Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cu])#[N:2].Cl[C:5]1[N:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[CH3:13].CC(OC)(C)C.N>CN(C=O)C>[OH:12][CH2:11][C:8]1[CH:7]=[C:6]([CH3:13])[C:5]([C:1]#[N:2])=[N:10][CH:9]=1
Reactant: Cc1cc(CO)cnc1Cl
Reactant: N#C[Cu]
Agent: N
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Cc1cc(CO)cnc1C#N
Temperature: 250 °C
Reaction time: 0.58 h
Yield: 62.7 %

Procedure:
CuCN (54.3 mg, 0.607 mmol) was added to a solution of (6-chloro-5-methyl-3-pyridinyl)methanol (47.8 mg, 0.303 mmol) in anhydrous DMF (2 ml) and the mixture was stirred under microwave irradiation at 250° C. for 35 min. Full conversion was observed by HPLC. TBME and 28% NH3 were added. Extraction, drying (MgSO4), filtration, and removal of the solvent afforded 5-(hydroxymethyl)-3-methyl-2-pyridinecarbonitrile (28.2 mg, 0.190 mmol, 62.8% yield) pure enough to be used in the next step.
Reaction SMILES: [CH:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[S:5][CH:4]=1)=[O:2].[BH4-].[Na+].CC(C)=O>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[S:5][CH:4]=1
Reactant: COC(=O)c1cccc2c(C=O)csc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCO
Product: COC(=O)c1cccc2c(CO)csc12
Reaction time: 1 h
Yield: 96.1 %

Procedure:
1.00 g of methyl 3-formyl-1-benzothiophene-7-carboxylate was dissolved in a mixed solution of 15 mL of ethanol and 15 mL of tetrahydrofuran, to which 86 mg of sodium borohydride was added at room temperature, and this solution was stirred for one hour at the same temperature. After acetone was added dropwise to the reaction mixture, from which the solvent was distilled out under reduced pressure, followed by addition of ethyl acetate and water, and this mixture was adjusted to pH 6 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.97 g of methyl 3-(hydroxymethyl)-1-benzothiophene-7-carboxylate as light yellow solid.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine (8.3 mg, 0.015 mmol) (Example 20) and methanesulfonyl chloride (10.5 μL, 0.135 mmol) in CH2Cl2 (500 μL) was added N,N-diisopropylethylamine (47.4 μL, 0.273 mmol). The reaction was stirred at room temperature for twenty minutes and then was poured into H2O (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 50% CH2Cl2/hexanes afforded N-[3,5-bis(trifluoromethyl)benzyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}methanesulfonamide. Rf=0.20 (50% CH2Cl2/hexanes). LCMS=628.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.69 (s, 1H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.47 (s, 2H), 7.28-7.30 (m, 2H), 6.94 (d, J=9.0 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 4.44 (d, J=15.0, 1H), 4.32 (d, J=15.0 Hz, 1H), 4.19 (d, J=15.6 Hz, 1H), 4.14 (d, J=15.6 Hz, 1H), 3.72 (s, 3H), 2.89 (m, 1H), 2.69 (s, 3H), 1.21-1.25 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCc1ccc2ccccc2c1
Solvent: CC#N
Product: OCCc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of 2-(2-hydroxy-ethyl)-naphthalene (58.5 g, 0.34 mol) in anhydrous acetonitrile (500 mL) was treated with N-bromo-succinimide (66.5 g, 0.37 mol). The resulting solution was stirred at room temperature under a nitrogen atmosphere and protected from light for 30 minutes, then heated in an oil bath at 50° C. for 2 hours. After cooling to room temperature, the reaction mixture was evaporated under vacuum to a viscous oil. The oil in diethyl ether (350 mL) was washed with water (350 mL), dilute aqueous sodium thiosulfate (300 mL), water (300 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to an oil (89.5 g) that solidified on standing. The crude product was chromatographed on a column of EM silica gel 60, eluting with methylene chloride, to afford a yellow solid (78.2 g). Recrystallization of this material from carbon tetrachloride provided the title compound (46.5 g) as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:19][CH2:18][C@@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C@@H:35]([O:43][CH3:44])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=2)[CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C@H:35]([O:43][CH3:44])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=2)[CH:27]=1
Reactant: CO[C@@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@H]3CCN3C(=O)OC(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CO[C@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to 8 mL of CH2Cl2. This mixture was added to 3-[[1-(tert-butoxycarbonyl)-2(R)-azetidinyl]methoxy]-5-[3-(2(S)-methoxy-3-phenylpropyl)phenyl]pyridine (470 mg, 0.96 mmol) at 0° C. under N2. The solution was stirred overnight at room temperature. After concentration in vacuo, the crude product (300 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm; UV detection, at 254 nm; mobile phase: A, water with 0.05% CF3COOH; B, CH3CN; 18-40% B in A in 6 min, 40-100% in 1 min). The product-containing eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3CN. The pH of the residue was adjusted to 8.0 with saturated aqueous NaHCO3 solution, and the product was extracted into EtOAc (3×60 mL). The combined organic phases were washed with brine and dried over Na2SO4. After filtration and concentration, the free amine (175 mg, 47%) was obtained as a colorless oil. LC-MS (ESI) m/z 389 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.C1C=CC=CC=1.C(O)C>N1C=CC=CC=1>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH:30][NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NNc1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1

