Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH:16]([CH3:18])[CH3:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:14]([C:12]2[C:11]([CH:16]([CH3:18])[CH3:17])=[N:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:13]=2)[OH:15])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1cccc(-n2cc(C=O)c(C(C)C)n2)c1
Solvent: C1CCOC1
Product: COc1cccc(-n2cc(C(O)C3CCCCC3)c(C(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution (20 mL) of 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (2.6 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (15.0 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give a crude product (2.6 g, 75%) of the title object compound as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 79.3 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-7-chloro-6-fluoro-1-(4-fluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example Q-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.15 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[Cl:6][CH2:7][C:8]([CH2:10][Cl:11])=[O:9].O>CN(C)C=O.[Zn]>[Cl:6][CH2:7][C:8]([C:2]([F:4])([F:3])[F:1])([OH:9])[CH2:10][Cl:11]
Reactant: FC(F)(F)I
Reactant: O=C(CCl)CCl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCl)(CCl)C(F)(F)F

Procedure:
A mixture of commercial zinc powder (1.30 g, 0.02 mole), trifluoromethyl iodide (2.15 g, 11 mmole) and 1,3-dichloroacetone (5.6 g, 44 mmole) in 30 ml dimethylformamide (DMF) is irradiated in the water bath of an ultrasound laboratory cleaner (35 Watts, 32 KHz) for 30 minutes. The mixture is partitioned between 2% w/v aqueous hydrochloric acid and diethyl ether. The ether extract is dried (MgSO4) and the solvent evaporated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=[CH:30][C:31](O)=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[CH:30]/[C:31]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C=CC(=O)O)c2ccccc12
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c4ccccc34)nc2n(CCC)c1=O
Yield: 56.1 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.33 g (14.6 mmol) of 3-(4-methoxynaphthyl)acrylic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.12 g (yield 56%) of Compound 62 as yellow needles.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9]C(=O)[C:7]2=[O:14].[OH-].[K+].OO.C(O)(=[O:23])C>O>[NH2:9][C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:16])[F:15])=[CH:5][C:6]=1[C:7]([OH:14])=[O:23]
Reactant: CC(=O)O
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
5-(Trifluoromethoxy)isatin (15.0 g, 65 mmol) and potassium hydroxide pellets (4 g) were mixed in water (35 mL) and cooled to 0° C. With vigorous stirring, a solution of 30% aqueous hydrogen peroxide (11.7 g), potassium hydroxide pellets (5.8 g), and water (80 mL) was added drop-wise keeping the temperature below 10° C. After stirring 1 hour at 0° C., glacial acetic acid (22 mL) was added dropwise, causing foaming and formation of a precipitate. The contents were stirred overnight and filtered to afford the 2-amino-5-trifluoromethoxybenzoic acid as an amber solid (12.5 g, 87%). A small amount was recrystallized from ethyl acetate-hexanes to afford amber needles for an analytical sample and the remaining compound was used without further purification: mp 142.5-144.2° C. 1H NMR (CDCl3, 300 MHz) 7.98 (s, 1H), 7.18 (d, 1H, J=8.0 Hz) 6.62 (d, 1H, J=8.0 Hz), 6.40 (brs, 2H). Anal. Calc'd for C8H6NO3F3 : C, 43.45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29]([O:31]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:35]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29](=[O:31])[NH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Yield: 44 %

Procedure:
A solution of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (166 mg, 0.39 mM) in 8 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 30 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 70 mg (44%) of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (CDCl3) δ 8.0 (d, 1H, J=8 Hz), 7.4-7.0 (m, 12H), 6.8 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.5 (m, 1H), 6.4 (m, 1H), 5.8 (s, 1H), 5.4 (s, 2H), and 4.2 (s, 2H). MS (ES) m/e 405, 407.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[CH:28]=1)[CH2:24][CH2:25][CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:32]=2)=[C:29]([Cl:35])[CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(C#N)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
N-methyl-N-(phenylsulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.10 g), 4-butyl-2-chlorobenzonitrile (0.60 g) and anhydrous aluminum chloride (0.50 g) are added to o-dichlorobenzene (10 ml) and stirred at 120° C. for 1 hour. On completion of the reaction, chloroform (100 ml) is added and washed with dilute hydrochloric acid. After washing with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solution of hexane-ethyl acetate as eluent to give 0.70 g of compound (refractive index: 1.5667).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:18][CH:19]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3cccc(C(F)(F)F)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 3-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 488.4. HPLC (Condition A), Rt: 4.84 min (HPLC purity: 64.4%).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6]/[C:7](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CO>[CH3:6]/[C:7](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(/C=C/C(=O)OC(C)(C)C)=C\c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CC(/C=C/C(=O)OC(C)(C)C)=C\c1ccc(N)cc1
Reaction time: 1.17 h
Yield: 85 %

