Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13]>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:12]#[N:13])[CH:19]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: CS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1

Procedure:
By a method similar to that in Example 81 and using 1-bromo-4-(methylsulfonyl)benzene and (3-cyanophenyl)boronic acid, the title compound was obtained as a pale-yellow powder (10.4 g, 95%).
Reaction SMILES: [CH2:1]([C:3]([CH2:16]C)([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11](Br)=[CH:10][C:8]=2[N:9]=1)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C(N(CC)C(C)C)(C)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:3]([CH3:1])([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][C:8]=2[N:9]=1
Reactant: CCC(C)(CC)Cc1nc2cc(Br)ccc2o1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1ccc2oc(CC(C)(C)C)nc2c1
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of 2-(2,2-diethylpropyl)-5-bromobenzoxazole (0.60 g, 0.00225 mol), ethyl acrylate (1.08 g, 0.0108 mol), palladium acetate (0.051 g, 0.00023 mol), trintolylphosphine (0.135 g,0.0045 mol) and N,N-diisopropylethylamine (0.585 g, 0.0045 mol) was heated at 100° C. for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 3:97, to give ethyl 3-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propenoate (0.634 g).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[C:12]([O:21]C)[CH:11]=[CH:10]4)[CH:7]=[CH:6][C:5]=2[CH:4]=1.C(Cl)Cl.B(Br)(Br)Br>O>[CH:4]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17](=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([OH:21])=[CH:13]4)[C:18]=2[CH:19]=[CH:20][C:3]=1[OH:2]
Reactant: COc1ccc2c(ccc3c4ccc(OC)cc4ccc23)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(ccc3c4ccc(O)cc4ccc23)c1
Temperature: -60 °C
Reaction time: 18 h

Procedure:
Under an argon gas flow, 24 g (0.083 mol) of 2,8-dimethoxychrysene and 2 L of methylene chloride were charged into a 3 L glass flask equipped with a condenser, and cooled to −60° C. Successively, 4.1 g (0.17 mol) of boron tribromide was slowly dropped into the flask, and then the contents of the flask were stirred at room temperature for 18 h. After completion of the reaction, 1 L of water was added to the flask to separate an organic layer from the reaction solution. The resultant crude crystal was short-passed through silica gel (using THF (tetrahydrofuran) as a developing solvent). The obtained product was concentrated under reduced pressure, and the resultant crude product (25 g) was directly used in the subsequent reaction.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[C:3]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:2]=1.[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:22]([N:21]([CH3:20])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:10]([OH:19])([C:11]([F:13])([F:14])[F:12])[C:15]([F:16])([F:18])[F:17])=[CH:2][CH:1]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CNCCc1ccccc1
Solvent: C1CCOC1
Product: CN(CCc1ccccc1)C(=O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
CDl (194.4 mg, 1.2 mmol) is added to the solution of 4-(2-hydroxyhexafluoroisopropyl) benzoic acid (288 mg, 1 mmol) in THF (10 mL) at room temperature. The reaction mixture is stirred for 10 minutes and N-methylphenethylamine (0.174 mL, 1.2 mmol) is introduced. The reaction mixture is then stirred for 14 hours. The solvent is removed and the residue is dissolved in EtOAc. The organic phase is washed with 1N HCl, saturated NaHCO3 and brine and dried over MgSO4. The product is obtained in pure form after removal of solvents (278.8 mg). 1H NMR (CD3OD, every peak appears as a pair) δ2.76 (t, 2H), 3.12 (s, 3H), 3.44 (t, 2H), 7.01 (d, 2H), 7.20 (d, 2H), 7.30 (m, 3H), 7.62 (d, 2H); ESIMS: m/z 406 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[C:15]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:14][CH:13]=[N:12]2)=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:11]2[C:15]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[C:14]([N+:28]([O-:30])=[O:29])[CH:13]=[N:12]2)=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)Nc1ccnn1-c1nn2c(c1Cl)CCCC2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
8.72 g (29.7 mmol) N-[1-(3-Chloro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)-5-pyrazolyl]propionamide was suspended in 33 ml acetic acid. Under ice cooling, at 0°-5° C., 3.31 g (32.5 mmol) acetic anhydride was added. 1.93 g (31 mmol) Fuming nitric acid was added dropwise. After stirring for 6 hours at room temperature, the mixture was concentrated. The residue was taken up in dichloromethane, neutralised with aqueous sodium hydrogen carbonate and washed with aqueous sodium chloride. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][CH2:19][C:20]([N:8]2[CH2:9][CH2:10][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C2CCN2)cc1
Reactant: O=C(Cl)CCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
A solution of 2-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 4-phenyl-1-(2-phenylazetidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 488 mg of colorless oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[N:40](COCC[Si](C)(C)C)[C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[NH:40][C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cn4)cc3)cc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cn4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-[4-(5-Cyclohexyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (16 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{-4-[2-[4-(5-cyclohexyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][NH:15][CH3:16].C1COCC1.CCN(CC)CC>>[CH3:14][N:15]([CH3:16])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1)=[O:13]
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Yield: 84 %

