Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:20]([C:24]([OH:26])=O)=[CH:19][CH:18]=[CH:17][C:16]=3[CH:15]2[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:29](C)C=O.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:24](=[O:26])[NH2:29])[CH:15]2[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1c2cccc(C(=O)O)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an orange solution of 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (3.8 g, 10.3 mmol) in N,N-dimethylformamide (60 mL) hydroxybenzotriazole ammonium salt (3.15 g, 20.7 mmol), 1-ethyl-3-(3′-dimethylamino) carbodiimide hydrochloric acid salt (3.34 g, 20.7 mmol) and N,N-diisopropylethylamine (5.3 mL, 30.9 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduce pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with sodium carbonate saturated aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol: 97:3) to afford the title compound (2.86 g, 74%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][N:26]([C:31](=[O:43])[CH2:32][CH2:33][C:34]2[C:35]([CH3:42])=[C:36]([CH:40]=O)[NH:37][C:38]=2[CH3:39])[CH2:25]1.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:40]\[C:36]1[NH:37][C:38]([CH3:39])=[C:34]([CH2:33][CH2:32][C:31]([N:26]2[CH2:27][C@H:28]([CH3:30])[NH:29][C@H:24]([CH3:23])[CH2:25]2)=[O:43])[C:35]=1[CH3:42])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (122 mg, 0.34 mmol), 4-[3-((3R, 5S)-3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (139 mg, 1.4 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 72 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a dark brown orange solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:4]([C:18]([OH:20])=O)[CH:3]=1.O=S(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[O:6][CH:5]2[CH2:7][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:18](=[O:20])[CH:4]2[CH:3]=1
Reactant: COc1ccc(CNCc2oc(Br)cc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN2CC3OC(Br)=CC3C2=O)cc1
Yield: 28.6 %

Procedure:
A solution of 5-bromo-2-[(4-methoxy-benzylamino)-methyl]-furan-3-carboxylic acid (618 mg, 1.82 mmol) and SOCl2 (0.136 mL) in DCM (2 mL) is stirred at 85° C. for 18 hours. The mixture is concentrated in vacuo and purified by silica gel column chromatography eluting with 7:3 petroleum ether:ethyl acetate to afford the title compound (0.169 g, 28%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccs3)CC12
Reaction time: 1 h
Yield: 74 %

Procedure:
N,N'-Carbonyldiimidazole (0.81 g) is added to a solution of 2-(2-thienyl)acetic acid (0.71 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) and triethylamine (0.7 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 2 hours at +5° C. and for 16 hours at 20° C. and is then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (10 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-thienyl)acetyl]-4-perhydroisoindolone (1.5 g) melting at 206° C. is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([NH:19][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([NH2:18])=[O:17])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: NC1CCc2ccccc21
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(NC3CCc4ccccc43)c2cc1OC
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.066 g, 0.25 mmol), 1-aminoindan (0.66 mg, 0.50 mmol), 2-butanole (2 ml), DMF (2 ml) was heated for 48 h at 100° C. After cooling, the solution was reduced by evaporation. The residue was dissolved in water (3 ml) and treated with aqueous ammonia. The solid product was fitered off washed with water air dried for 0.5 h, washed again with heptane and dried. The residue was purified by chromatography on silica (CH2Cl2/MeOH) to give 63 mg, (70%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].B.O1CCCC1>O1CCCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][OH:7]
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: NCc1cccc(CO)c1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A 20 g sample of 3-cyanobenzoic acid (12) (136 mmol) was suspended in 100 mL of dry tetrahydrofuran (THF). Borane-tetrahydrofuran complex (400 mL of 1.0 M solution in THF) was added dropwise over one hour and then stirred for an additional 3 hours. The reaction was quenched with 220 mL of concentrated HCl:water (1:1) to cleave the borane-alcohol complex. The THF was then evaporated off under vacuum. Solid NaOH pellets, 70 g total, were added slowly to neutralize the acid and bring the pH of the solution to 12. The aqueous phase was then extracted 4 times with 500 mL portions of ether. The ether extract was dried over MgSO4 and evaporated under vacuum to give 18 g (131 mmol) of 3-(aminomethyl)benzyl alcohol (13) as a light colored oil. 1H NMR (CDCl3/TMS) δ=1.95 (broad s, 3H, —OH and —NH2, exchangeable with D2O), 3.86 (s, 2H, —CH2—NH2), 4.66 (s, 2H, —CH2—OH), 7.27 (m, 4H, aromatic).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:6])[CH3:3].[C:36]([Si:38]([CH3:41])([CH3:40])[CH3:39])#[CH:37]>C(NCC)C.C(Cl)Cl.[Cu]I>[CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:37]#[C:36][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:10][N:9]=1)=[O:6])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nnnn1-c1cccc(F)c1F
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#C[Si](C)(C)C)cc1-c1nnnn1-c1cccc(F)c1F
Temperature: 50 °C
Yield: 29.3 %

