Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:17][O:18][C:19](=[O:34])[C:20]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=1.Cl>ClC(Cl)C>[CH3:17][O:18][C:19](=[O:34])[C:20]1[CH:29]=[C:28]([S:30](=[O:31])(=[O:32])[NH:4][C:3]2[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=2[F:10])[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Reactant: Nc1c(F)cc(F)cc1F
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Temperature: 0 °C

Procedure:
2.94 g (20 mmol) of 2,4,6-trifluoroaniline is dissolved in 50 ml of dichloroethane with exclusion of moisture, 3.16 g (40 mmol) of pyridine is added and the solution is cooled to 0° C. With this temperature being maintained, a solution of 5.85 g (20 mmol) of 5-chlorosulfonylisophthalic acid dimethyl ester in 50 ml of dichloroethane is instilled. It is stirred for 30 more minutes at 0° C. and 5 more hours at room temperature. The suspension is shaken out three times with 2N hydrochloric acid and twice with water, the organic phase is dried on sodium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. The fractions, concentrated by evaporation, of corresponding polarity yield 6.34 g (15.72 mmol)=78.6% of the theoretical yield is obtained as a partially crystalline product.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([CH2:11][OH:12])[O:6][CH2:5]1)=[N+:2]=[N-:3].[CH3:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([C:19](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([O:12][CH2:11][C@H:7]2[O:6][CH2:5][C@H:4]([N:1]=[N+:2]=[N-:3])[CH2:9][C@@H:8]2[OH:10])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18]2[CH:35]=[CH:36][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: [N-]=[N+]=N[C@H]1CO[C@H](CO)[C@@H](O)C1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OC[C@H](N=[N+]=[N-])C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 77.1 %

Procedure:
0.52 g (3.0 mmole) of 1,5-anhydro-2-azido-2,3-dideoxy-D-glucitol (11) were dissolved in 9 ml of pyridine. Thereafter, 1.1 g (3.2 mmole) of 4,4′-dimethoxytritylchloride in 9 ml of pyridine are added at r.t. within 30 min under stirring. The reaction mixture was stirred for another 3 h at r.t. Then pyridine was evaporated and the residue was dissolved in 100 ml of ethyl acetate und washed twice with 60 ml of 5% sodium hydrogencarbonate solution. Organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in 5 ml of ethyl acetate and purified by flash-chromatography over silica gel (n-hexane/ethyl acetate/1% triethylamine gradient). Product fractions were combined, evaporated and dried at high vacuum to yield 1.1 g (77%) of a colorless foam.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[N:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Nc1ccncc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccncc5)nc34)cc21
Temperature: 150 °C
Yield: 13 %

Procedure:
Prepared similarly to that described in Example 82 using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 58 mg, 0.195 mmol), pyridin-4-amine (22.00 mg, 0.234 mmol, Aldrich), BrettPhos precat (Strem, Newburyport, Mass.; 8.25 mg, 9.74 μmmol), Brettphos (Strem, Newburyport, Mass.; 5.70 mg, 9.74 μmmol), and LHMDS (1.0M in THF; 429 μl, 0.429 mmol), heating at 150° C. for 40 min in a microwave (Biotage Initiator). Purification by silica gel chromatography (100% DCM to 10% MeOH/DCM) provided 2-(2-(pyridin-4-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (13% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 2.85 (t, J=7.04 Hz, 2H) 3.62 (t, J=7.04 Hz, 2H) 6.99 (s, 1H) 7.11 (d, J=9.00 Hz, 1H) 7.39 (t, J=7.73 Hz, 1H) 7.64 (dd, J=8.02, 1.17 Hz, 1H) 7.75 (d, J=6.46 Hz, 2H) 7.94 (dd, J=7.43, 1.17 Hz, 1H) 8.14 (d, J=8.80 Hz, 1H) 8.33 (d, J=6.26 Hz, 2H). MS (ESI, pos. ion) m/z: 356.3 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[N+:22]([C:18]1[CH:17]=[C:16]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of 1-Boc-hexahydro-1,4-diazepine (150 mg), 3-bromonitrobenzene (125 mg) and cesium carbonate (507 mg) in 1,4-dioxane (3 mL), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (26 mg) was added at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 70% hexane in ethyl acetate) to obtain tert-butyl 4-(3-nitrophenyl)-1,4-diazepane-1-carboxylate (C27, 15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][NH2:60])=[CH:54][CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:60][CH2:59][CH2:58][C:55]3[CH:56]=[CH:57][C:52]([CH2:51][N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)=[CH:53][CH:54]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCCc1ccc(CN2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(CN4CCCC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AC using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (76 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), TEA (0.030 mL, 0.22 mmol) and 2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethanamine (40 mg, 0.20 mmol) in DMF (5 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([C:14](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:15])[CH2:9][C@H:10]([CH3:13])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].OO.S(=O)(O)[O-:35].