Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:3]=1[Cl:18]>C(O)(=O)C.[Zn]>[Cl:18][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cc2cccc(Cl)c2Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Cc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
1,2-Dichloro-3-(4-nitrobenzyl)benzene (25.0 g, 88.6 mmol) obtained in Step 1 was dissolved in acetic acid (400 ml) and zinc powder (70 g, 1.1 mol) was added by portions at 0° C. The mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated under reduced pressure and the solid precipitated during concentration was collected by filtration. The solid obtained by the filtration was washed with diethyl ether, and dissolved in ethyl acetate (500 ml) and water (500 ml). A 4N aqueous sodium hydroxide solution was added to neutralize the aqueous layer. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure and the solid precipitated during the concentration was collected by filtration. The solid obtained by filtration was washed with n-hexane and vacuum-dried to give an object product (18.1 g, yield 81%) as a pale-brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[S:10]
Reactant: Nc1ccccn1
Reactant: S=C=Nc1ccc(Br)cc1
Product: S=C(Nc1ccc(Br)cc1)Nc1ccccn1

Procedure:
The title compound was synthesized according to the procedure in Example 8 by employing 4-bromophenyl isothiocyanate instead of phenyl isothiocyanate and 2-aminopyridine instead of 4-methyl-2-aminopyridine.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:48][C:49]([F:58])([F:57])[C:50]1[CH:51]=[C:52](O)[CH:53]=[CH:54][CH:55]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:23]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:55]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[C:49]([F:58])([F:57])[F:48])[N:10]=[CH:9]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.08 h

Procedure:
300 mg of 1-(triphenylmethyl)-4-(3-hydroxypropyl)-1H-imidazole (0.81 mmol) are dissolved in 8 ml of freshly distilled THF. 277 mg of triphenylphosphine (1.06 mmol) and 145 mg m-trifluoromethylphenol are added thereto, and the resulting mixture is cooled and stirred for 5 minutes under nitrogen. Diethyl azodicarboxylate (184 mg; 1.06 mmol), dissolved in freshly distilled THF (4 ml), is added gradually to the reaction mixture and while stirring continuously at room temperature for 12 hours. After removal of the solvent in vacuo, column chromatography (SiO2; first eluent: petroleum spirit; second eluent: petroleum spirit/diethyl ether (50:50)) performed on the crude reaction mixture gives a white powder which is reduced in petroleum ether to give an oil of 1-(triphenylmethyl)-4-[3-(trifluoromethylphenoxy)-propyl]-1H-imidazole. The latter (210 mg; 0.41 mmol) is heated at 70° C. for 3 hours in THF (5 ml) and 2N HCl (12 ml). The THF is removed under reduced pressure and Ph3COH is extracted with diethyl ether. The aqueous phase is neutralized with potassium carbonate and the product is extracted into diethyl ether or chloroform. This solution is dried and evaporated, giving an oil which is dissolved in 2-propanol. Oxalic acid (1.5 equivalents) is added and the abovementioned product (on addition of diethyl ether) in the form of the oxalate, m.p.: 204-208° C.
