Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:29].Cl.[CH3:31][NH2:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)C>[ClH:28].[CH3:31][NH:32][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: CN
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CNC(=N)c1cccc(COc2cc(C)cc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in step (a) of Example 6, in methylene chloride (10 mL) was added 37% HCl in ethanol (15 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated and the residue was concentrated in vacuo from methylene chloride several times. The residue was dissolved in ethanol (10 mL), treated with methylamine hydrochloride (270 mg, 4.0 mmol) and Na2CO3 (212 mg, 2.0 mmol), and then stirred at room temperature for 2 days. The reaction mixture was partitioned between methylene chloride (150 mL) and 10% K2CO3. The organic phase was washed with 10% K2CO3 (50 mL) and dried over K2CO3. After removing the solvent in vacuo, HCl in methanol (30 mL) was added and the solvent was removed in vacuo. The residue was then purified by flash column chromatography (10% methanol/methylene chloride) and crystallized from methanol/ethyl acetate to give the title compound as white crystals (145 mg, 30%). 1H-NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3 H), 3.01 (s, 3 H), 5.10 (s, 2 H), 6.53 (s, 1 H), 6.56 (s, 1 H), 6.87 (s, 1 H), 7.58 (t, 1 H, J=7.0 Hz), 7.63 (t, 1 H, J=7.6 Hz), 7.73 (m, 2 H), 7.86 (m, 3 H), 7.94 (d, 1 H, J=4.0 Hz), 9.05 (br S, 1 H), 9.55 (br s, 1 H), and 9.94 (br s, 1 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C22H21N2O4SCl: 445.1 (M+H). Found: 445.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[C:8]#[CH:9])=[O:5].C=O.[CH:20](NC(C)C)(C)C>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[CH:8]=[C:9]=[CH2:20])=[O:5]
Reactant: CC(C)NC(C)C
Reactant: C#CC(C)N(C(=O)COC)c1c(C)csc1C
Agent: C=O
Solvent: C1COCCO1
Product: C=C=CC(C)N(C(=O)COC)c1c(C)csc1C
Temperature: 25 °C

Procedure:
To a solution of 10.0 g (0.04 mol) 2-methoxy-N-(2,4-dimethylthien-3-yl)-N-(1-butin-3-yl)acetamide in 80 ml dioxan are added 1.92 g (0.064 mol) paraformaldehyde, 4.85 g (0.048 mol) diisopropylamine and 1.89 g cuprous bromide and the mixture heated to reflux for 6 hours. The mixture is cooled to room temperature, filtered, evaporated in vacuo, the residue partitioned between ethylacetate and 1 M aqueous citric acid solution, the organic phase separated, washed subsequently with a saturated aqueous NaHCO3 -solution, water, is dried over MgSO4 and the solvent evaporated in vacuo.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]([F:18])([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1)[CH:6]([F:8])[F:7].CCOCC>O>[F:4][C:5]([F:18])([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:1]#[N:2])=[CH:12][CH:11]=1)[CH:6]([F:8])[F:7]
Reactant: [C-]#N
Reactant: FC(F)C(F)(F)Oc1ccc(CBr)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: N#CCc1ccc(OC(F)(F)C(F)F)cc1
Reaction time: 0.67 h
Yield: 87.9 %