Procedure:
Tin(ii) chloride dihydrate (11.5 g, 51 mmol) was added to a stirred solution of tert-butyl (E,E)-4-methyl-5-(4-nitrophenyl)penta-2,4-dienoate (3.67 g, 12.7 mmol) in methanol (75 ml). The mixture was stirred and heated at reflux and the reaction monitored by HPLC. After 70 min, 4% starting material remained and there were two new products comprising 90 and 6% respectively. The cool mixture was concentrated in vacuo, water (75 ml) was added to the residue and then 2N NaOH solution until at pH 11. Ethyl acetate (150 ml) was added and the mixture filtered through Celite. The EtOAc layer was washed with 5% NaCl solution, dried over MgSO4 and concentrated in vacuo. The residual oil was stirred in diisopropyl ether (20 ml) for 10 min, insoluble by-products removed by filtration and the filtrate concentrated in vacuo to give 2.8 g (86%) of a yellow solid, mp 99-101° C.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1.[CH2:51]1[CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])[S:54][S:53][CH2:52]1>O1CCCC1>[S:53]1[CH2:52][CH2:51][CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60]([NH:50][CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][O:42][CH2:43][CH2:44]2)=[O:61])[S:54]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCCCC1CCSS1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCCCC1CCSS1)NCCN1CCOCC1
Reaction time: 20 h
Yield: 88 %

Procedure:
4.5 g of hydroxybenzotriazole, 10.5 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 7.8 g of diisopropylethylamine and 3.9 g of 2-morpholino-1-ethylamine are added at room temperature to a solution of 6.2 g of thioctic acid in 180 ml of tetrahydrofuran. After 20 hours, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed and then dried over Na2SO4. Concentration under reduced pressure yields 8.4 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[Cl:25][C:3]1[C:2]([N:1]([S:27]([CH3:26])(=[O:29])=[O:28])[S:27]([CH3:26])(=[O:29])=[O:28])=[CH:23][CH:22]=[C:21]([Cl:24])[C:4]=1[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100 mg), methanesulfonyl chloride (120 mg) and triethylamine (162 mg) in dichloromethane (3 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with 1N-hydrochloric acid, aqueous saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate and concentrated in vacuo. The residual oil was crystallized from ethanol to give 6-[2,6-dichloro-3-bis(methanesulfonyl)aminobenzoyl-amino]-1,2,3,4-tetrahydrodibenzofuran (87 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[S:36])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=CC(=O)N2CCNCC2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(=CC(=S)N2CCNCC2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
1.155 g of the 1-[3,3-bis(4-methoxyphenyl)acryloyl]piperazine [prepared as described in step (a) above] were dissolved in 12 ml of benzene, and the resulting solution was heated under reflux for 2 hours with 1.326 g of Lawesson's Reagent. At the end of this time, the reaction mixture was cooled to room temperature, after which it was poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through 30 g of silica gel eluted with a 19:1 by volume mixture of methylene chloride and methanol, to give 1.177 g of 1-[3,3-bis(4-methoxyphenyl)thioacryloyl]piperazine as a powder.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21]([O:23]C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:25]>C1COCC1.[OH-].[NH4+]>[CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21](=[O:23])[NH2:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCC1
Temperature: 35 °C

Procedure:
A solution of 9-[(cyclopentyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (110 mg, 0.34 mmol) in 3 mL of THF and 20 mL of concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped, and the mixture heated to 35° C. with stirring until tlc indicated complete consumption of starting material (20 h). The THF was evaporated, and the aqueous layer was filtered. The resultant solid was triturated with ether to afford 50 mg (0.162; 48%) of the title compound as a greenish-white solid. IR (KBr, cm−1) 3416, 3199, 3126, 1630, 1599. 1442, 1262, 778. 'FAB HRMS m/e, Calcd for C20H21N2O2: 309.1603. Found: 309.1607 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[N:3]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=2)[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)n(-c2ccc(C(=O)O)cc2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(C(=O)Cl)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
To a suspension of 4-(3,5-dimethylpyrazol-1-yl)benzoic acid (1.34 g) in dichloromethane (25 ml) was added oxalyl chloride (1.0 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo yielded 4-(3,5-dimethylpyrazol-1-yl)benzoyl chloride (0.80 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13](Br)=[C:12]([O:20][CH2:21][CH3:22])[CH:11]=2)=[CH:4][N:3]=1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([CH2:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:11]=[C:12]([O:20][CH2:21][CH3:22])[C:13]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:26][CH3:23])[CH:11]=1)[CH3:18]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1Br
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(OC)c1
Temperature: 25 °C