Reaction SMILES: O1CCCC1.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(OCC)(=O)C.O>[CH3:24][S:25]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:12]=1)(=[O:27])=[O:26]
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(OS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A tetrahydrofuran solution (50 mL) of 15.0 g (100 mmol) of p-hydroxypropiophenone and 12.143 g (1.2 equivalents) of triethylamine was cooled to 5° C. To this solution, 12.60 g (1.1 equivalents) of methanesulfonyl chloride was added dropwise over 30 minutes, followed by 1 hour of stirring. To the resulting solution, 40 mL of water and 70 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. A white solid was obtained as a result. This white solid was crystallized from 40 mL of ethyl acetate and 120 mL of hexane to thereby obtain white crystals of p-(methanesulfonyloxy)propiophenone (21.17 g, isolation yield: 93%). To a tetrahydrofuran solution (20 mL) of 4.560 g (20 mmol) of p-(methanesulfonyloxy)propiophenone, a hexane solution (5 mL) of 3.516 g (1.1 equivalent) of bromine was added at 15° C., followed by 1 hour of stirring. To the resulting solution, 30 mL of saturated sodium hydrogen carbonate and 30 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 20 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. 1-[4-(Methanesulfonyloxy)phenyl]-2-bromo-1-propanone was obtained as an yellow, oily substance (10.12 g, crude yield: 97%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1.N1C=CC=CC=1.Cl.[N:17]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.O>ClCCl.C(OCC)(=O)C>[N:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:2][CH:3]2[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]2)=[O:24])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1=CCC(N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC1=CCC(NC(=O)c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a suspension of 1-amino-4-methylcyclohex-3-ene hydrochloride (103 mg) in dichloromethane (5 ml) were added in turn pyridine (0.14 ml), 4-pyridinecarbonyl chloride hydrochloride (0.124 g) and N,N-dimethylaminoyridine (0.11 g) at 0° C. The mixture was allowed to warm to ambient temperature and was allowed to stir for 1 hour. The reaction mixture was taken up into a mixture of water and ethyl acetate, and adjusted pH to 4.6. The separated organic layer was washed in turn with water and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 1-(pyridin-4-ylcarbonylamino)-4-methylcyclohex-3-ene (46 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:8]([CH3:10])([CH3:9])[C:7]2[C:11]([CH2:13][CH2:14][CH2:15][C:6]=2[C:5]1([CH3:17])[CH3:16])=[O:12].[CH:18](OCC)=[O:19]>C(COC)OC>[CH3:17][C:5]1([CH3:16])[C:6]2[CH2:15][CH2:14][CH:13]([CH:18]=[O:19])[C:11](=[O:12])[C:7]=2[C:8]([CH3:9])([CH3:10])[CH:4]1[CH3:3]
Reactant: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1C(C)(C)C2=C(C(=O)C(C=O)CC2)C1(C)C
Reaction time: 8 h

Procedure:
A 2 L reaction flask was charged with sodium hydride (NaH) (40 g) in dimethoxyethane (DME) (CH3OCH2CH2OCH3) (1.39 Kg) and a mixture of Cashmeran™ (520 g) and ethyl formate (185 g) at room temperature. The mixture was stirred for 8 hours to provide 1,1,2,3,3-pentamethyl-4-oxo-2,3,4,5,6,7-hexahydro-1H-indene-5-carbaldehyde. Dimethylformamide (DMF) (300 mL) and hydroxylamine hydrochloride (NH2OH*HC1) (174 g) were then added and the temperature was heated to and maintained at 130° C. for 8 hours. Water was then added and the organic layer was extracted by toluene and washed once with water. Toluene was distilled off using a Rotovap to provide crude product 5,6,7,8-tetrahydro-6,6,7,8,8-pentamethyl-4H-indeno[5,4-D]isoxazole (260 g), which was then recrystallized to afford a pure product with a melting point of 80.96° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[C:12]([CH:15]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16](OCC)=[O:17])(=O)[CH3:13]>CC1C=CC=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:15]1[C:12]([CH3:13])=[N:1][C:2]2[N:6]([N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=2)[C:16]=1[OH:17])[CH3:26]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: CCOC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1O
Yield: 75.3 %

Procedure:
A suspension of ethyl 5-amino-1H-pyrazole-3-carboxylate (35.5 g, 229 mmol, prepared according to WO 2008015271), diethyl 2-acetylsuccinate (51.2 mL, 275 mmol) and TsOH.H2O (0.218 g, 1.144 mmol) in o-xylene (500 mL) was refluxed using a Dean-Stork condensor for 5 h. (Note: The suspension turned into a clear homogeneous solution and then in about 15 min a yellow solid started precipitated out of solution). Then, the reaction mixture was cooled, diluted with hexanes (250 mL), filtered, washed with hexanes and dried to afford ethyl 6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (53 g, 75% yield) as light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.61 (br. s., 1H), 6.49 (s, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.34 (s, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H). LCMS (M+H)=308.04.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][CH:10]=2)=[O:7])=[C:4]([NH:23][CH2:24][CH2:25][OH:26])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>O1CCCC1>[CH3:36][S:37]([O:26][CH2:25][CH2:24][NH:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=1[C:6](=[O:7])[NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:20])[N:16]2[CH3:19])=[CH:11][CH:10]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCO)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCOS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Chloro-2-[(2-hydroxyethyl)amino]-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide was dissolved in tetrahydrofuran, diisopropylethylamine and methanesulfonyl chloride were added, followed by stirring at room temperature for 3 hours. By post-treating the reaction liquid, 2-({5-chloro-2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamoyl]phenyl}amino)ethyl methanesulfonate was obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[C:20]([I:21])[C:12]=3[C:11](=[O:22])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.C(OCC1C2CCC3C=CC=CC=3C(=O)C=2C(I)=CC=1)(=O)C.O.Cl>O1CCCC1.CO.[OH-].[Na+]>[I:21][C:20]1[C:12]2[C:11](=[O:22])[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][OH:4])[C:16]=3[CH2:15][CH2:14][C:13]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OCc1cccc2c1CCc1cccc(I)c1C2=O
Agent: CC(=O)OCc1ccc(I)c2c1CCc1ccccc1C2=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2cccc(CO)c2CCc2cccc(I)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g of the mixture of (6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate and (4-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate prepared in Example 1-g was dissolved in a mixed solvent of 5 ml of tetrahydrofuran and 5 ml of methanol, and 0.1 ml of 5N sodium hydroxide solution was added at room temperature, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 1.3 g of a mixture of the title compound with a 4-iodo form as a colorless powder.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=O)[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CO>[N:22]1([C:12]2[CH2:13][CH2:14][C@@:15]3([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]4[C@@H:17]3[CH2:18][CH2:19][C@@:2]3([CH3:1])[C@H:6]4[CH2:5][CH2:4][C:3]3=[O:21])[CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C1CCNC1
Solvent: CO
Product: C[C@]12CCC(N3CCCC3)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.08 h

Procedure:
A solution of 113.5 parts of crude androst-4-ene-3,17-dione in 427 parts of methanol is heated to just below reflux temperature. To the resulting stirred solution there is added 4.3 parts of pyrrolidine. After five minutes, more pyrrolidine is added at a steady rate so that 33.2 parts are added over a period of 25 minutes. The warm mixture is then stirred for an additional 15 minutes before it is cooled to 5°-10° C. The solid product which formed during the reaction is then separated by filtration and washed several times with methanol at 10° C. The solid is then dried to give 3-(1-pyrrolidinyl)androsta-3,5-dien-17-one melting at about 217°-220° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]2[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>ClC(Cl)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:25][C:26]2[CH:39]=[CH:38][C:29]([C:30](=[O:31])[NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[CH:28][CH:27]=2)[C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: CC(C)(C)c1ccc(NCc2ccc(C(=O)Nc3nn[nH]n3)cc2)cc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.50 mmol 3-isocyanatobenzoic acid methyl ester dissolved in 5 mL dichloroethane was added to the above resin 4-[(4-tert-butylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (500 mg). Shaking the mixture 5 hours at 25° C. followed by filtration and washing of the resin with dichloromethane (2×10 mL), DMF (2× mL) and THF (3×10 mL) afforded the resin bound title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]Cl)[CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: ClCc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)cc1COc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(chloromethyl)benzene (12.2 g, 50.85 mmol) and phenol (4.79 g, 50.85 mmol) in DMF (102 mL) under nitrogen atmosphere, K2CO3 was added (35.14 g, 254.25 mmol). The resulting mixture was stirred at r.t. for 18 h. After completion of the reaction as confirmed by TLC, the reaction mixture was passed through celite plug and the filterate was evaporated. The residue obtained was dissolved in ethyl acetate (100 mL) and washed with water (2×100 mL) and brine (2×100 mL) successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 Ethyl acetate:Pet. Ether) to afford the title compound (14.7 g, 97.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[OH-].[Na+]>C(O)C>[C:12]([C:11](=[CH:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1)[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:13]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C#N)=Cc2cccc(Cl)c2)cc1OC