Procedure:
Add a solution of 1.0 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 50 ml of pyridine dropwise to a solution of 0.31 ml of phenyl hydrazine in 5 ml of pyridine and stir the resulting reaction mixture at room temperature for 4 hours. Pour the thus-produced solution onto ice and water and chromatograph on silica gel with benzene/ethanol (9:1) to obtain 3-(5-nitro-2-furyl)-1,N'-diphenylpyrazole-4-carbohydrazide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.[C:31]([N:50]1[CH:54]=[C:53]([CH:55]=O)[CH:52]=[N:51]1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1CCCC1>CO>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[C:7]2=[CH:55][C:53]1[CH:52]=[N:51][N:50]([C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:54]=1
Reactant: O=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2
Solvent: CO
Solvent: C1CCNC1
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 70 °C
Yield: 62.1 %

Procedure:
To a suspension of 4-(7-methyl-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzonitrile (300 mg, 0.773 mmol) and 1-trityl-1H-pyrazole-4-carbaldehyde (303 mg, 0.928 mmol) in methanol (5 ml) was added pyrrolidine (0.323 ml, 3.87 mmol). The reaction mixture was heated at 70° C. overnight. After cooled to room temperature, the reaction mixture formed a precipitate. The solid was collected and washed with cold methanol to give the title compound of 13B as a bright yellow solid (340 mg, 63.2% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([C:18]1([S:24]([N:27]2[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([C:18]1([S:24]([N:27]2[CH2:28][CH2:29][CH:30]([CH2:33][CH2:34][CH:35]=[O:36])[CH2:31][CH2:32]2)(=[O:26])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(CCCO)CC2)CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(CCC=O)CC2)CCOCC1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
A 50 mL round-bottom flask was charged with oxalyl chloride (0.4 mL, 3.82 mmol) and methylene chloride (9 mL). The flask was then immersed into a dry ice/acetone bath. Afterward, dimethylsulfoxide (0.54 mL, 7.7 mmol) was added dropwise, maintaining the temperature at less than −65° C. After complete addition, the mixture was stirred for 15 min. A solution of the alcohol from Example A7 (1.50 g, 3.82 mmol) in methylene chloride (9 mL) was then added dropwise while maintaining the temperature at less than-65° C. The resulting mixture was stirred for 45 min after complete addition. Diisopropylethylamine (3.3 mL, 19 mmol) was then added dropwise. Subsequently, the mixture was stirred for 30 min with cooling. The dry ice/acetone bath was then removed. After 1 hr, the reaction mixture was diluted with methylene chloride (50 mL) and extracted with water (50 mL). The aqueous layer was re-extracted with methylene chloride (25 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography using a gradient of 10–30% ethyl acetate/hexane afforded a white crystalline solid (1.24 g, 83% yield). 1H NMR (CDCl3) δ 1.20–1.42 (m, 5H), 1.51 (s, 9H), 1.53–1.59 (m, 2H), 1.68 (d, J=11.2 Hz, 2H), 2.10 (td, J=4.5, 12.8 Hz, 2H), 2.31 (d, J=11.2 Hz, 2H), 2.92 (t, J=12.6 Hz, 2H), 3.30 (t, J=12.4 Hz, 2H), 3.62 (t, J=6.6 Hz, 2H), 3.76 (d, J=12 Hz), 3.95 (dd, J=4, 11.6 Hz, 2H); Electrospray mass spectrometry showed m/z=390 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1COCC1.ClCCl>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:12][C:10]2[S:11][C:7]3[C:6]([CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reaction time: 60 h
Yield: 70.7 %