Procedure:
Tetrakis-triphenylphosphine-palladium (57 mg; 0.050 mmol) is suspended in dimethoxyethane (1 ml), while gassing with argon, and 2,4-diamino-5-(4-bromo-3,5-diethoxybenzyl)pyrimidine (367 mg; 1 mmol) in dimethoxyethane (6 ml) is added. After stirring for a quarter of an hour at room temperature, 3-methory-phenylboron acid (228 mg; 1.5 mmol) in ethanol (1.5 ml) is added, the mixture is stirred for a further 5 minutes at room temperature, an aqueous 2 M sodium carbonate solution (4.2 ml; 8.5 mmol) is added and the mixture is then boiled under reflux (bath temperature 85° C.) for 2.5 hours. The reaction mixture is concentrated and the residue is stirred with water and a little methanol and filtered off with suction. The filter cake is stirred with water, filtered off with suction and dried under a high vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=2[C:14]([OH:16])=O)[N:7]=1)=[O:5])[CH3:2].[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@@H:26]([CH2:34][OH:35])[NH:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:35][CH2:34][C@@H:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][N:25]1[C:14]([C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[N:8]1[C:9]([CH3:11])=[CH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]1)=[O:16]
Reactant: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)O)n1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
To an ice cooled solution of 2-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)-5-nitrobenzoic acid (25.0 g, 78.4 mmol) in DMF (250 mL) were added (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (31.0 g, 62.7 mmol), EDC.HCl (23.0 g, 117.5 mmol), HOBT (13.75 g, 101.9 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water, extracted with EtOAc (500 mL×2) twice. The combined organic layers were washed with water (500 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the ‘off white’ title compound 18 g (49%). Rf=0.45 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.70-8.35 (m, 2H), 8.15-7.98 (m, 1H), 7.25-6.95 (m, 4H), 6.82-6.58 (m, 1H), 5.20-3.80 (m, 8H), 3.40-2.40 (m, 2H), 2.38-2.10 (m, 3H), 1.30-0.80 (m, 3H); ES-MS: m/z 465.3 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)C(N)(CO)CO>ClC(Cl)C>[CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:11][CH2:12][N:13]([C:30]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:31])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2OC2(CCNCC2)CN1Cc1ccccc1
Reactant: O=C(Cl)C1CCCC1
Agent: NC(CO)(CO)CO
Solvent: CC(Cl)Cl
Product: O=C1c2ccccc2OC2(CCN(C(=O)C3CCCC3)CC2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 30 (0.010 mmol) in dichloroethane (0.7 mL) were added cyclopentanecarbonylchloride (0.020 mmol) and poly(4-vinylpyridine) (2% cross-linked, Aldrich, CAS#9017-40-7) (5.3 mg). The mixture was stirred overnight at 25° C. To the reaction mixture was added PS-trisamine (Argonaut, product number 800229, loading; 4.36 mmol/g) (6.9 mg), and the mixture was stirred overnight at 25° C. The mixture was filtered and the filtrate was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19]O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>O>[Cl:41][CH2:19][CH2:18][C:3]1([CH2:1][CH3:2])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCCl)OCC3
Yield: 51 %

Procedure:
A solution of compound 1 (136 mg, 0.5 mmol), PPh3 (262 mg, 1.0 mmol, 2.0 eq), and CCl4 (2.5 mL) was refluxed overnight. The resulting mixture was then diluted with water and extracted three times with CH2Cl2. The organic phases were combined, dried with Na2SO4, concentrated, and purified by column chromatography using 5:95:EtOAc:Hexane to give a white solid (74 mg, 51%): mp 106–107° C. (dec). 1HNMR (CDCl3, δ TMS): 0.93 (t, 3H), 1.37 (t, 3H), 1.91 (m, 2H), 2.34 (m, 2H), 2.76 (m, 2H), 2.87 (q, 2H), 3.46 (dm, 2H), 3.99 (m, 2H), 7.04–7.38 (m, 3H, Ar—H), 7.55 (br, 1H, NH). MS−: m/z 326 (MCl−), 290 ([M−H]−). Anal. (C17H22NOCl): C, H, N.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]([CH3:24])([CH3:23])[CH2:20][NH:21][CH3:22])[CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[C:26](Cl)(=[O:28])[CH3:27]>C1COCC1>[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]([CH3:24])([CH3:23])[CH2:20][N:21]([C:26](=[O:28])[CH3:27])[CH3:22])[CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: CNCC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N(C)CC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
Pyridine (0.055 mL, 0.68 mmol) is added to a solution of [3-(1,1-dimethyl-2-methylamino-ethyl)-isoxazol-5-yl]-carbamic acid tert-butyl ester (150.0 mg, 0.59 mmol) in THF (2.0 mL) followed by the addition of acetyl chloride (0.048 mL, 0.68 mmol). The reaction mixture is stirred at room temperature for 3 h. After this time, more pyridine (0.028 mL, 0.34 mmol) and more acetyl chloride (0.024 mL, 0.34 mmol) are added to the reaction mixture and stirred for another 1 h. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate twice. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides 87.0 mg of the title compound. Yield: 47%. m/z 312 [M+H].