 g) was hydrogenated at room temperature and a hydrogen pressure of 50 psi overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in pyridine (2 L) and the solution was cooled to 0° C., and 1,3-dicyclohexylcarbodiimide (30.0 g, 0.145 mol) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 48 hours. The solvent was removed and the residue was slurried with 10% hydrochloric acid and filtered. The filtrate was extracted with ether, the aqueous phase was made basic with sodium carbonate and then extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography (silica gel, methylene chloride) provided 5.1 g of the title compound as a white solid. 1H NMR (CDCl3): 7.55 δ (broad s, 1H); 7.18 δ (d, 1H); 7.10 δ (d, 1H); 7.00 δ (s, 1H); 3.18 δ (s, 2H); 2.80 δ (broad s, 4H); 2.40 δ (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH2:14].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)(=[O:29])C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:20]([NH:14][C:6]1[CH:7]=[C:8]2[C:12]([CH2:11][CH2:10][C:9]2=[O:29])=[CH:13][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:2]=1[F:1])(=[O:22])[CH3:21]
Reactant: Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: CC(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2=O
Reaction time: 0.5 h

Procedure:
120 g of 6-(2,4-difluorophenoxy)-5-indanylamine is kept in 1.2 l of acetic acid and 0.5 l of acetic anhydride for 30 minutes at 50° C. and then, at this temperature, a solution of chromium trioxide (110 g) in 50 ml of water and 300 ml of acetic acid is added dropwise thereto. After 30 minutes at 50° C., the mixture is concentrated, water is added, the mixture is extracted with chloroform and chromatographed with chloroform over a silica gel column, yielding 30 g of 6-acetylamino-5-(2,4-difluorophenoxy)-1indanone, mp 210° C. This quantity is dissolved in 500 ml of tetrahydrofuran, and the solution is combined at 40° C. with a phenylmagnesium bromide solution in ether (prepared from 24 g of magnesium, 108 ml of bromobenzene, and 500 ml of ether). After 16 hours at 20° C., the mixture is decomposed with ammonium chloride solution. The organic phase is stirred for 5 minutes with 8 g of p-toluenesulfonic acid. After filtration, the mixture is concentrated, the residue is extracted by stirring with petroleum ether and recrystallized from ethanol, thus obtaining 22 g of N-[6-(2,4-difluorophenoxy)-3-phenyl-5-indenyl]acetamide. This product is dissolved in 60 ml of dioxane and 240 ml of ethanol and hydrogenated over 1.2 g of palladium-charcoal (10%). Concentration and crystallization from petroleum ether yield 16.5 g of N-[6-(2,4-difluorophenoxy)-3-phenyl-5-indanyl]acetamide, mp 117° C. This product is stirred in 200 ml of acetone with a solution of 8 g of chromium trioxide, 20 ml of sulfuric acid, and 40 ml of acetic acid for 16 hours at 20° C. After adding sodium bisulfite, the mixture is concentrated, taken up in chloroform, the chloroform solution is washed with sodium hydroxide solution and concentrated. Chromatography over silica gel with toluene-ethyl acetate yields 6 g of 5-acetylamino-6-(2,4-difluorophenoxy)-3-phenyl-1-indanone, mp 163° C. This quantity is refluxed in 50 ml of ethanol and 10 ml of hydrochloric acid (10-normal) for 2 hours. After concentration, the mixture is made weakly alkaline with ammonia, vacuum-filtered, dried, taken up in 60 ml of pyridine, and combined with 2.3 g of methanesulfonyl chloride. The mixture is concentrated after having been left for 25 hours at 20° C., combined with water, vacuum-filtered, dissolved in 1N sodium hydroxide solution, and acidified with 10N hydrochloric acid. Vacuum-filtering yields 3.1 g of 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-3-phenyl-1-indanone, mp 101° C.