Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [In].[CH3:2][O:3][CH:4]([O:7][CH3:8])[CH:5]=[O:6].[CH2:9](Br)[CH:10]=[CH2:11]>C(O)C>[OH:6][CH:5]([CH2:11][CH:10]=[CH2:9])[CH:4]([O:7][CH3:8])[O:3][CH3:2]
Reactant: COC(C=O)OC
Reactant: C=CCBr
Agent: [In]
Solvent: CCO
Product: C=CCC(O)C(OC)OC
Temperature: 40 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Indium powder (0.52 mol, 1 eq., 60 g, 100 mesh) was added to an ethanol (250 mL) solution containing 2,2-dimethoxyacetaldehyde (0.52 mol, 1.0 eq., 90.62 g, 60 wt % solution in water) and allyl bromide (0.79 mol, 1.5 eq., 66.5 mL). The suspension was stirred at 40° C. for 3 h. The slurry was then centrifuged and the supernatant was decanted. The pellet was suspended and washed 3 times with ethanol (350, 350, and 450 mL). The combined supernatants were mixed with 1500 mL deionized water and 1500 mL saturated sodium chloride. The crude product was extracted with chloroform (1500, 300 mL). The combined organic layers were washed with 1500 mL saturated sodium chloride. The chloroform extract was dried over sodium sulfate, filtered and evaporated at reduced pressure. Yield 40.4 g (53% yield) product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([N:12]3[CH2:17][CH2:16][N:15]4[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]4[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NCc1nccnc1Cl)N1CCn2c(nnc2C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nnc2n1CCN(c1ncc3c(Cl)nccn13)C2
Temperature: 60 °C
Reaction time: 24 h
Yield: 25.1 %

Procedure:
To N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1.382 mmol, 500 mg) in ethyl acetate (5 ml) at 0° C. was added phosphorus oxychloride (5.53 mmol, 0.515 ml). The reaction mixture was stirred at room temperature for two days and at 60° C. for one day. The reaction mixture was cooled to 0° C., an excess solid sodium hydrogencarbonate was added and the suspension was stirred at 0° C. for 10 minutes and at room temperature for 20 minutes. Then the suspension was again cooled to 0° C., water was added and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane applying a gradient 0 to 10% methanol) to give 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (119 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][O:7][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCN(CC)CCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
A solution of 3-diethylamino-1-propanol (2.97 mL, 20 mmol) in THF (40 mL) at 0° C. is treated potassium tert-butoxide (2.36 g, 1.05 equiv.) in one portion. The reaction mixture is stirred at 0° C. for 5 min during which time it becomes reddish brown. Neat 1-fluoro-4-nitrobenzene (2.82 g, 1 equiv.) is added dropwise and the ice-bath is removed. The reaction mixture is stirred at room temperature for 15 min. The dark green reaction mixture is quenched with ice-water (300 mL), and extracted with EtOAc (2×200 mL). The combined organic extracts are washed with water (2×300 mL) and brine (1×300 mL) and dried over anhydrous Na2SO4. The oily brown residue obtained after evaporation, is purified by chromatography, (silica gel, 1:4 MeOH:CHCl3) to give the named compound as a brown oil (3.59 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OC/C=C/c1ccc(Br)cc1
Temperature: 78 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g, 96 mmol) in DCM (300 ml) under nitrogen and cooled to −78° C. was added dropwise DIBAL-H (240 ml, 1M in DCM, 240 mmol) in about 20 minutes. The mixture was stirred at 78° C. for 2 hours. Then, the dry ice bath was removed. The reaction was diluted with DCM (500 mL), quenched with HCl (1N), and partitioned. The combined organic phases were washed with H2O, dried and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): 1.43 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (d, J=15 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 214 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7]3[C:6]=2[C:5]([C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]=23)=[CH:4][CH:3]=1
Reactant: O=C1CCCCCC1
Reactant: CN1CCc2c(Cl)cccc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCO
Product: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCCCC4
Temperature: 25 °C
Yield: 34.1 %

Procedure:
To a solution of 7-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.20 g, 5.32 mmole) in 1-propanol (100 mL) was added cycloheptanone (6.65 g, 59.3 mmole) followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmol) and the resulting reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.55 g of the title compound as a white solid, mp 132-134° C. MS (ESI) m/z 303 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[N+:23]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>CO.O1CCCC1.[Fe]>[NH2:23][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[O:13][C:12]1[CH:26]=[CH:27][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(C(=O)O)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of the product of Example 43A (0.73 g, 2.0 mmol), iron powder (1.12 g, 20 mmol) and ammonium chloride (1.08 g, 20 mmol) in methanol (20 mL), tetrahydrofuran (20 mL), and water (10 mL) was heated at 80° for 48 hours. After cooling to room temperature, the mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum then purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (670 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:26])[S:12][C:11]([C:13]3[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=3)=[N:10][C:9]2([F:25])[F:24])=[CH:4][CH:3]=1.C1[CH:28]=[CH:29][C:30]2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N)CCC>CN(C=O)C.ClCCl>[CH2:31]([NH:33][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([F:26])[C:9]([F:24])([F:25])[N:10]=2)=[CH:14][CH:15]=1)[CH2:30][CH2:29][CH3:28]
Reactant: O=C(O)COc1ccc(C2=NC(F)(F)C(F)(c3ccc(Cl)cc3)S2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCCCN
Solvent: CN(C)C=O
Product: CCCCNC(=O)COc1ccc(C2=NC(F)(F)C(F)(c3ccc(Cl)cc3)S2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 2-(4-(5-(4-chlorophenyl)-4,4,5-trifluoro-4,5-dihydrothiazol-2-yl)phenoxy)acetic acid (45.7 mg, 114 μmol) in DMF (5.7 mL) were added the coupling agents HOBt (18.4 mg, 136 μmol) and EDC.HCl (26.1 mg, 0.136 mmol). Then, butylamine was added (13.6 μL, 136 μmol) and the mixture was stirred for 2 h at room temperature. When the reaction was completed, it was diluted with dicloromethane (20 mL) and washed with H2O (3×5 mL). The organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was absorbed onto silica then subjected to flash chromatography (SiO2, hexane:AcOEt, 6:4), obtaining 18.1 mg of N-butyl-2-(4-(5-(4-chlorophenyl)-4,4,5-trifluoro-4,5-dihydrothiazol-2-yl)phenoxy)acetamide (35% yield). RMN1H (CDCl3, 400 MHz): δ 8.03-7.93; (m, 2H), 7.64; (d, J=8.3 Hz, 2H), 7.45; (d, J=8.4 Hz, 2H), 7.09-7.01; (m, 2H), 6.48; (bs, 1H), 4.58; (s,), 3.53-3.26; (m, 2H), 1.59-1.50; (m, 2H), 1.41-1.34; (m, 2H), 0.98-0.90; (m, 3H) ppm. RMN19F (CDCl3, 400 MHz): δ −78.81; (dd, J=217.4, 9.8 Hz), −103.30; (dd, J=217.3, 8.8 Hz), −130.96; (m, J=9.3 Hz) ppm.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13]([OH:15])=O)[C:11]([CH3:17])([CH3:16])[S:10][CH2:9]1)=O)(C)(C)C.P([Cl:34])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[C@H:35]1([NH2:41])CCCC=[CH:36]1.CS(O)(=O)=O>CCOC(C)=O>[Cl:34][CH2:36][CH2:35][NH:41][C:13]([C@@H:12]1[C:11]([CH3:16])([CH3:17])[S:10][CH2:9][NH:8]1)=[O:15]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: N[C@@H]1C=CCCC1
Reactant: CC(C)(C)OC(=O)N1CSC(C)(C)[C@H]1C(=O)O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CC1(C)SCN[C@@H]1C(=O)NCCCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound was prepared as follows. (R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1 (1.95 g, 7.47 mmol) was dissolved in EtOAc (25 mL) and cooled to 0° C. Diphenyl chlorophosphate (1.71 mL, 8.23 mmol) was added followed by TEA (1.14 mL, 8.23 mmol). The reaction was stirred at 0° C. for 1 h, and treated with (S)-Cyclohex-2-enylamine (0.8 g, 8.23 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between 1N HCl (25 mL) and EtOAc (30 mL). The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a yellow oil. The resulting oil (2.54 g, 7.47 mmol) was dissolved in EtOAc (30 mL) and then cooled to 0° C. Methanesulfonic acid (2.27 mL, 33.62 mmol) was added and the solution was stirred at 0° C. for 15 minutes, then at room temperature for 4 h. The mixture was re-cooled to 0° C. and quenched with 10% Na2CO3 (30 mL) then extracted with EtOAc (30 mL). Organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a yellow oil 3. The resulting yellow oil (1.86 g, 7.74 mmol) was dissolved in EtOAc (77 mL). BOC-AHPBA 4 (2.29 g, 7.74 mmol) was added followed by HOBt (1.05 g, 7.74 mmol). The mixture was stirred at room temperature 1 h, then cooled to 0° C. DCC (1.60 g, 7.74 mmol) was slowly added as