Reaction time: 8 h
Yield: 78.3 %

Procedure:
3,4-dimethoxyphenylacetonitrile (purchased from Tokyo Kasei), 1.77 g (10.0 mmole), and 1.41 g (10.0 mmole) of 3-chlorobenzaldehyde (purchased from Tokyo Kasei) were dissolved with heating into 10 ml of ethanol (purchased from Kokusan Kagaku), two drops of a 20% sodium hydroxide solution were added thereto, the mixture was stirred overnight, and deposited crystals were filtered, washed with ethanol twice and subsequently with hexane twice and dried to obtain 2.35 g (yield: 78.3%) of α-cyano-3'-chloro-3,4-dimethoxystilbene (yellow crystal).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[N:5][N:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.C(N(C(C)C)CC)(C)C.[C:21]1([C:27]2[N:28]=[C:29]3[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][N:30]3[CH:36]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:21]1([C:27]2[N:28]=[C:29]3[N:34]=[C:33]([NH:35][C:9]([C:3]4[N:4]([CH3:8])[N:5]=[C:6]([CH3:7])[C:2]=4[Cl:1])=[O:11])[CH:32]=[CH:31][N:30]3[CH:36]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nn(C)c(C(=O)O)c1Cl
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.57 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) were added to a solution of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 100 mg, 0.48 mmol) in ethyl acetate (3 ml). At 0° C., propylphosphonic acid anhydride (1-propanephosphonic acid cyclic anhydride, 50% in ethyl acetate, 0.7 ml, 2.5 eq.) was added dropwise to the mixture. After stirring for 30 min at 0° C., the mixture was stirred overnight at RT. The mixture was taken up in ethyl acetate, washed (water), dried (Na2SO4), and concentrated under reduced pressure. The title compound (16 mg, 9%) was obtained from the residue by preparative HPLC (254 nm, Agilent Zorbax XdB-C18, Run: 7 min, Flow: 30 ml/min, Gradient: 0.0 min: 95/5 H2O/CH3CN; 0.5 min: 95/5 H2O/CH3CN 4.5 min: 5/95 H2O/CH3CN; 6.9 min 5/95 H2O/CH3CN; 7 min 95/5 H2O/CH3CN).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C@H:13]([C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)/[C:8](O)=[O:9])[N:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:55][O:56][C:57]1[CH:78]=[CH:77][C:60]([CH2:61][O:62][C:63]([C:65]2[N:66]3[C@H:69]([S:70][CH2:71][C:72]=2[CH2:73][Cl:74])[C@H:68]([NH2:75])[C:67]3=[O:76])=[O:64])=[CH:59][CH:58]=1.C1(NC2CCCCC2)CCCCC1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)(=O)C>[CH3:55][O:56][C:57]1[CH:58]=[CH:59][C:60]([CH2:61][O:62][C:63]([C:65]2[N:66]3[C@H:69]([S:70][CH2:71][C:72]=2[CH2:73][Cl:74])[C@H:68]([NH:75][C:8](=[O:9])/[C:7](/[C:5]2[N:6]=[C:2]([NH2:1])[S:3][CH:4]=2)=[N:11]\[O:12][C@H:13]([C:28]([O:30][CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)[C:67]3=[O:76])=[O:64])=[CH:77][CH:78]=1
Reactant: CC(=O)Oc1ccc([C@H](O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\O[C@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(N)n4)C(=O)N23)cc1
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
To a suspension containing the product obtained in Step 5 (21.8 g) and (6R,7R)-7-amino-3chloromethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid p-methoxybenzyl ester p-toluenesulfonate (19.5 g) in dry dichloromethane (250 ml) were added dicyclohexylamine (7.2 ml) and diethylaniline (11.5 ml), and the mixture was cooled to -15° C. A solution of phosphorus oxychloride (3.4 ml) in dry dichloromethane (30 ml) was added dropwise to the suspension over a period of 40 minutes, and the mixture was stirred for 1.5 hours at -15° C. Ethyl acetate (1 liter) was added, and the mixture was washed twice with 1 N hydrochloric acid (300 ml), twice with saturated sodium bicarbonate solution (200 ml), then once with brine (300 ml), and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether, giving 29.9 g of the objective compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=O)[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])[CH3:2].[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11](=[O:13])[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([O:23][C:22]([F:21])([F:31])[F:32])[CH:25]=2)[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (2R,5S)-1-benzyl-pyrrolidine-2,5-dicarboxylic acid monoethyl ester (2 g, 7.21 mmol) in DMF (25 mL) was added 3-(trifluoromethoxy)aniline (1.53 mL, 8.65 mmol), HBTU (4.19 g, 10.8 mmol) and diisopropylethylamine (3.78 mL, 21.6 mmol). The reaction mixture was stirred at RT overnight. EtOAc and 1N HCl were added, the layers were separated and the aqueous one was back-extracted with EtOAc (×3). The combined organic extracts were washed with an aqueous solution containing 5% of NaHCO3, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 80:20) to give the title compound. MS (LC/MS): 437.2 [M+H]+; tR (HPLC conditions b) 5.50 min.