Procedure:
To a stirred solution of 250 mg (0.95 mmol) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and 0.95 ml (5.53 mmol) N-ethyldiisopropylamine in 10 ml THF at room temperature was added dropwise a solution of 216 mg (1.14 mmol) 4-(chloromethyl)benzoyl chloride in 3 ml dichloromethane and stirring continued at room temperature for 60 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 280 mg (71%) 4-chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 441 (M{37Cl}+Na+, 7), 439 (M{35Cl}+Na+, 21). 419 (M{37Cl}+H+, 41), 417 (M{35Cl}+H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)[N:2]=1.C(N(CC)CC)C.ClC(OCC)=O.O.[NH2:31][NH2:32]>C1COCC1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([NH:31][NH2:32])=[O:16])[CH2:10][CH2:9]2)[N:2]=1
Reactant: O=C(O)[C@H]1CC[C@H](Oc2cccnn2)CC1
Reactant: NN
Agent: CCOC(=O)Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: NNC(=O)[C@H]1CC[C@H](Oc2cccnn2)CC1
Reaction time: 1 h

Procedure:
To a solution of cis/trans-4-(pyridazin-3-yloxy)-cyclohexanecarboxylic acid (1:1) (0.780 g, 3.51 mmol) and triethylamine (0.489 ml, 3.37 mmol) in THF (17 ml) was added ethyl chloroformate (0.334 ml, 3.51 mmol) at 0° C. The reaction mixture was stirred for 1 h. The ammonium salts were removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.351 g, 7.02 mmol) in methanol (20 ml). The reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and a 1:1 mixture of 1 M aqueous sodium hydroxide solution and brine (30 ml). The organic layer was separated. The aqueous layer was extracted with five 75-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.580 g, 70%) as off-white solid, which was used in the next step without further purification. MS m/e: 237 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4](Br)Br.[Cl-].[Na+].C([OH:17])C>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[O:17]
Reactant: CCO
Reactant: N#Cc1cccc(C(Br)Br)c1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: N#Cc1cccc(C=O)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The crude product of the compound from Example II is dissolved in 1.5 l of 95% ethanol and warmed to 60° C. A solution of 186 g (1.1 mol) of silver nitrate in 380 ml of water which has been mixed with 750 ml of ethanol is rapidly added dropwise thereto at this temperature. After addition is complete, the mixture is subsequently stirred for one hour and then mixed with 50 ml of saturated sodium chloride solution. After cooling, the silver salts are filtered off and the filtrate is concentrated. The residue is taken up in methylene chloride and purified by filtration through a short silica gel column (eluent: dichloromethane). After concentrating the product fractions, 88 g (81%) of the title compound are obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([OH:35])[CH:34]=1.[F-].[Cs+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[N:3]=[C:2]([C:31]3[CH:32]=[C:33]([OH:35])[CH:34]=[C:29]([F:28])[CH:30]=3)[C:10]=12
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A mixture of 3-iodo-1-((1-phenyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 141 (1.0 g, 2.14 mmol), 3-fluoro-5-hydroxyphenylboronic acid (0.4 g, 2.56 mmol), Pd(dppf)Cl2 (0.2 g) and CsF (0.65 g, 4.3 mmol) in DME (20 mL) and H2O (2 mL) was refluxed overnight. Then the mixture was cooled to room temperature, added H2O (50 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and then concentrated in vacuo. The residue was treated with CH2Cl2 and filtered to give 153 (300 mg, yield 31%) as a grey solid. LCMS (ESI), M+H+=450.16. 1HNMR (400 MHz, DMSO) δ 5.795 (s, 2H), 6.606-6.633 (d, J=10.8 Hz, 1H), 6.720-6.724 (d, J=8.8 Hz, 1H), 6.800 (s, 2H), 7.065-7.083 (d, J=7.2 Hz, 1H), 7.213-7.260 (m, 2H), 7.400 (s, 5H), 7.657-7.676 (d, J=7.6 Hz, 1H), 8.119 (s, 1H), 10.139 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5](O)=[O:6].CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1>CN(C)C(=O)C.O1CCCC1>[CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5]([NH:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1)=[O:6]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CC1(C)CC1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5(C)C)cn4n3)ccc2F)n(C)n1
Yield: 16.1 %

