Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1)=O.[CH3:19][O:20][C:21]1[CH2:25][NH:24][C:23](=[O:26])[CH:22]=1>CS(C)=O>[CH3:19][O:20][C:21]1[C:25](=[CH:1][C:3]2[NH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=2)[NH:24][C:23](=[O:26])[CH:22]=1
Reactant: CCCCCCCCCCCc1ccc(C=O)[nH]1
Reactant: COC1=CC(=O)NC1
Solvent: CS(C)=O
Product: CCCCCCCCCCCc1ccc(C=C2NC(=O)C=C2OC)[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-formyl-5-undecylpyrrole (4 g; 16.03 mmols) and 4-methoxy-3-pyrrolin-2-one (3.63 g; 32.06 mmols) in DMSO (53 ml) 2N sodium hydroxyde (45 ml) is added under nitrogen atmosphere and the mixture is stirred at 60° C. for 8 hours. After dilution with water (200 ml) the yellow suspension is extracted with dichloromethane (600 ml). The organic phase is shaken with water and brine, anhydrified over anhydrous sodium sulphate and evaporated to dryness. The crude material is taken up in hexane and filtered to give 4-methoxy-5-(5-undecyl-1H-pyrrol-2-yl-methylene)-1,5-dihydro-pyrrol-2-one (4.86 g; 14.11 mmols) as a yellow crystalline solid. Yield: 88%.
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=1>[Pd].C1COCC1>[NH:15]1[C:16]2[C:12](=[C:11]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(-c2cccc3[nH]ccc23)cn1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 83.7 %

Procedure:
Palladium catalyst Pd(PPh3)4 (142 mg, 0.12 mmol) and freshly prepared aqueous sodium hydroxide (493 mg, 12.33 mmol in 6 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (1 g, 4.11 mmol) and 2-amino-5-bromopyridine (853 mg, 4.93 mmol) in THF (20 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 80° C. in an oil bath for 4.5 hours. It was then cooled to room temperature and ethyl acetate (300 mL) was added. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give 720 mg (84%) of 5-(1H-indol-4-yl)-pyridin-2-ylamine as a thick brown syrup.
Reaction SMILES: [CH:1]([N:4]([CH:9]([CH3:11])[CH3:10])[CH:5]([CH3:8])[C:6]#N)([CH3:3])[CH3:2].[CH2:12]([Mg]Br)C.O>C(OCC)C>[CH:1]([N:4]([CH:5]([CH2:6][CH3:12])[CH3:8])[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2]
Reactant: CC[Mg]Br
Reactant: CC(C)N(C(C)C)C(C)C#N
Solvent: O
Solvent: CCOCC
Product: CCC(C)N(C(C)C)C(C)C

Procedure:
A solution of 2-(diisopropylamino)propionitrile (25.00 g, 0.162 mol) in diethyl ether (20 ml) was added dropwise to a 1M solution of ethyl magnesium bromide in diethyl ether (32.4 ml, 0.324 mol) and the mixture was refluxed for 30 min. Water (25 ml) was added and white precipitate was filtered off and washed with diethyl ether (2×100 ml). The ether solutions were combined, dried over anhydrous magnesium sulfate and the product was isolated by distillation: 13.80 g, 51%, bp 60°-62° C./20 mm Hg. 1H NMR CDCl3 δ ppm, 0.85 (t, J=6.5 Hz, 3H, CH3) , 0.98 (d, J=6.5 Hz, 6H, CH3) 0.99 (d, J=6.5 Hz, 3H, CH3), 1.05 (d, J=6.5 Hz, 6H, CH3) , 1.17-1.44(m, 2H, CH2), 2.70 (m, 1H, CH), 3.08 (sep, J=6.5 Hz, 2H, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[N:11]=[C:10](SC)[C:9]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[N:11]=[C:10]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)[C:9]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CSc1nc2nc(Nc3ccc(Oc4ccncc4)cc3)nn2c(-c2cccc(Cl)c2)c1C#N
Solvent: CCOC(C)=O
Product: CN1CCN(c2nc3nc(Nc4ccc(Oc5ccncc5)cc4)nn3c(-c3cccc(Cl)c3)c2C#N)CC1

