Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:33][C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (100 mg) was dissolved in DMF (2 mL), 2-bromoacetophenone (52 mg) was added, and potassium carbonate (36 mg) was further added. The reaction solution was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After the solution was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was recrystallized from IPE to obtain 69 mg of white crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][C:23]1([CH3:27])[O:26][CH:24]1C.CCO>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:12][C:10](=[O:11])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH:1][CH2:22][C:23]([OH:26])([CH3:27])[CH3:24]
Reactant: CC1OC1(C)C
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Phe-Leu-OMe (0.69 mmol) in CH2Cl2 (1 mL) was added dimethyl propylene oxide (0.075 mL). The reaction mixture was stirred at room temperature overnight, however, no change was observed. Two additional mLs of the oxide were added and then the reaction mixture was transferred with EtOH (excess) to a closed tube reactor, heated to 100° C. for 5 hours, stirred at room temperature for 2 days, and concentrated to yield 0.24 g of N-(2-hydroxy-2-methylpropyl)-L-phenylalanyl-L-leucine methyl ester.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C@H:6]([CH3:10])[CH2:5]1.C(N(CC)C(C)C)(C)C.[Cl:20][C:21]1[C:26]([F:27])=[C:25](Cl)[N:24]=[C:23]([CH3:29])[N:22]=1>ClCCl>[Cl:20][C:21]1[C:26]([F:27])=[C:25]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C@H:6]2[CH3:10])[N:24]=[C:23]([CH3:29])[N:22]=1
Reactant: C[C@@H]1CN(C)CCN1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@H]2C)n1
Temperature: 35 °C
Reaction time: 72 h
Yield: 118.2 %

Procedure:
To a solution of (3R)-1,3-dimethylpiperazine dihydrochloride (Example 63) (5.88 g, 31.4 mmol) in dichloromethane (126 mL) was added N,N-diisopropylethylamine (18.11 mL, 104 mmol), and 4,6-dichloro-5-fluoro-2-methylpyrimidine (5.69 g, 31.4 mmol). The solution was heated at 35° C. and stirred for 3 days. The solution was cooled to room temperature, diluted with DCM (100 mL), and washed with sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (9.60 g, >100% yield) as a brown oil that was used without further purification. LCMS: (M+H)+: 258.9.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][C:20](OCC)=[O:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[NH2:9][C:8]1[C:3]2[CH:4]=[N:5][N:6]([CH3:7])[C:2]=2[NH:1][C:20](=[O:21])[C:19]=1[C:11]1[NH:10][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: Cn1ncc(C#N)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc2c(N)c(-c3nc4ccccc4[nH]3)c(=O)[nH]c21
Reaction time: 18 h

Procedure:
5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (1.0 eq) and ethyl 1H-benzimidazol-2-ylacetate (1.0 eq) were dissolved in THF and dried over sieves. LiHMDS (3 eq) was added dropwise and the mixture stirred for 18 hours. The mixture was filtered and diluted with EtOAc, then washed with an aqueous saturated NH4Cl solution. The aqueous layer was washed with EtOAc (3×), and the organic layers combined, dried over MgSO4, and concentrated yielding pure product. LC/MS m/z 281.0 (MH+), Rt 1.41 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.[NH:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18].BrC1C=CC=CC=1CCN1C(=O)CN(C)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][N:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18]
Reactant: OCCc1ccccc1Br
Reactant: O=C1COCC(=O)N1
Agent: CN1CC(=O)N(CCc2ccccc2Br)C1=O
Product: O=C1COCC(=O)N1CCc1ccccc1Br

Procedure:
2-Bromophenethyl alcohol (402 mg, 2 mmol) and morpholine-3,5-dione (322 mg, 2.8 mmol) were treated as described in the preparation of compound 436. Purification was done by flash chromatography (petroleum ether/ethyl acetate 4:1) to provide the title compound as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:15]=[C:14]([C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)C.[OH-].[Li+]>O1CCCC1.O>[CH3:26][N:24]([CH3:25])[S:23]([C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:15]=2)=[O:29])=[CH:22][CH:21]=1)(=[O:27])=[O:28]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N(C)C)cc2)c2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(=O)c2cc(CC(=O)O)cc3ccccc23)cc1
Yield: 77878.5 %