solution in EtOAc (30 mL). The mixture was allowed to gradually warm to room temperature and stirred overnight. The mixture was filtered and the filtrate was washed with 1N HCl (40 mL), saturated NaHCO3 (40 mL), brine (40 mL), dried over Na2SO4 and concentrated to give a crude white solid (contaminated with DCU). The DCU was removed by flash chromatography (30% to 50% EtOAc in hexanes) to provide a white solid (4 g, 7.73 mmol), which was dissolved in EtOAc (30 mL) and then cooled to 0° C. Methanesulfonic acid (2.35 mL, 34.76 mmol) was added and the solution was stirred at 0° C. for 15 minutes, then at room temperature for 3 h. The mixture was re-cooled to 0° C. and quenched with 10% Na2CO3 (35 mL) then extracted with EtOAc (30 mL). Organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a material which was recrystalized from 60% EtOAc in hexanes to provide the titled compound (2.41 g, 80%) as a white solid. 1H NMR (DMSO-d6) δ 8.21 (d, J=8.1, 1H), 7.31–7.17 (m, 5H), 5.80 (d, J=5.6, 1H), 5.52–5.48 (m, 2H), 5.30–5.25 (m, 2H), 4.89 (s, 2H), 4.26 (s, 1H), 4.21–4.00 (m, 3H), 3.15–2.70 (m, 2H), 2.50–2.00 (m, 2H), 2.00–1.00 (m, 4H), 1.49 (s, 3H), 1.31 (s, 3H); Anal. Calcd for C22H31N3O3S: C, 63.28; H, 7.48; N, 10.06. Found: C, 63.40; H, 7.20; N, 9.98.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([Mg]Br)#[CH:21].O>O1CCCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18](=[O:19])[C:20]#[CH:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Reactant: C#C[Mg]Br
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C#CC(=O)c1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a cold (−78° C.) suspension of 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (0.94 g, 3.42 mmol) in tetrahydrofuran (20 mL) was added ethynylmagnesium bromide (15 mL, 0.5 M in tetrahydrofuran, 7.5 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at 0° C. for 2 hours. The resulting solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a white solid. This solid was dissolved in dichlormethane (60 mL) and to this solution was added manganese dioxide (10 g, 115 mmol). The reaction mixture was stirred at room temperature for 1 hour. The suspension was filtered through a pad of Celite and the filtrate was concentrated and purified by silica gel chromatography (1:1 hexanes:ethyl acetate) to give 1-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-one (0.56 g, 55%) as a white solid. 1H NMR (CDCl3) δ 9.67 (d, 1H), 7.68 (m, 3H), 7.12 (m, 3H), 2.89 (s, 1H); 19F NMR (CDCl3) δ −111.6; MS m/z 299 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11](I)=[N:10]1.C([Mg]Cl)(C)C.[CH2:28]([Sn:32]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])Cl)[CH2:29][CH2:30][CH3:31]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11]([Sn:32]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH2:29][CH2:30][CH3:31])=[N:10]1
Reactant: FC(F)Oc1ccc2c(c1)c(I)nn2CCC1OCCCO1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCC2OCCCO2)c2ccc(OC(F)F)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-3-iodo-1H-indazole (242 mg, 571 mmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath), isopropylmagnesium chloride 2M in THF (319 μL, 639 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (214 mg, 178 μL, 656 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum and taken into next step without further purification yielding 1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole, assumed quantitative and used into the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[OH:40]/[N:39]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][CH:10]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)NCC(=O)O)c3)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2cccc(-c3cccc(C(=O)NCC(=O)O)c3)c2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 4, from ({3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carbonyl}-amino)-acetic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which precipitated as a white solid on work up, MS (ESI−): m/z=506.2 ([M−H]−).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>C(#N)C>[N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:15][CH2:16][N:17]([C:35]4[CH:44]=[N:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)[CH2:18][CH2:19]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 120 °C
Yield: 66 %

Procedure:
To a stirred solution of 2-(2-(2H-1,2,3-triazol-2-yl)benzyl)-2,9-diazaspiro[5.5]undecan-1-one (TFA salt) (200 mg, 0.354 mmol, contains 2.0 moleq. TFA) and diisopropylethylamine (0.64 mL, 3.61 mmol) in acetonitrile (1 mL) was added 2-chloroquinoxaline [1448-87-9] (121 mg, 0.72 mmol). The mixture was heated at 120° C. for 40 min under microwave conditions. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude mixture was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (106 mg, 65%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.81 (s, 1H), 8.11 (s, 2H), 7.80 (d, 1H), 7.59-7.63 (m, 1H), 7.56-7.59 (m, 2H), 7.44-7.55 (m, 2H), 7.33-7.40 (m, 1H), 7.24-7.29 (m, 1H), 4.54 (br. s, 2H), 4.19-4.29 (m, 2H), 3.39-3.49 (m, 2H), 3.13 (t, 2H), 1.99-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.73-1.83 (m, 2H), 1.54-1.65 (m, 2H); LCMS RtA=1.16, [M+H]+=454.4].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1OCCCCCO.C(N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCO
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(C(C)=O)c1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
A solution of 0.62 g (2 mmol) of 2[(5-hydroxypentyl)oxy]-5-acetylbenzenepropanoic acid methyl ester and 2 mL of triethylamine, in 6 mL of ethyl acetate was stirred with ice-bath cooling while 0.6 mL of methanesulfonyl chloride was added dropwise. The resulting mixture was stirred at 0°-5° C. for 1.33 hr and then poured into ice-3N HCl. Work-up with ethyl acetate in the usual manner gave 0.96 g of 2-[[5-(methylsulfonyl)oxy]pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester as an oil which was used without further purification.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[Cl:13].[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:13][C:4]1[C:5]([F:12])=[C:6]([O:9][CH2:10][CH3:11])[CH:7]=[CH:8][C:3]=1[C:28]1([OH:31])[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C@H:20]2[CH2:19][CH2:18][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:22][CH2:21]2)[CH2:30][CH2:29]1
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Reactant: CCOc1ccc(Br)c(Cl)c1F
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](CCC2CCC(O)(c3ccc(OCC)c(F)c3Cl)CC2)CC1
Temperature: 43 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
1.0 g of well dried magnesium and 30 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 10.0 g of 1-bromo-2-chloro-4-ethoxy-3-fluorobenzene (6) dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 43 to 51° C., followed by stirring for 30 minutes. Thereafter, 21.2 g of 4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanone (7) dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 55° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 16.4 g of 1-(2-chloro-4-ethoxy-3-fluorophenyl)-4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanol (8). The resulting compound (8) was a yellow solid matter.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC([O-])=O.[Na+]>CN(C)C=O>[C:3]1([CH:2]=[CH:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: Brc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Dimethylformamide (Aldrich) was used in anhydrous form. All the aryl bromides, iodobenzene and alkene substrates were purified before use (Aldrich). 6.0 mmol each of styrene and bromobenzene, 6.6 mmol of NaOAc (base) were mixed with 50 ml of DMF (dimethylformamide). 20 ml of this solution was placed in a 50 ml round bottom-flask equipped with a magnetic stirring bar and condenser connected to a vacuum line. The solution was flushed five times with nitrogen using a vacuum nitrogen cycle. The catalysts prepared in Example 12, generations 0 through 4, were then added. The autoclave was placed in an oil bath and the 120° C. was reached by stirring on a hot plate. After the appropriate reaction time, the reaction was allowed to cool to room temperature. The resulting solution was filtered to remove the catalyst. The filtrate was extracted with diethyl ether (4×40 ml), and the ether extracts were washed with brine and distilled water, followed by drying over magnesium sulfate. The product, trans stilbene, was analyzed by 1H NMR spectroscopy and/or gas chromatography, and identified by comparison of spectral results with literature data. Results are shown in Tables 6-7 below. The yields of stilbene was significantly less when generation 3 and 4 dendrimer complexes are used as catalysts. The best turnovers in terms of molecules of trans-stilbene formed per mol of palladium was achieved with the generation 2 catalyst.