Procedure:
Using 2,2-dimethylcyclopropanecarboxylic acid (82 mg, 0.72 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (63 μL, 0.72 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 239, the title compound (37 mg, 16%) was obtained as a white powder.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.N1CCCC1.CC(O)=O>CO>[CH2:4]1[CH2:5][CH2:6][C:1](=[C:11]2[CH:10]=[CH:9][CH:8]=[CH:12]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: C1=CCC=C1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: C1=CC(=C2CCCCC2)C=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
7 g of cyclohexanone (71 mmol) and 14.35 ml of cyclopentadiene(175 mmol) were charged in a 300 ml reaction bottle. 70 ml of CH3OH was added as a solvent. Then, 8.75 ml of pyrrolidine (105 mmol) was added gradually and the mixture was stirred at room temperature for 30 minutes. Next, 6.3 ml of CH3COOH (105 mmol) was added gradually and stirred for 10 minutes. 200 ml of H2O and 200 ml of pentane were used for extraction. The upper pentane portion was collected. The lower water portion was further extracted with pentane three times. The collected pentane portion was dehydrated with MgSO4, held still for 30 minutes, filtered, and concentrated under reduced pressure to afford a yellow liquid product (8.7 g, yield=83.3%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:43](=[O:44])[N:14]2[C:15]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:16]([CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH3:26])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:43](=[O:44])[N:14]2[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH3:26])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncsc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncsc1C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Benzhydryl 7-(phenoxyacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylate (0.725 g) was dissolved in anisole (2 ml), to which trifluoroacetic acid (7 ml) was added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was concentrated under reduced pressure to give a syrup, whcih was then solidified by addition of isopropyl ether thereto. The solid obtained was pulverized and was mixed with isopropyl ether for the washing purpose, and the mixture was filtered to recover the solid which was then dried under reduced presssure. 7-(Phenoxyacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (0.512 g) was thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Li]C(C)(C)C.Br[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Ni]([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>[CH3:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Ni]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Product: Cc1cccc(-c2ccccc2C#N)c1
Yield: 46.7 %

Procedure:
3-Bromotoluene (17.5 mmoles, 3.0 g) was reacted with t-BuLi (19.3 moles) and ZnCl2 (19.3 mmoles, 2.62 g) followed by a Ni(PPh3)4 coupling to 2-bromobenzonitrile (17.5 mmole, 3.2 g) as in Preparation 1. The intermediate was purified by chromatography over silica gel eluted with 20% ether in hexane to yield 1.58 g of 2-(3-methylphenyl)-benzonitrile (MS)