Procedure:
was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (0.57 g, 2.67 mmol) with 2.0 M N,N-dimethylamine in THF (1.60 mL, 3.20 mmol) and Et3N (0.447 mL, 3.20 mmol) in a manner as described in Method A to give the desired amide as brown solid (0.54 g, 84%). 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H, J=4.85 Hz), 7.74 (s, 1H), 7.35 (d, 1H, J=5.02 Hz), 3.28 (s, 3H), 3.22 (s, 3H); ESIMS (MH+): 240.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1.[CH3:36][NH:37][CH3:38].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([N:37]([CH3:38])[CH3:36])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)O)c3)cc12
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (100 mg, 0.19 mmol), dimethylamine (2 N solution in THF, 0.19 mL, 0.38 mmol), diisopropylethylamine (49 mg, 0.38 mmol) in THF was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluromiumhexafluorophosphate (110 mg, 0.29 mmol). The resulting suspension was heated to 60° C. with stirring till the O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluromiumhexafluorophosphate completely dissolved. The THF was evaporated and the residue was used in the next step reaction without further purification. MS: m/z 517 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][OH:4].[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17]>>[CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][O:4][C:16](=[O:17])[C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:20]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)CC(C)CC(C)CC(C)CO
Product: CC(C)CC(C)CC(C)CC(C)COC(=O)c1ccccc1N
Temperature: 120 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A one liter, four necked, round bottom flask, equipped with an overhead stirrer, sub-surface gas inlet tube, thermowell, Dean-Stark trap, and Friedrick's condenser, is charged with 313.4 grams (1.56 moles) of 2,4,6,8-tetramethyl-nonan-1-ol. The flask is purged with nitrogen and warmed to 120 degrees C. 3.7 grams (46 mmoles) of a 50 percent by weight solution of NaOH in water is added drop-wise over 1 minute. The mixture is stirred at 120 degrees C. for 1 hour and water is collected in the Dean-Stark trap. 250 grams of isatoic anhydride (1.53 moles) is added portion-wise, supra-surface, over a period of 50 minutes. The mixture is stirred at 145 degrees C. for 6 hours. 9 grams of Fax-5 filter aid is added to the flask and stirred. The mixture is filtered and cooled to yield 456 grams of the product, in the form of a brown liquid. The product has a TBN, by ASTM D2896, of 150.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[C:12]4[S:19][CH:18]=[N:17][C:13]4=[CH:14][CH:15]=3)[C:10]3([C:31]4[C:22](=[CH:23][C:24]5[O:29][CH2:28][CH2:27][O:26][C:25]=5[CH:30]=4)[O:21][CH2:20]3)[C:9]2=[O:32])=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[S:19]1[C:12]2=[C:11]3[C:16](=[CH:15][CH:14]=[C:13]2[N:17]=[CH:18]1)[NH:8][C:9](=[O:32])[C:10]13[C:31]2[C:22](=[CH:23][C:24]3[O:29][CH2:28][CH2:27][O:26][C:25]=3[CH:30]=2)[O:21][CH2:20]1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3c2ccc2ncsc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a solution of 6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one (1.9 g, 4.0 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (40 mL) was added at ambient temperature trifluoromethanesulfonic acid (1.8 mL, 20 mmol). The mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography and eluted with 50% ethyl acetate in hexanes to afford 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one (0.65 g, 44%): 1H NMR (300 MHz, CDCl3) δ10.86 (s, 1H), 9.06 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 6.21 (s, 1H), 4.68 (s, 2H), 4.19-4.01 (m, 4H); MS (ES+) m/z 353.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12](=[S:15])[NH:13][N:14]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:14][N:13]=[C:12]([S:15][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[N:11]=1
Reactant: COc1cc(C)ccc1-c1n[nH]c(=S)[nH]1
Reactant: Cc1ccc(CCl)nc1
Product: COc1cc(C)ccc1-c1nc(SCc2ccc(C)cn2)n[nH]1
Yield: 14 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 1a) and 2-(chloromethyl)-5-methylpyridine (example 2a). Yield 14%. 1H NMR (500 MHz, CDCl3): δ2.29 (s, 3H), 2.41 (s, 3H), 4.00 (s, 3H), 4.51 (s, 2H), 6.75 (s, 1H), 6.90 (s, 1H), 7.40 (s, 1H), 8.1 (d, 1H), 8.4 (s, 1H), 11.5-11.7 (bs, 1H). MS(M+H, 327.1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH2:4][CH:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(Br)cc1F
Yield: 95.7 %

Procedure:
Using 1.02 g of 2-fluoro-4-bromobenzaldehyde, 0.33 g of malononitrile, 8 ml of ethanol, 1.5 ml of water and 57 mg of sodium borohydride, and according to the process described in the REFERENCE PRODUCTION EXAMPLE 19, there was obtained 1.21 g of (2-fluoro-4-bromobenzyl)malononitrile (the intermediate (29)).
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]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([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]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>>[CH:1](=[CH:10][C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=CC=Cc1ccccc1
Product: O=C(Cl)C=CC=Cc1ccccc1
Temperature: 45 °C