Procedure:
Over a period of 40 minutes, a hot solution of 75.1 g (1.15 mol) of potassium cyanide in 140 ml of water is added to a mechanically stirred 75° C. solution of 160.99 g (0.561 mol) of p-(1,1,2,2-tetrafluoroethoxy)benzyl bromide and 500 ml of anhydrous 2B alcohol. The resulting mixture is refluxed for 1.75 hours. After sitting overnight the reaction mixture is poured into 500 ml of cold water and 400 ml of ether. The combined ether solutions are washed twice with 500 ml of water, dried with sodium sulfate, filtered, and then evaporated on a rotary evaporator to give 114.95 g of an oil. A vacuum distillation of this oil gives, as one distillation fraction, 37.10 g (28%) of the nitrile, boiling point 85° C. to 100° C. at 0.29 mm Hg.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=1[CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(N)c(C)c1
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccc(OC)cc1C
Yield: 76.1 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (4.95 g, 20 mmol), 4-methoxy-2-methylaniline (5.15 ml, 40 mmol) and 1,4-dioxan (20 ml) were heated at reflux for 1 hour, the solvent evaporated, the residue taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(4-methoxy-2-methylphenylamino)-8-methylquinoline (5.30 g), m.p. 114°-115°.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].Cl.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH:2]([C:4]3[CH:9]=[CH:8][C:7]([C:10]4([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]4)=[CH:6][CH:5]=3)[CH3:3])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CC(=O)NC1(c2ccc(C(C)Cl)cc2)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CC(=O)NC1(c2ccc(C(C)N3CCN(c4ccc(F)cc4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=149-150° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C.O.C(OCC)(=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-trifluoromethylphenol (1.62 g) in anhydrous acetonitrile was treated with cesium carbonate (3.25 g) and ethyl bromoacetate (1.75 g) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with water and ethyl acetate and the organic layer washed with water and dried with brine and over sodium sulfate. Evaporation of ethyl acetate gave the title compound as a colourless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[S:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC=CC=1.O.CCOCC.C(O)C>[CH3:2][C:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[S:12])=[CH:6][CH:5]=2)[O:16][CH2:15][CH2:14][O:3]1
Reactant: CC(=O)c1ccc(CC(O)=S)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC1(c2ccc(CC(O)=S)cc2)OCCO1
Reaction time: 1 h
Yield: 54.6 %

Procedure:
A solution of 4-acetylphenylthioacetic acid (8.4 g, 40 mmol) (obtained as described by Walker and Leib in J. Org. Chem. 1963, 28, 3077-3082), ethylene glycol (4.96 g, 80 mmol) and a catalytic quantity of p-toluenesulphonic acid in benzene (80 ml) was heated at reflux for 16 hours using a Dean and Stark apparatus. Water (1.5 ml, 80 mmol) was collected. The solvent was removed by evaporation to give an oil. Ethanol (30 ml) and 2N sodium hydroxide solution (1 equivalent) were added and the mixture was stirred for one hour. The mixture was concentrated in vacuo. The residue was diluted with water to give a volume of 80 ml. Ether (50 ml) was added and the mixture was stirred vigorously with cooling in ice. A 10% aqueous solution of citric acid was added to give a pH of 6.5. The mixture was extracted with ether (20×50 ml). The combined extracts were dried (N2SO4) and the solvent was removed by evaporation to give a white solid. Water was added to the solid and the mixture was stirred. The solid was collected by filtration and dried in vacuo over phosphorus pentoxide. There was thus obtained 4-(2-methyl-1,3-dioxolan-2-yl)phenylthioacetic acid (B) as a solid (5.2 g, 51% yield); NMR spectrum (200 MHz, d6 -DMSO): 1.49(s, 3H), 3.62(m, 2H), 3.72(s, 2H), 3.9(m, 2H), 7.25(m,4H).
Reaction SMILES: CCN(CC)CC.[N:8]([C@H:11]1[CH2:15][C@@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@@H:12]1[OH:24])=[N+:9]=[N-:10].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:25][S:26]([O:24][C@@H:12]1[CH2:13][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][C@H:11]1[N:8]=[N+:9]=[N-:10])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](OCc2ccccc2)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C[C@H](OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a cooled mixture of Et3N (9.49 g, 94.0 mmol) and (1S,2S,4R)-2-azido-4-(benzyloxy)cyclopentanol (18.25 g, 78.3 mmol) in DCM (500 mL) was added dropwise methanesulfonyl chloride (9.87 g, 86.2 mmol) in DCM (50 mL) at 0° C. The mixture was stirred overnight at a temperature of 0° C. to RT. After complete conversion, aq NaHCO3 (5%, 300 mL) was added. The mixture was extracted with DCM, washed with brine, and dried over Na2SO4 to give the title compound as an oil (23.58 g, 75.8 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 1.83-1.89 (m, 1H), 2.06-2.13 (m, 1H), 2.34-2.49 (m, 2H), 3.04 (s, 3H), 3.94-3.99 (m, 1H), 4.08-4.13 (m, 1H), 4.64 (s, 2H), 4.93-4.98 (q, J=5.6/7.0 Hz, 1H), 7.25-7.36 (m, 5H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:1]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCc1ccccc1
Product: NS(=O)(=O)OCc1ccccc1
Yield: 38 %