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.C1COCC1>[C:1]([O:5][C:6](=[O:29])[CH2:7][C@H:8]([CH2:9][C@H:10]([CH3:13])[CH2:11][CH3:12])[C:14]([OH:15])=[O:35])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S([O-])O
Reactant: CC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
To ester 112 (7.26 g, 0.018 mol) in H2O (53 mL) and THF (176 mL) at 0° C. was added a premixed solution of LiOH (37 mL of a 0.8 M solution) and H2O2 (10.57 mL of a 30% solution) and the solution warmed to room temperature. After 2 hours sodium bisulfite (7 g), sodium sulfite (13 g), and water (60 mL) was added and the two layers were separated and the aqueous layer extracted with ether. The combined organic phases were concentrated to an oil that was dissolved in heptane (200 mL). The resultant solid was filtered off and the filtrate dried (MgSO4) and concentrated to afford an oil (4.4 g) that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([F:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH3:2].[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([F:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[F:19])[CH3:2]
Reactant: CCOC(=O)Nc1cc2ccccc2cc1F
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1c(F)cc2ccccc2c1F
Temperature: 70 °C

Procedure:
A mixture of 1.63 g (7 mmol) of N-(3-fluoro-2-naphthyl)carbamic acid ethyl ester, and 2.73 g of Selectfluor® (7.7 mmol) in 10 mL of trifluoroacetic acid is heated to 70° C. under an atmosphere of nitrogen for 4 hours. After cooling to room temperature, the mixture is concentrated in vacuo and 30 mL of ice water is added. The mixture is extracted 3 times with 40 mL of CH2Cl2. The combined organic layers are washed with 40 mL each of H2O, saturated aqueous NaHCO3, saturated brine, dried over MgSO4. Evaporation of the solvents gives a residue that is purified by flash chromatography on silica gel (50% CH2Cl2/hexane) to give N-(1,3-difluoro-2-naphthyl)carbamic acid ethyl ester, which is hydrolyzed to 1,3-difluoro-2-aminonaphthalene under conditions described above.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([Pb+3])[CH:19]=1.[C:23]1(=[O:30])[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1.C1(C)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([CH:24]2[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:23]2=[O:30])[CH:19]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)CCCC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-ethylphenyllead triacetate (20.00 g, 35.2 mmol) (described in WO08/071,405) in chloroform (100 ml) is added cyclohexane-1,3-dione (3.94 g, 35.2 mmol) and 4-dimethylaminopyridine (22.36 g, 176 mmol). After stirring the reaction at room temperature for 5 minutes toluene (50 ml) is added and the solution is heated at 80° C. for 4 hours. After cooling to room temperature the mixture is allowed to stand overnight, followed by treatment with 2M aqueous hydrochloric acid. Following filtration of the precipitate the biphasic solution is separated, and the aqueous phase is extracted again with dichloromethane (×2). Organic fractions are combined then evaporated under reduced pressure to yield a crude product which is purified by flash column chromatography (10% ethyl acetate/hexane to 70% ethyl acetate/hexane eluant) to afford 2-(5-bromo-2-ethylphenyl)cyclohexane-1,3-dione as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[C:4]([OH:18])[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[OH:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)c2ccccc2)c(O)cc1Br
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(Cc2ccccc2)c(O)cc1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
