Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.C(OCC)C.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>CCCCCC>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]([C:7]1[S:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)[OH:24]
Reactant: c1ccc2scnc2c1
Reactant: O=Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1nc2ccccc2s1)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
47 mL of 1.6M-butyllithium in hexane was added dropwise to a solution of benzothiazole (10 g, from Aldrich) and diethyl ether (200 mL) at -78° C. under nitrogen. The red brown solution was stirred at -78° C. for 30 min., followed by the addition of a solution of o-chlorobenzaldehyde (10.8 g) and diethyl ether (100 mL) at -78° C. The mixture was then stirred at -78° C. for 2 hours before it was allowed to warm to room temperature and stirred at room temperature overnight.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:18])=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:18][C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:7]=1)=[CH:17][CH:16]=2
Reactant: Nc1ccccc1
Reactant: Cc1cc2cc(Nc3ccnc(Cl)n3)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2cc(Nc3ccnc(Nc4ccccc4)n3)ccc2[nH]1
Temperature: 60 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine (0.1 mmol) and aniline (0.1 mmol) were dissolved in 0.5 ml DMF. To this was added p-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60° C. for 5 hours, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 85%.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>N1C=CC=CC=1>[F:26][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a suspension of 3-(4-aminophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.2 g, 7.12 mmol) in pyridine (10 mL) at 0° C. was added methanesulfonyl chloride (1.1 mL, 14.24 mmol) over 5 minutes, and then warmed up to room temperature under stirring conditions. After 2 hours the reaction was complete, and water was added in portions under vigorous stirring. The organic phase was then separated and concentrated and the resulting solids were filtered and dried under high vacuum. The solids were heated in acetonitrile, stirred until room temperature was achieved, then filtered off to give 3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.49 g). 1H NMR (DMSO, 400 MHz) δ 9.87 (s, 1H); 8.60 (s, 1H); 8.31 (d, J=8.0 Hz, 1H); 8.09 (s, 1H); 7.65 (d, J=8.0 Hz, 1H); 7.57 (d, J=8.4 Hz, 2H); 7.27 (d, J=8.4 Hz, 2H); 3.01 (s, 3 H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].C([O-])([O-])=O.[K+].[K+].Cl.Br[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCOC(=O)c1cn([C@H]2CCCNC2)c2ncc(Br)cc2c1=O
Reactant: BrCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn([C@H]2CCCN(CCN3CCOCC3)C2)c2ncc(Br)cc2c1=O
Temperature: 120 °C

Procedure:
(S)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate hydrochloride Intermediate 33, 0.400 g, 0.96 mmol) and K2CO3 (0.663 g, 4.80 mmol) were taken up in acetonitrile (3 mL) and 4-(2-bromoethyl)morpholine hydrochloride (0.221 g, 0.96 mmol) added. The reaction mixture was heated to 120° C. in the microwave for 30 min. The reaction mixture was cooled to room temperature and filtered, and the inorganics were washed with EtOAc two times. The solvent was removed in vacuo. (S)-ethyl 6-bromo-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (0.420 g, 89%) was recovered as a tan solid and will be carried on without further purification. MS (ES)(M+H)+: 494 for C22H29BrN4O4.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=O.Cl.[NH2:29][OH:30].N1C=CC=CC=1>C(O)C>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:3]([CH:1]=[N:29][OH:30])[N:4]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 18 h

Procedure:
To a stirred mixture of 4-formyl-2-fluoro-1-triphenylmethylimidazole (0.356 g.) and hydroxylamine hydrochloride (0.035 g.) in ethanol (4 ml.) was added pyridine (0.2 ml.). Stirring was continued at ambient temperature for 18 hours and the precipitated solid was filtered to give 2-fluoro-4-hydroxyiminomethyl-1-triphenylmethylimidazole, m.p. 147°-149°. Further amounts of product could be isolated from the mother liquors.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:37])[CH3:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([OH:27])[CH2:28][NH:37][CH2:35][CH3:36])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCN
Solvent: CO
Product: CCNC[C@H](O)COc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(COCC)n2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B3) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (S)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[OH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1
Reactant: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2cccnc2)cnc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 20 %

Procedure:
5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (2.6 mmol) is dissolved in DMF (12 ml), 3-hydroxypyridine (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 120° C. in the microwave for 45 min. The solvent is removed in vacuo and dissolved in water (200 ml) and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-ethoxy)-2-nitro-5-(pyridine-3-yloxy)-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 20%. HPLC (method C): 1.23 min; LC-MS (method A): 1.18 min, 292.15 (MH+).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[NH2:15])[NH:11][C:10](=[O:16])[C:9]2([CH3:18])[CH3:17].Cl>>[CH3:17][C:9]1([CH3:18])[C:8]2[C:12](=[CH:13][C:14]3[N:15]=[N:1][NH:5][C:6]=3[CH:7]=2)[NH:11][C:10]1=[O:16]
Reactant: O=N[O-]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: Cl
Agent: [Na+]
Product: CC1(C)C(=O)Nc2cc3nn[nH]c3cc21
Temperature: 25 °C