Procedure:
The title compound was prepared by the procedures of Example 33 from sulfamoyl chloride and benzyl alcohol being careful to use reduced pressure at about 35° C. to remove solvents in order to avoid violent decomposition observed in another trial at higher temperature. A white solid, mp 75°-78° C., was obtained in 38% yield.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9][CH2:8]2)([CH3:3])[CH3:2].[CH3:16][Mg]I>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12]([C:11]([CH3:16])=[CH:10][CH2:9][CH2:8]2)=[CH:13][CH:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2c(c1)CCCC2=O
Reactant: C[Mg]I
Product: CC1=CCCc2cc(OC(C)C)ccc21

Procedure:
Using general procedure A (Exp. 1.1), 6-isopropoxy-3,4-dihydro-2H-naphthalen-1-one was reacted with MeMgI to give 7-isopropoxy-4-methyl-1,2-dihydro-naphthalene as a colorless oil. MS: 203.4 ([M+H]+).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:27])=[C:14]([C@:16]2([CH:24]([F:26])[F:25])[C@@H:22]3[C@@H:20]([CH2:21]3)[O:19][C:18]([NH2:23])=[N:17]2)[CH:15]=1.[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1)#[C:29][CH3:30]>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:25][CH:24]([F:26])[C@@:16]1([C:14]2[CH:15]=[C:10]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([C:28]#[C:29][CH3:30])[CH:32]=3)[CH:11]=[CH:12][C:13]=2[F:27])[C@@H:22]2[C@@H:20]([CH2:21]2)[O:19][C:18]([NH2:23])=[N:17]1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC#Cc1cncc(-c2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)c1
Temperature: 110 °C
Yield: 73.9 %

Procedure:
A microwave vial was charged with mixture of potassium phosphate (0.19 g, 0.90 mmol), (1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16f-B, 0.10 g, 0.30 mmol), (5-(prop-1-yn-1-yl)pyridin-3-yl)boronic acid (0.12 g, 0.75 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (10.56 mg, 0.015 mmol) in dioxane/water (2.0/0.5 mL). The reaction mixture was heated to 110° C. for 30 min in the microwave. The reaction mixture was then diluted with water and extracted with DCM three times. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the crude material was purified by silica gel chromatography (0-100% EtOAc-DCM) to obtain the title compound as a white solid (82.3 mg, 74% yield). MS m/z=372 [M+H]+. Calculated for C20H16F3N3O: 371.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]34[CH2:23][CH2:22][C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:20][CH2:21]3)[O:18][CH2:17]4)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]34[CH2:21][CH2:20][C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:22][CH2:23]3)[O:18][CH2:17]4)=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc([N+](=O)[O-])cc4)cc3)(CC1)CO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cc4)cc3)(CC1)CO2
Yield: 90 %

Procedure:
To a round bottom flask containing methyl 2-(4-(4′-nitrobiphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (716 mg, 1.88 mmol) was added Pd(OH)2 on activated carbon (395 mg, 2.82 mmol). EtOAc (15 ml) and MeOH (3 ml) were added and the mixture was stirred under 1 atm. of hydrogen at room temperature for 2 hours. The resulting mixture was filtered through a pad of celite and concentrated to afford a crude residue. Column purification affords the title compound as off-white solid after drying (595 mg, 90% yield). LC/MS, ESI-MS(+): 352.3, RT: 1.29 (Condition E).
Reaction SMILES: [F:1][C:2]1[C:7]([Br:8])=[C:6](Br)[CH:5]=[C:4]([Br:10])[CH:3]=1.[CH:11](=[O:13])[CH3:12]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([Br:10])[CH:5]=[C:6]([CH:11]([OH:13])[CH3:12])[C:7]=1[Br:8]
Reactant: Fc1cc(Br)cc(Br)c1Br
Reactant: CC=O
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc(F)c1Br
Temperature: -70 °C
Reaction time: 2 h

Procedure:
120 g (0.36 mol) of 6-fluoro-1,2,4-tribromobenzene in 120 ml of tetrahydrofuran are added dropwise to 290 ml (0.38 mol, 1.3 M solution in tetrahydrofuran) of isopropylmagnesium chloride/lithium chloride complex cooled to −70° C., and the mixture is stirred at −50° C. for 2 h. The mixture is subsequently cooled to −70° C., before 17.6 g (0.4 mol) of acetaldehyde in 40 ml of tetrahydrofuran are added dropwise. The batch is slowly warmed to −20° C. and then quenched by the addition of saturated ammonium chloride solution.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:26]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C=Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Fc1ccc(/C=C/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 80.3 %