Procedure:
7-(3-Chlorophenyl)-5-methylsulfanyl-2-[4-(pyridin-4-yloxy)phenylamino]-1,2,4-triazolo[1,5-a]pyrimidine-6-carbonitrile (50 mg, 0.10 mol) is heated at 100° C. for 18 h in 1-methylpiperazine (1 ml) in a closed vessel. Ethyl acetate (5 ml) is added to the cooled solution, and the precipitate which forms is filtered off, washed with diethyl ether and dried, giving 32 mg (0.06 mmol, 55%) of “136”, [M+H]+ 539.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]1([N:19]=[CH:20]OCC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[C:13]1([NH:19][CH:20]=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][NH:11][CH:12]=3)=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC=Nc1ccccc1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Solvent: CC(C)=O
Product: C(=Nc1ccc(-c2c[nH]cn2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Five grams of 4-(4-aminophenyl)-1-H-imidazole were added to a solution of 4.6 gm of ethyl N-phenyl-formimidate [Org. Synth., 35, 65 (1965)] in 25 ml of acetone. After stirring for four hours at room temperature, the solid that separated was filtered and dried under vacuum. The product was treated with acetone and acidified with glacial acetic acid. N-Phenyl-N'-[4-(imidazol-4-yl]-formamidine crystallized as acetate salt which was filtered to give 4.6 gm of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (10.0 g, 53 mmol), 3,4-dihydro-2H-pyran (9.5 mL, 93 mmol) and p-toluenesulfonic acid monohydrate (1.0 g, 5.0 mmol) in THF (100 mL) was heated at 100° C. for 18 h, then cooled to RT and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 10% ethyl acetate in cyclohexane) affording 2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine as a cream solid (10.9 g, 75%). 1H NMR (400 MHz, CDCl3): δ 8.33 (1H, s), 5.77 (1H, dd, J=10.4, 2.4 Hz), 4.19 (1H, m), 3.78 (1H, dt, J=11.6, 2.9 Hz), 2.17 (1H, m), 2.09 (1H, m), 1.98 (1H, m), 1.87-1.69 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC(C)([O-])C.[K+].Br[CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[CH:21]([O:20][C:18](=[O:19])[CH2:17][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)([CH3:23])[CH3:22]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.4 %

Procedure:
A solution of 3-hydroxybenzaldehyde (6.75 g, 55.2 mmol) in DMF (55 mL) was stirred at room temperature under a nitrogen atmosphere as potassium tert-butoxide (6.2 g, 55.3 mmol) was added in portions. The resulting suspension was stirred an additional 15 minutes at room temperature before isopropyl bromoacetate (7.10 mL, 55.2 mmol) was added. The reaction was stirred at room temperature for 15 h and was then quenched with water (250 mL). The resulting aqueous solution was extracted with ethyl acetate, and the combined organic layers were washed several times with water, dried over MgSO4, filtered, and concentrated in vacuo. Purification via medium pressure liquid chromatography (0-10% hexane/ethyl acetate) afforded the title compound (5.2 g, 65%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, 6H) 5.04-5.32 (m, 1H) 7.21-7.28 (m, 1H) 7.38 (s, 1H) 7.44-7.60 (m, 2H) 9.98 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@@:11]([C:14]([F:16])([F:15])[F:17])([OH:18])[CH:12]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC

Procedure:
In the same way as in Example 148, 300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 172 mg (0.97 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.55 ml of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 450 mg of crude imine are cyclized in the same way as in Example 148 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 56 mg of desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>C(#N)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 25 g quantity of 1-(2-hydroxyphenyl)ethanone and 76 g of potassium carbonate were suspended in 500 ml of acetonitrile, and 31 ml of allyl bromide was added. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 34 g of pale yellow oily 1-(2-allyloxyphenyl)ethanone.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>N1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][S:28]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC

Procedure:
5.6 g of 2-amino-2',5-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine overnight at 100° C. The pyridine is evaporated off to dryness, water and ethyl acetate containing a small amount of DCM are added and the mixture is extracted. After washing several times with water and drying over sodium sulfate, the extract is evaporated under vacuum and 7.7 g of the expected product are recrystallized from a DCM/AcOEt mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](Br)[S:7][CH:6]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:16]1[O:17][CH:18]=[CH:19][N:20]=1)CCC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1csc(-c2ncco2)c1
Temperature: 100 °C
Yield: 37.2 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid methyl ester (0.3 g, 1.35 mmol) was dissolved in toluene (5 mL), 2-tributylstannyl oxazole (0.311 mL, 1.48 mmol) was added then the reaction mixture was purged with nitrogen before addition of palladium tetrakis(triphenylphosphine) (0.14 g, 0.12 mmol). The reaction mixture was heated at 100° C. over the weekend. The mixture was filtered then evaporated and the residue was purified by chromatography on a silica II cartridge, eluting with 10-20% DCM in pentane to give the title compound as a yellow solid (0.105 g). LCMS m/z 210 [M+H]+and 251.23 [M+MeCN+H]+ R.T.=3.03 min (Analytical Method 6).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1>[CH:17]1([C:16]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccccc1)(C1C=CC=C1)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 67.8 mmol of lithium-fluorene in 50 cm3 of tetrahydrofuran was added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance which precipitated out was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.2 g (84.2%) of 1-cyclopentadienyl-1-(9-fluorenyl)-ethylbenzene were obtained (correct elemental analyses; 1 H-NMR spectrum). 10.0 g (19.9 mmol) of the compound were dissolved in 60 cm3 of tetrahydrofuran and 26 cm3 (65 mmol) of a 2.5 molar hexane solution of n-butyllithium were added at 0° C. After the mixture had been stirred for 15 minutes, the solvent was stripped off in vacuo. The dark red residue which remained was washed several times with hexane and dried under an oil pump vacuum. 15.6 g of the red dilithium salt were obtained as the tetrahydrofuran adduct which contained about 30% of tetrahydrofuran. A suspension of 4.78 g (14.9 mmol) of HfCl4 in 70 cm3 of CH2CH2 was reacted with 14.9 mmol of the dilithium salt and the reaction product was worked up. Crystallization at -35° C. gave 2.6 g (30%) of the hafnocene dichloride compound as orange crystals. Correct elemental analysis.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: -5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of L-hydroxyproline methyl ester hydrochloride (the compound obtained in Reference Example 1-1); 24.37 g, 134 mmol) and triethylamine (41.2 ml, 295 mmol) in methylene chloride (240 ml) was stirred at room temperature for 10 minutes, cooled to -5° C., treated dropwise with a solution of allyl chloroformate (14.9 ml, 140 mmol) in methylene chloride (30 ml). The reaction mixture was stirred at -5° C. for 1 hour, and washed twice with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford the title compound (30.8 g, 100% yield) as an oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[Cl:11].CC(C[AlH]CC(C)C)C.Cl.[OH2:22]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:22])=[CH:5][C:4]=1[Cl:11]
Reactant: O
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise DIBAl-H (1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11](=[O:12])[C:10](Br)=[C:9]([CH3:14])[N:8]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:16])[CH:7]=1)=[O:5])[CH3:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[CH2:1]([NH:3][C:4]([C:6]1[C:11](=[O:12])[C:10]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)=[C:9]([CH3:14])[N:8]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:16])[CH:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid ethylamide (preparation 10, 50 mg, 0.129 mmol), 3-trifluoromethyl-phenylboronic acid (29 mg, 0.155 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 0.012 mmol) in acetonitrile (1 mL) is added 2 M aqueous K2CO3 solution (0.20 mL, 0.40 mmol). After stirring for 24 h at 75° C., the reaction mixture is diluted with methanol and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 56 mg (96% of theory); ESI mass spectrum: [M+H]+=454; Retention time HPLC: 0.93 min (Z011_S03).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6]([CH3:11])([CH3:12])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC1=CC(C)(C)c2ccc(O)cc2O1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
One hundred grams of 7-hydroxy-2,4,4-trimethyl-4H-1-benzopyran (synthesized by the method of Japanese Laid-Open Patent Publication No. 5475/1981), 79 g of p-chloronitrobenzene, 42 g of potassium hydroxide, 500 ml of N,N-dimethylformamide and 500 ml of toluene were introduced into a flask equipped with the Dean-Stark condenser, and heated at 110° to 116° C. While removing the distilled water as an azeotrope with toluene, the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, and 1 liter of water, 500 ml of ethyl acetate and 120 ml of 2N-HCl were added. The insoluble materials were separated by filtration. The filtrate was subjected to oil-water separation. The oil layer was washed with 500 ml of brine, and dried over magnesium sulfate. The solvent was evaporated. Methanol (650 ml) was added to the residue, and crystals that precipitated were collected, washed with 650 ml of hexane, and dried to give 106 g (yield 67%) of the desired product as a brown powder (melting point 80° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CS(O[CH2:21][CH:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:23])(=O)=O>C1(C)C=CC=CC=1>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([CH2:21][CH:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:23])[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Reactant: CC(COS(C)(=O)=O)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 18.4 %

Procedure:
1.0 g of a 80% mineral oil dispersion of sodium hydride is added in small portions, at room temperature, to a mixture of 6.0 g (30 mmoles) of N-(2,6-dimethylphenyl)-methanesulfonamide and 100 ml of dry toluene, and the resulting mixture is heated to 100° C. within 0.5 hours. 7.0 g (30 mmoles) of 1,2-bis(methanesulfonyloxy)-propane are added to the mixture at 100°-105° C. within one hour, and the reaction mixture is stirred at the same temperature for 5 hours. The mixture is cooled, washed thrice with 20 ml of water, twice with 25 ml of 1 n aqueous sodium hydroxide solution and then thrice with 30 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The resulting oily substance, weighing 5.9 g, is triturated with diethyl ether to obtain 4.4 g (44%) of a crude, solid product, m.p.: 70°-80° C. The crude product is recrystallized twice from isopropanol to obtain 1.85 g (18.5%) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-methanesulfonyloxy-propane, m.p.: 117°-120° C. This compound is identical with the product obtained according to Method (A).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH:27][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[CH:8][C:7]2[N:6]=[C:5]3[NH:21][C:2](=[O:1])[NH:3][C:4]3=[CH:13][C:12]=2[CH:11]=1)[CH3:23]
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1

Procedure:
This compound, m.p. 274°-276° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and glycine ethyl ester.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:7]=1.[CH2:13]([OH:15])[CH3:14]>>[Cl:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11](=[NH:12])[O:15][CH2:13][CH3:14])[CH2:9][CH2:10]2)[CH:7]=1
Reactant: N#CC1(n2cc(Cl)cn2)CC1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dry hydrogen chloride gas was bubbled through a solution of 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (1.2 g, 0.75 mmol) in ethanol (10 mL) at 0° C. for 15 min. The mixture was then stirred at room temperature for 1 h. The solvent was removed under reduced pressure to afford ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate. The crude material was used without further purification.