To a solution of (4-bromo-2-hydroxy-5-methoxyphenyl)(phenyl)methanone (100 mg, 0.325 mmol) in 0.22 mL of anhydrous DCM (C=1.5M), were successively added dropwise trifluoroacetic acid (0.25 mL, 10 eq) and triethylsilane (0.21 mL, 4 eq). After 17 h of stirring at r.t., the reaction mixture was hydrolyzed with a saturated NH4Cl solution (5 mL) The layers were diluted with 20 mL of DCM and 20 mL of water and then separated. The aqueous layer was extracted twice with DCM (2×5 mL). The combined organic phase was washed twice with a saturated NaHCO3 solution (2×20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (Cyclohexane/AcOEt 97:3) to afford the desired product in 72% yield (68.5 mg) as an uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.28 (m, 2H), 7.28-7.20 (m, 3H), 7.01 (s, 1H), 6.70 (s, 1H), 4.89 (s, 1H), 3.96 (s, 2H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 150.3 (C), 148.1 (C), 139.4 (C), 128.8 (CH), 128.7 (CH), 127.5 (C), 126.6 (CH), 120.7 (CH), 115.0 (CH), 109.4 (C), 57.0 (OCH3), 36.4 (CH2Bn); MS (ESI) m/z: 310.1, 312.1 [M+NH4, 79Br, 81Br]+; 602.0, 604.3, 606.1 [2M+NH4, 79Br, 81Br]+.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CO>O>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 123 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To 300 g of polyphosphoric acid (112% phosphoric acid) heated at 88° C. was added 68.2 g of 2,5-di(4-methylanilino)terephthalic acid over a period of 35 minutes, the temperature being maintained below 120° C. by adjustment of the addition rate. The reaction mixture was heated at 123° C. for two hours. The melt was cooled to 93° C. and then slowly poured into 494 g of methanol, the temperature being maintained below 64° C. by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour, cooled to below 60° C., diluted with water, collected by filtration, and washed with water until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 5.5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for one hour. The slurry was cooled, filtered, and washed with water until alkaline free, then reslurried in water. After adjustment of the pH to 9.5, the slurry was heated at 143° C. for two hours in a closed system (e.g., a pressure reactor), and cooled to 40° C. After the slurry was acidified to pH 3.3, an emulsion of 2.2 g of an anionic surfactant, 30 g of a petroleum distillate, and 80 g of water was added, and the slurry was stirred for three hours. The wet cake was dried in an oven at 60° C. to give approximately 60 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:5]=3[C:4]=2[CH:3]=1.[C:24]([NH2:29])(=[O:28])[CH:25]([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>[Cu]I.O1CCOCC1>[CH2:22]([O:21][CH2:20][C:13]1[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:5]2[C:4]3[CH:3]=[C:2]([NH:29][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:12]=1)[CH3:23]
Reactant: CC(C)C(N)=O
Reactant: CCOCc1nc2cnc3ccc(Br)cc3c2n1CC(C)(C)O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOCc1nc2cnc3ccc(NC(=O)C(C)C)cc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 68.2 %

Procedure:
1-[8-Bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (0.550 g, 1.45 mmol), isobutyramide (0.150 g, 1.74 mmol), copper(I) iodide (0.055 g, 0.290 mmol), potassium phosphate (0.647 g, 3.05 mmol), and 1,4-dioxane (1.5 mL) were added to a scintillation vial. 1,2-(±)-trans-Diaminocyclohexane (0.035 mL, 0.290 mmol) was added. The vial was flushed with nitrogen, sealed with a Teflon-lined cap and heated at 110° C. for 72 hours. The vial was cooled to ambient temperature and the reaction was diluted with dichloromethane and methanol. Purification by chromatography with a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 1-15% CMA in chloroform) provided 0.38 g of N-[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]-2-methylpropanamide as a dark semi-solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C1(P(C(C)(C)C)C(C)(C)C)C=CC=CC=1.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26](Cl)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C1(C(N)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[F:22][C:23]([F:35])([F:36])[C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1)[CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