Procedure:
A solution of 1 (10.4 mg, 0.0315 mmol) in 0.4 mL of 95% aqueous ethanol was added dropwise to a solution of 4-fluorostyrene (9.8 mg, 0.080 mmol) and palladium(II) acetate (0.2 mg, 0.0009 mmol) in 0.10 g of 95% aqueous ethanol. The reaction mixture was heated on an oil bath at 70° C. for 5 h. After cooling, the mixture was filtered through a pad of Celite 545 and purified by SiO2 column chromatography (9:1 hexane/CH2Cl2) to give 2b (8.2 mg, 77% yield) as colorless crystals; m.p. 85.0-86.2° C. IR (ATR): {tilde over (v)}=1593, 1508, 1236, 1159, 1099, 964, 831, 818 cm−1. MS (GC, EI): m/z=324 [M+], 197 [M+ SF5], 177. 1H NMR (500 MHz, CDCl3): δ=7.73 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.51 (dd, J=8.8, 5.4 Hz, 2H), 7.15 (d, J=16.4 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 7.01 (d, J=16.4 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=162.8 (C), 152.3 (C), 140.4 (C), 132.6 (C), 130.7 (CH), 128.4 (2CH), 126.3 (2CH), 126.2 (2CH), 126.2 (CH), 115.8 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.9 (quint, J=150.2 Hz, 1 F), 63.0 (d, J=150.2 Hz, 4 F), −112.7 (m, 1 F) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2([C:38](O)=[O:39])[CH2:37][CH2:36]2)=[O:34])=[C:28]([CH3:41])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:35]5([C:33]([NH:32][C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=6[CH3:41])=[O:34])[CH2:37][CH2:36]5)=[O:39])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1cc(F)ccc1NC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1NC(=O)C1(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
N-[6-(4-Amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 1-[(4-fluoro-2-methylphenyl)carbamoyl]cyclopropanecarboxylic acid (120 mg, 0.51 mmol) and HATU (230 mg, 0.60 mmol) were suspended in N,N-dimethylformamide (3.0 mL), and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) was added. After stirring at room temperature for 8 hr, the reaction mixture was diluted with ethyl acetate (5.0 mL) and tetrahydrofuran (5.0 mL). The mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration. The obtained precipitate was recrystallized from ethanol/water to give the title compound (110 mg, 45%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:42])=[C:11]([C:38]([F:41])=[CH:39][CH:40]=1)[CH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:14]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:42][C:10]1[C:11]([CH2:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([Si:28]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:36])[CH3:37])[CH:29]([CH3:30])[CH3:31])[CH:14]=2)=[C:38]([F:41])[CH:39]=[CH:40][C:9]=1[OH:8]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2c(F)ccc(OCc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2c(F)ccc(O)c2F)c2cc(-c3cccnc3)cnc21
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To 3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (548, 510.0 mg, 0.87 mmol) in methanol (20.0 mL) was added 20% Pd(OH)2/C (50 mg). The reaction was stirred under an atmosphere of hydrogen for 2 hours. Filtration and concentration gave the compound as white solid (549, 427 mg, 99%).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-]>CO.O>[C:21]1([CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:7][CH2:8]2)=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CN1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
A mixture of [4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetic acid ethyl ester (1.17 g, 3.07 mmol) and LiOH (645 mg, 15.35 mmol) in MeOH: H2O (3:1, 40 ml) stirred at room temperature for 2 days. The solvent was then evaporated and residue dissolved in water. Upon acidified with 2N HCl to pH 3, product precipitated in aq. phase, filtered and washed few times with water and dried to give the desired product in 78% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.I([O-])(=O)(=O)=[O:23].[Na+]>[Ru](=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[CH:12]=[N:13][N:14]=[C:7]2[CH3:6])=[C:4]([CH:3]=1)[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23]
Reactant: Cc1nnc2cc(-c3ccccc3)c3cc(Br)ccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Br)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 3, 7-bromo-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-bromo-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.C[N:30](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:30])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (100 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (42 mg) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (53 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1-ethyl acetate), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (82 mg, yield: 82%) as pale-yellow prism crystals. MS: 435 (MH+). melting point 193-194° C.