Procedure:
240 mg. (3.5 mMole) sodium nitrite were added portionwise to a suspension of 570 mg. (3 mMole) 5,6-diamino-3,3-dimethylindolin-2-one in 6 ml. 1N hydrochloric acid, the temperature being maintained between 0° and 5° C. by ice cooling. A red solution is obtained which is heated to 50° to 60° C. for 5 minutes. After cooling to ambient temperature, the crystalline precipitate obtained is filtered off with suction and washed with water. There are obtained 380 mg. of the title compound in the form of red crystals; m.p. 288°-291° C. (decomp.).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=1[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32]([NH2:42])[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>>[O:38]1[C:39]2[CH:40]=[CH:41][C:33]([CH2:32][NH:42][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([NH:22][C:23](=[O:31])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:16]=3)=[O:21])=[CH:34][C:35]=2[O:36][CH2:37]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1sc(C(=O)O)cc1NC(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1NC(=O)Cc1ccccc1
Yield: 95.7 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.26 g, 1.7 mmol), 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid from Example 10, Step 1 (0.3 g, 1.1 mmol), and piperonyl amine (0.17 g, 1.1 mmol) to afford 0.43 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide. A sample of the product was chromatographed on silica gel, eluting with ethyl acetate. Evaporation of the effluent under reduced pressure gave product with a mp 138-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.[F:39][CH:40]([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:41][CH:40]([F:50])[F:39])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH2:16][CH2:15]1
Reactant: Cc1cccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)n1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(CC(F)F)C4)CC2)n1
Temperature: 25 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and N,N-diisopropylethylamine (0.080 ml, 0.49 mmol) in dichloromethan (1 ml) was treated with trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (63 mg, 0.29 mmol) at 0° C. The cooling bath was removed after 30 min. and the reaction mixture was stirred at room temperature over night. The mixture was partitioned between aqueous saturated ammonium chloride solution (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with one 50-ml portion of ethyl acetate. The combined organic layers were washed with two 50-ml portions of a 1 M aqueous solution of sodium carbonate. The aqueous layers were each extracted with one 50-ml portion of ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concenrated in vacuo. Purification by flash column chromatography gave the title compound (98 mg, 85%) as white solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:14]CC2C=CC=CC=2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)(=O)[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[F:22][C:6]1[C:7]([OH:14])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:1]([CH3:2])[NH:11]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Reaction time: 2 h

Procedure:
A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10% palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressure for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate, brine and evaporated to give 4-fluoro-5-hydroxy-2-methylindole. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (317) to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16].[CH:30](=[O:32])[CH3:31]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:30]([OH:32])[CH3:31])[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)CN(C(=O)OC(C)(C)C)CCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (1.3 mL, 9.092 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (10 mL) was treated with a solution of n-butyllithium in hexanes (3.4 mL, 8.524 mmol, 2.5 M). After stirring at −78° C. for 30 minutes, the mixture was treated with a solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (1.394 g, 5.683 mmol) in anhydrous tetrahydrofuran (10 mL). After stirring at −78° C. for 20 minutes, the mixture was treated with acetaldehyde (0.96 mL, 17.05 mmol). After stirring at room temperature for 1 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 40 mL). The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (1.476 g, 90%) as a yellow oil and as a 2:1 mixture of diastereoisomers.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1O)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCc1ccccc1)C(=O)CCC2
Yield: 62.8 %

Procedure:
A mixture of 4.5 g (0.0233 mole) of 7-hydroxy-6-methoxy-1-tetralone, 5.4 g (0.032 mole) of benzyl bromide and 10 g (0.072 mole) of K2CO3 in 150 ml of acetone was heated to reflux overnight. The reaction as cooled, poured into water and extracted with EtOAc. The EtOAc was dried over Na2SO4 and evaporated to give 7 g of crude product. Crystallization with Et2O gave 4.13 g of product as a white solid, mp 110-111° C.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:28]=2)[N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccn4)nc3c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccn5)nc4c3)c12
Temperature: 80 °C