Procedure:
To a stirred solution of [4-(4-dimethylsulfamoyl-benzoyl)-naphthalen-2-yl]-acetic acid ethyl ester (180 g, 0.42 mmol) in tetrahydrofuran:water (1:1; 4 mL) was added lithium hydroxide (40 mg, 0.97 mmol) at room temperature, and the resulting mixture was heated at reflux for 6 hours. The solvents were removed under reduced pressure, and the residue was washed with diethyl ether (5×5 mL), and then acidified with 50% aqueous hydrochloric acid solution (10 mL) and extracted with ethyl acetate (3×25 mL). The collected organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude solid, which was further washed with a hexane/ethyl acetate/ether mixture and freeze dried to give pure [4-(4-dimethylsulfamoyl-benzoyl)-naphthalen-2-yl]-acetic acid (130 g, 77%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.35 (br. s, 1 H), 7.96-8.11 (m, 5 H), 7.91 (d, J=8.2 Hz, 2 H), 7.52-7.68 (m, 3 H), 3.83 (s, 2 H), 2.66 (s, 6 H); HRMS cald. for C21H19NO5S (ESI+) [(M+H)+] 398.1057, obsd. 398.1056.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]12C[CH:10]([CH2:11][CH2:12]1)[CH:9]=[CH:8]2>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C1(C)C=CC=CC=1>[CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1=CC2CCC1C2
Reactant: C=CCCCC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCC=CCCCCCCCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, an anhydrous toluene solution (2 ml) containing 1-hexene (75 μl: 6.0 mol %) and a Grubbs I catalyst (4.1 mg: 0.05 mol %) was added to an anhydrous toluene solution (23 ml) containing the norbornene monomer J (1.60 g: 10.0 mmol), and stirred at room temperature for 20 hours. However, the reaction system was heterogeneous, and a polymer was precipitated. The obtained polymer (pO) was insoluble to chloroform, THF, and the like.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16]>O1CCCC1.COC(C)(C)C.[Pd](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1cc(F)c(F)c(F)c1
Temperature: 105 °C

Procedure:
A well-inertized pressure vessel was initially charged with a mixture of 49.6 g (0.113 mol) of a 40% solution of 3,4,5-trifluorophenylboronic acid in tetrahydrofuran from preliminary stage a) with 121.6 g (0.304 mol) of a 10% sodium hydroxide solution and 19.7 g (0.124 mol) of 2-nitrochlorobenzene. The particular ligand was then added at room temperature, the mixture was stirred and the palladium(II) chloride was finally added. Subsequently, the reaction mixture was heated to 105° C. This established a pressure of approx. 3-4 bar. After about 12 hours of reaction time, the pressure vessel was decompressed to standard pressure and cooled to 30° C., and the reaction mixture was discharged. For workup, the reaction mixture was taken up in tert-butyl methyl ether, the phases were separated and the aqueous phase re-extracted twice with tert-butyl methyl ether. The solvents were distilled off completely under reduced pressure, the final weight was determined and the content of the crude 3,4,5-trifluoro-2′-nitrobiphenyl was analyzed by means of quantitative HPLC. If desired, the crude 3,4,5-trifluoro-2′-nitrobiphenyl can be purified further, for example by crystallization from isobutanol.
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[ClH:19]>O>[Cl:19][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)c2c1OCCO2
Temperature: 40 °C
Yield: 62 %

Procedure:
29.3 g of 8-amino-1,4-benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated to 40° C. and then cooled to 5° C. and a solution of 10.5 g of sodium nitrite in 20 ml of water was added in portions with the temperature being maintained at from 5°-10° C. The mixture was agitated and then poured into a solution of 12 g of cuprous chloride in 45 ml of hydrochloric acid (d=1.18) with the temperature being maintained below 30° C. The precipitate was dried off, washed in 300 ml of water and 25 g of sodium bicarbonate. The solution was filtered and treated with hydrochloric acid. The precipitate was dried off, washed with water and dried. 20 g of 8-chloro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 195° C.; yield: 62%).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]([C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:34]5[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=5)[CH:25]=[CH:24][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)[O:20][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a degassed solution of 5-(4-(6-bromobenzo[d]thiazol-2-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (697 mg, 1.646 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (764 mg, 2.470 mmol), and potassium carbonate (683 mg, 4.94 mmol) in dioxane (12 mL) and water (4 mL) was added Pd(Ph3P)4 (114 mg, 0.099 mmol). The mixture was stirred at 100° C. under argon overnight. The mixture was cooled to rt, diluted with water (40 mL), and extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford tert-butyl 4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (238 mg, 0.453 mmol, 28% yield) as a yellow foam. LCMS (m/z)=526 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([OH:13])([CH3:12])[CH3:11]>>[C:1]1([NH:7][C:8](=[O:9])[O:13][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: O=C=Nc1ccccc1
Product: CC(C)OC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.1 %