Procedure:
Cinnamylidene acetyl chloride was prepared by stirring approximately 17.15 gms of cinnamylidene acetic acid with 30 ml thionyl chloride in 300 ml of petroleum ether for 12 hours at room temperature. The reaction mixture was then refluxed for 4 hours in an oil bath at a temperature of approximately 40 to 50° C. The excess thionyl chloride and the petroleum ether were removed under reduced pressure. 1HNMR: 3=6.2 ppm (d, 2H), δ=6.9 ppm (q, 2H), δ=7.5 ppm (m, 5H). UV (in dichloromethane): λmax=333 nm, λmin=256 nm.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCCC(F)(F)C2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C2CC2)c(OCC2CCCC(F)(F)C2)cc1F
Reaction time: 3 h

Procedure:
A solution of tert-butyl 5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoate (191 mg) in dichloromethane (1.0 mL) and trifluoroacetic acid (0.5 mL) was stirred at 0° C. for 30 min then at rt for 3 h. The contents were concentrated. The residue was suspended in toluene and concentrated. The beige solid was dried under vacuum (162 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[Na].[C:16]1([PH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[P:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: BrCCCCCCCCCCCCBr
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Na]
Product: c1ccc(P(CCCCCCCCCCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
In a like manner to Examples 3 and 4, one-half molar equivalent of 1,12-dibromododecane is reacted with one molar equivalent of the sodium salt of diphenylphosphine to produce (C6H5)2P(CH2)12P(C6H5)2, a waxy colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:14][Mg+].[Br-]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:13])[CH3:14])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=Cc1cc(Cl)cc2c1OCCO2
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1cc(Cl)cc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7-Chloro-2,3-dihydrobenzo[b][1,4]dioxine-5-carbaldehyde (0.26 g, 1.32 mmol) was dissolved in 10 mL of diethyl ether and cooled to 0° C. MeMgBr (1.1 mL, 3.31 mmol) was added to the solution and the ice bath was removed. The reaction was allowed to stir at rt for 10 min. and at reflux for 30 min. The reaction was cooled to 0° C. and 10 mL of sat NH4Cl were added to quench the reaction. The diethyl ether layer was separated and washed with water (20 mL×2). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to collect the desired product (258 mg, 91%). 1H NMR (400 MHz, CDCl3): δ 6.91 (s, 1H), 6.77 (s, 1H), 5.02 (m, 1H), 4.24 (m, 4H), 1.45 (d, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([Cl:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][C:3]2[C:12]3[C:7](=[C:8]([Cl:13])[CH:9]=[CH:10][CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[CH:19][CH:18]=1
Reactant: Clc1cccc2c(CBr)ccnc12
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(OCc2ccnc3c(Cl)cccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
4-Bromomethyl-8-chloroquinoline (0.8 g, 3.11 mmol) was dissolved with stirring in dry THF (10 mls) and sodium hydride (0.15 g, 60% dispersion in mineral oil, 6.23 mmol) added. The mixture was stirred at room temperature for 15 minutes and 4-fluorophenol (0.52 g, 3.11 mmol) added. The mixture was stirred at room temperature overnight and worked up to provide the product (0.46 g, 51.2%) as a white solid, mp 144-5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=O)(C)(C)C>>[N:1]1([C:20]([C:19]2[CH:23]=[CH:24][C:16]([CH2:15][NH2:14])=[CH:17][CH:18]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: C1CCNCC1
Product: NCc1ccc(C(=O)N2CCCCC2)cc1
Yield: 100 %

Procedure:
Use the General Procedure 6-1, using piperidine (373 mg, 4.4 mmol) and 4-(tert-butoxycarbonylamino-methyl)-benzoic acid to give the title compound as a white solid (1.03 g, 100%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:12]Br>O>[Br:12][CH2:10][C:9](=[O:11])[CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)C(CC)C(C)=O
Solvent: O
Product: CCOC(=O)C(CC)C(=O)CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-ethyl-3-oxobutanoate (5.17 g, 32.7 mmol) in water (10 mL) at 0° C. was added bromine (1.684 mL, 32.7 mmol) dropwise over 2 h. The resulting solution was stirred at rt for 16 h. The mixture was extracted with ethyl acetate (100 mL) and the organic phase was dried over sodium sulfate and concentrated to give ethyl 4-bromo-2-ethyl-3-oxobutanoate. 1HNMR (500 MHz, CDCl3), δ4.327-4.284(m, 2H), 2.412(s, 2H), 2.320-2.212 (q, 2H), 1.338-10309 (m, 3H), 1.042-1.013 (t, J=7.3 Hz, 3H).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1>>[O:32]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([C:3]([C:4]2[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[CH:8][CH:9]=2)=[O:25])[CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: O=S1(=O)CCNCC1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 100 %

Procedure:
As described for example 95, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) was converted, using thiomorpholine-S,S-dioxide instead of thiomorpholine, to the title compound (133 mg, 100%) which was obtained as a white foam. MS: m/e=446.0 [M+H]+.