Procedure:
The mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-ylamine (62.8 mg 0.200 mmol), 2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (79.1 mg, 1.2 eq.), Pd(PPh3)4 (14.0 mg, 6% eq.) and Na2CO3 (53.0 mg, 2.5 eq.) in DMF (5 ml)/H2O (1 ml) was flushed with N2 for 30 min at rt and heated at 80° C. for 16 h under N2. After that time, the reaction mixture was treated with H2O (20 ml), and was then extracted with CH2Cl2 (2×25 ml). The extracts were washed with H2O (2×20 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, the crude yellow oil (105 mg) was purified by MS directed purification system to obtain a yellow solid of 3-cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine; 1H NMR (CDCl3, 400 MHz) δ 2.05-2.09 (m, 1H), 2.15-2.22 (m, 1H), 2.48-2.56 (m, 2H), 2.62-2.72 (m, 2H), 3.85 (quintet, 1H, J=8.4 Hz), 5.27 (s, 2H), 7.09-7.10 (d, 1H, J=4.8 Hz), 7.15-7.16 (d, 1H, J=4.8 Hz), 7.36-7.39 (m, 1H), 7.86-7.90 (m, 1H), 7.97 (m, 2H), 8.31-8.33 (d, 1H, J=8.8 Hz), 8.43 (s, 1H), 8.59-8.61 (d, 1H, J=8.8 Hz), 8.67-8.69 (d, 1H, J=7.6 Hz), 8.75-8.76 (d, 1H, J=4.0 Hz); MS (ES+): 393.4 (M+1), tR (polar—5 min)=2.2 min.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[N:9]([CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]=[O:11]>O1CCOCC1>[O:8]=[C:3]1[NH:4][C:5](=[O:7])[CH2:6][N:2]1[NH:1][C:10]([NH:9][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11]
Reactant: NN1CC(=O)NC1=O
Reactant: CCOC(=O)C(N=C=O)c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)NN1CC(=O)NC1=O)c1ccccc1
Temperature: 25 °C

Procedure:
1.15 g. (0.01 mol.) of 1-amino-2,4-dioxoimidazolidine are dissolved in 50 ml. of dioxane while heating. The solution is permitted to cool to room temperature while stirring, wherein a portion of the 1-amino-2,4-dioxoimidazolidine crystallizes out. 2.05 g. (0.01 mol.) of α-isocyanatobenzeneacetic acid, ethyl ester are added and the reation mixture is stirred overnight at room temperature. On the next day the mixture is concentrated and the residue is triturated with ether. 3.0 g. of α-[[[(2,4-dioxo-1-imidazolidinyl)amino]-carbonyl] amino]benzeneacetic acid, ethyl ester are obtained, m.p. 148°-151°.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>[OH-].[Na+].C(OCC)(=O)C>[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH:13][C:22](=[O:23])[CH2:21][C:20](=[O:24])[CH3:19])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C=C1CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reaction time: 1 h
Yield: 61.8 %

Procedure:
5.44 g of 7-aminocephalosporanic acid were dissolved in 20 ml of a 1N aqueous solution of sodium hydroxide, and 1.68 g of diketene were added, with ice-cooling, to the resulting solution. The mixture was stirred at the same temperature for 1 hour, after which it was diluted with 20 ml of ethyl acetate and then acidified. The mixture was extracted twice with ethyl acetate and the combined extracts were washed with an aqueous solution of sodium chloride, dehydrated over anhydrous magnesium sulphate and then concentrated by evaporation under reduced pressure, giving 4.4 g of the title compound as crystals melting at 150° C. (with decomposition).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[N+:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C-:19]>C1COCC1>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:14][CH:19]=[N:18][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (20 mL, 144 mmol) was added to a solution of 4-chlorobenzoyl chloride (8.4 g, 48 mmol) in THF (100 mL) at 0° C. Ethyl 2-isocyanoacetate (6.0 g, 53 mmol) was added dropwise and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column with ethyl acetate and hexanes as eluents to give the desired compound. MS (m/z) 252.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12]/[CH:13]=[N:14]/[NH:15]C(OCC)=O.[S:21](Cl)(Cl)=O>>[S:21]1[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:13][N:14]=[N:15]1
Reactant: CCOC(=O)N/N=C/CN1C(=O)c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1cnns1
Reaction time: 24 h
Yield: 59.9 %

Procedure:
Ethyl (2E)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethylidene]hydrazinecarboxylate (612 mg, 2.22 mmol) was slowly added to thionyl chloride (1.5 ml), and the mixture was stirred for 1 day. Crystals were collected by filtration and washed with ethyl acetate to give 308 mg (59.9%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]([F:32])([F:45])[F:44])[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 11.7 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated 2-trifluoromethoxybenzeneboronic acid (38 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (7 mg, 12%). MS m/e 491.19 (M+H+)