Procedure:
A liquid mixture of 50 g (0.42 mol) of phenyl isocyanate and 6.43 ml (0.084 mol) of isopropanol was stirred at room temperature for 20 minutes and thereafter an unreacted raw material was distilled away under a reduced pressure to obtain 16.1% of isopropyl N-phenylcarbamate.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:4](=[O:3])[CH:5]([NH2:6])[CH2:7][OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: NCc1ccccc1
Agent: Cl
Product: NC(CO)C(=O)NCc1ccccc1
Yield: 34.2 %

Procedure:
To a stirred methanolic solution (250 mL) of L-serine methyl ester hydrochloride ((S)-6) (20.00 g, 128 mmol) was added benzylamine (55.9 mL, 512 mmol), and then the reaction solution was heated at reflux (18 h). The solvent was removed under reduced pressure, the insoluble salts were filtered, and the excess benzylamine was removed under high vacuum (Kugelrohr). The residue was dissolved in H2O (100 mL), and the product was extracted with CHCl3 (8×200 mL). The organic layers were combined and dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was triturated with Et2O (150 mL) and filtered to give 8.50 g (34%) of the product as a white solid: mp 76-80° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH2:21][F:22])[N:5]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:4]=2[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]([NH2:38])[CH:32]=[C:33]2[C:37]=1[NH:36][N:35]=[CH:34]2>>[CH:23]1([N:5]2[C:4]3[N:3]=[C:2]([NH:38][C:31]4[CH:32]=[C:33]5[C:37](=[C:29]([F:28])[CH:30]=4)[NH:36][N:35]=[CH:34]5)[N:11]=[CH:10][C:9]=3[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@H:6]2[CH2:21][F:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Nc1cc(F)c2[nH]ncc2c1
Reactant: N#Cc1cccc(N2C(=O)[C@@H](CF)N(C3CCCC3)c3nc(Cl)ncc32)c1
Product: N#Cc1cccc(N2C(=O)[C@@H](CF)N(C3CCCC3)c3nc(Nc4cc(F)c5[nH]ncc5c4)ncc32)c1

Procedure:
This compound was prepared from 3-[(7S)-2-chloro-8-cyclopentyl-7-(fluoromethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile and 7-fluoro-1H-indazol-5-amine, according to procedures similar to step e for the preparation of Example 18.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CC1(C)CC(C)OB([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])O1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:21]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])=[N:3][N:4]=[CH:5]2
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1nncc2cc(-c3cc(C(=O)OC)ccc3C)ccc12)C(F)(F)F
Temperature: 100 °C
Yield: 69.9 %