0.619 g (7.2 mmol) of methyl acrylate, 38.7 mg (120 μmol) of NBu4Br, 6.7 mg (30 μmol) of palladium acetate and 26.7 mg (120 μmol) of phenyldi(t-butyl)phosphine are weighed into a Schlenk vessel. 1.49 g (6 mmol) of 3,5-bis(trifluoromethyl)chlorobenzene and 1.53 ml (7.2 mmol) of dicyclohexylmethylamine and also 3.5 ml of dimethylacetamide are then added. The Schlenk vessel is placed in a heating bath at 130° C. and the contents are stirred. After 4 hours, the contents are poured into 30 ml of water and the product is extracted by shaking with t-butyl methyl ether. After drying the organic phase over MgSO4, the solvent is removed under reduced pressure and the product is isolated. Yellowish, crystalline solid, yield: 1.34 g (97% of theory).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:16])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 74.3 %

Procedure:
A solution of (S)-(−)-1-Boc-2-piperidine carboxylic acid 1 g (4.27 mmol), 1-benzylpiperazine 0.77 g (4.27 mmol), EDC 1.64 g (8.54 mmol) and catalytic amount of 4-(dimethylamino) pyridine in methylene chloride (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.23 g of desired product in 74.5% yield.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)=CC=O)=CC=1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O.C([O:48][C:49](=[O:70])/[CH:50]=[CH:51]/[CH:52]=[C:53]([C:62]1[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=1)[C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=1)C>C(Cl)(Cl)(Cl)Cl.CO.[OH-].[Na+]>[CH3:69][O:68][C:65]1[CH:64]=[CH:63][C:62]([C:53]([C:54]2[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=2)=[CH:52]/[CH:51]=[CH:50]/[C:49]([OH:70])=[O:48])=[CH:67][CH:66]=1
Reactant: CCOC(=O)/C=C/C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1ccc(C(=CC=O)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=C/C=C/C(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3-bis(4-methoxyphenyl)-2-propenal (22.7 g) and (carbethoxymethylene)triphenylphosphorane (30 g) in carbon tetrachloride (200 mL) was stirred overnight at room temperature and then at reflux for 5 hours to complete the reaction. The crude product (28.4 g) obtained from the usual work up consisted mainly of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid ethyl ester. The crude ester (28.4 g) in a mixture of methanol (200 mL) and 2N sodium hydroxide solution (100 mL) was heated at reflux for 30 minutes, then most of the methanol was distilled from the reaction. The base mixture was cooled, diluted with water (300 mL), extracted with dichloromethane (3×400 mL) and then was poured into a stirred mixture of concentrated hydrochloric acid (50 mL), water (200 mL) and ice (200 mL). The yellow precipitate was filtered off, washed with water and dried. The material was triturated with ether (3×100 ml) to provide 21.5 g of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid, mp 187°-189° C. Crystallization from dichloromethane-hexane furnished the pure acid, mp 189.5°-190.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:26]=[N+:27]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methyl 3-amino-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (181 mg, 0.487 mmol) was dissolved in trifluoroacetic acid (2.4 mL) and cooled in an ice bath. Solid sodium nitrite (67 mg, 0.97 mmol) was added with stirring to give a dark red mixture. After 10 minutes, solid sodium azide (317 mg, 4.87 mmol) was added followed by diethyl ether (2.4 mL). This was stirred in the ice bath for 10 minutes and then partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. The gave methyl 3-azido-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (161 mg) as a yellow solid. MS (ESI) m/z 398.9 (M+H). 1H NMR (CDCl3) δ ppm 7.85 (1H, d, J=2.14 Hz), 7.75 (1H, s), 7.71 (1H, dd, J=8.55, 2.14 Hz), 7.01 (1H, d, J=8.55 Hz), 4.01 (3H, s), 3.96 (3H, s).
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16])[CH:5]=[CH2:6].[CH3:17]N(C)C=O.CI>C(OCC)C>[CH3:17][CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:4][CH:5]=[CH2:6])[C:11]1=[O:16]
Reactant: CN(C)C=O
Reactant: C=CCc1cccc2c1CCC2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: C=CCc1cccc2c1CC(C)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.88 g of sodium methylate in 15 ml of ethyl ether is cooled to 0° C., a solution composed of 2.8 ml of ethyl formiate and 3 g of 4-(2-propenyl)-indanone in 6 ml of ether is introduced over 15 minutes, 5 ml of ether is added, with agitation for 15 minutes, and the suspension is allowed to rise to 20° C. 70 ml of dimethylformamide is added, with agitation for 2 hours, 2.15 ml of methyl iodide and 2 ml of ether are introduced, followed by agitation for 2 hours. The resulting mixture is then poured over 100 ml of ice water and extracted with ethyl ether, the extracts are dried and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (95-5) and 1.62 g of expected product is obtained.