Procedure:
A mixture of methyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (1.0 g, 3.2 mmol), 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (0.99 g, 4.48 mmol), tetrakis(triphenylphosphine)palladium (185 mg, 0.16 mmol), and sodium carbonate monohydrate (1.2 g, 9.59 mmol) in dioxane/H2O (3:1, 12 mL) was heated in a microwave reactor at 100° C. for 80 min. The reaction mixture was partitioned between EtOAc (30 mL) and H2O (30 mL); the layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting dark oil was dissolved in 2% Et3N in EtOAc, evaporated onto some silica gel, and purified by flash chromatography (Biotage Si 40+S, 20-60% of 2% Et3N in EtOAc/hexanes) to provide methyl 4-methyl-3-(1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-yl)benzoate (833 mg, 70% yield) as a brown solid. MS (ESI, pos. ion) m/z: 373.2 (M+1).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.CN(C)CCN(C)C.[CH3:24][C:25]1([CH3:43])[CH2:29][O:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)=[N:26]1.CON(C)[C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CCCCCC>[CH3:24][C:25]1([CH3:43])[CH2:29][O:28][C:27]([C:30]2[C:31]([C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:54])=[CH:32][C:33]([N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)=[N:34][CH:35]=2)=[N:26]1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CN1CCN(c2ccc(C3=NC(C)(C)CO3)cn2)CC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCN(c2cc(C(=O)c3ccccc3)c(C3=NC(C)(C)CO3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
2,2,6,6-Tetramethylpiperidine (0.932 g, 6.6 mmol) was placed in a three-necked flask. Under argon 10 ml of hexane were added, the solution was cooled to 0° C. and n-butyl lithium (1.6 M solution in hexane) was added slowly. After stirring the yellow suspension for 10 min at 0° C., N,N,N′,N′-tetramethylethylenediamine (767 mg, 6.6 mmol) was added. This mixture was added dropwise to a suspension of 1.65 g (6 mmol) of 1-[5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridin-2-yl]-4-methyl-piperazine in 20 ml of hexane at −78°. After stirring the yellow solution for 30 min at this temperature and for 45 min at 0° C., a solution of 1.19 g N-methoxy-N-methyl benzamide (7.2 mmol) in 2 ml hexane/2 ml tetrahydrofuran was added slowly at 0° C. After 30 min, the cooling bath was removed and stirring was continued at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to give a brown oil, which was purified by flash chromatography with dichloromethane/methanol to yield 1.16 g (51%) of the product as a yellow solid.
Reaction SMILES: [N:1]1[C:2]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Na+]>O.NN.C(O)C>[N:1]1[C:2]([CH2:10][NH2:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1c2ccccc2C(=O)N1Cc1cn2ccccc2n1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCc1cn2ccccc2n1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A solution of 1.37 g (4.94 mmol) of 2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-isoindole-1,3(2H)-dione in 14 ml of hydrazine hydrate 98% and 1 ml of ethanol. Was stirred at room temperature for an hour. The mixture was then poured into 25 ml of sodium hydroxide 35% and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 0.426 g of the title compound crystallized from diethylether.
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([O:9][C:10](=[O:31])[C@H:11]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([CH3:8])([CH3:7])[CH3:6].[CH2:32]([NH:50][C:51]([O:53][CH:54]([CH2:62][O:63][C:64](=[O:84])[NH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:55][S:56][CH2:57][CH2:58][C:59](O)=[O:60])=[O:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>N1C=CC=CC=1>[C:5]([O:9][C:10](=[O:31])[C@H:11]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:59](=[O:60])[CH2:58][CH2:57][S:56][CH2:55][CH:54]([O:53][C:51](=[O:52])[NH:50][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:62][O:63][C:64](=[O:84])[NH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[CH:16][CH:15]=1)([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)O)OC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of phosphorus trichloride (19 mg) in pyridine (4 ml), 4-aminobenzoyl-glutamic acid di-t-butyl ester (106 mg) was added, followed by stirring at room temperature for 1 hour. To this mixture, 6,7-bis(octadecylcarbamoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 10 (216 mg) was added, followed by stirring at 50° C. for 1 hour. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel preparative TLC (dichloromethane:methanol=50:1×3) to yield the title compound (102 mg, yield 32%) as a colorless solid.
Reaction SMILES: O.O.O.C([O-])(=[O:6])C.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[CH2:21][CH2:20][CH2:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>C(OO)(=O)C.ClCCl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]23[O:6][CH:21]2[CH2:20][CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)[O-]
Reactant: COc1cccc(C2=CCCC2)c1
Agent: CC(=O)OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C23CCCC2O3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 298 %

Procedure:
A solution of sodium acetate trihydrate (6 g) in peracetic acid (38 ml) was added dropwise to a stirred solution of 1-(3-methoxyphenyl) cyclopentene (33.5 g) in dichloromethane (200 ml), maintaining the temperature in the range 0°-10°. The solution was stirred for 3 hours at room temperature and then washed with 8% aqueous sodium bicarbonate (700 ml) and 8% sodium thiosulphate solution (400 ml). The organic phase was separated, dried and evaporated and the residue was distilled in vacuo to give the title compound as a colourless oil (25 g) b.p. 89°-92° (0.01 mm).