Procedure:
In a tube was placed N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-bromopyridin-2-amine (2.3 g, 4.1 mmol) in diethylamine (10 mL) with ethynyltrimethylsilane (1.5 g, 15.3 mmol) and the reaction was deoxygenated with a stream of nitrogen gas. To the mixture was added copper(I) iodide (554 mg, 2.9 mmol). The reaction vessel was sealed and warmed to 50° C. to achieve dissolution. To the mixture was added PdCl2dppf2.CH2Cl2 (190 mg, 0.06 eq). The reaction vessel was sealed and the mixture sonicated at 50° C. for 10 minutes. The reaction was diluted with methylene chloride, filtered through Celite™, concentrated, and purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (713 mg, 1.2 mmol, 30%) as a yellow solid; LC-MS: m/e=471.3 [M-Boc+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[CH2:11]([O:13][CH:14]([O:20]CC)[C:15](OCC)=O)C>C[N+]([O-])=O.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:15]2[C:14]([O:13][CH3:11])=[O:20]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: OCCc1ccccc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C1OCCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TiCl4 (76 g, 0.4 mol) was added over a period of 10 min to an ice-cooled mixture of 2-(2-bromophenyl)ethanol (20 g, 0.1 mol) and ethyl bis(ethyloxy)acetate (21.1 g, 0.120 mol) in 120 mL of CH3NO2. After stirring for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature overnight. The mixture was poured into ice/aqueous 1N HCl. Extracted with DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel column chromatography to give the product methyl 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(#N)C.ClCCl>[CH2:16]([N:18]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: COc1ccc(OCCCl)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: ClCCl
Solvent: CC#N
Product: CCN(CC)CCOc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
4-(2-chloroethoxy)-1-methoxy-2-nitrobenzene (0.15 g, 0.67 mmol) was dissolved in acetonitrile (1 ml). Excess diethylamine (1.5 ml, 17.7 mmol) was added and the reaction heated in the microwave (T=120° C., 40 min) to complete conversion. The reaction mixture was diluted with dichloromethane, then washed with 5M sodium hydroxide and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as an orange oil.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[CH:19][C:18]=1[O:29][CH3:30])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:21]1[CH:20]=[CH:19][C:18]([O:29][CH3:30])=[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:7]=2[CH2:6][S:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH:22]=1)[CH3:28]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)O)cc2CSC(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)NC(C)(C)C)cc2CSC(C)(C)C)c1
Reaction time: 8 h

Procedure:
3-tert-Butylsulfanylmethyl-4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-benzoic acid (0.2 g, 0.46 mmol), tert-butylamine (0.15 mL, 13.9 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.11 g, 0.55 mmol), and N-hydroxybenzotriazole (0.074 g, 0.55 mmol) were combined in CH2Cl2 (8 mL) and stirred overnight. The mixture was concentrated and purified by preparative HPLC to give the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9].[CH2:17](O)[CH3:18]>>[F:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([O:10][CH2:17][CH3:18])=[O:9]
Reactant: CCO
Reactant: CCCCCC[C@H](F)C(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCC[C@H](F)C(=O)OCC
Yield: 87 %

Procedure:
Partial Resolution of of Ethyl 2-fluorooctanoate by Enzyme Catalysed Hydrolysis.-Ethyl 2-fluorooctanoate 65 (71.6 g, 0.377 mol) was added to 0.063M phosphate buffer (pH 7.0) (280 ml) and deionised water (280 ml) in a beaker fitted with a pH electrode, magnetic stirrer bar and a cooling bath. Pseudomonas lipase (Amano PS) (22 mg) was added and the mixture was stirred at ca 5° C. The pH was maintained at ca. 7 by adding 1.0M sodium hydroxide solution via a syringe pump. Hydrolysis continued until 151 ml of the hydroxide solution had been added (40% conversion). The mixture was extracted with ether (3 times) and the combined organic solutions were washed with brine, dried (K2CO3) and evaporated to give partially resolved (R)-ester. The aqueous layer was acidified to pH 2.7 with conc. hydrochloric acid and extracted with ether. The organic solutions were dried and evaporated to give partially resolved (S)-(-)-2-fluorooctanoic acid. Concentrated sulphuric acid (2 ml) was added to (S)-2-fluorooctanoic acid (24.0 g, 0.15 mol) in ethanol (200 ml) and the solution was heated under reflux for 4 h. Most of the ethanol was distilled off at atmospheric pressure; dichloromethane was added and the solution was washed with sat. sodium bicarbonate solution until neutral. brine, dried (MgSO4) and evaporated. The yellow liquid was distilled to give partially resolved ethyl (S)-(-)-2-fluorooctanoate 66 (25.13g, 87%) b.p. 68° C. at 0.45 mm Hg.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=3)=[O:29])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCBr)c1ccc(O)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCC(=O)c2ccc(O)cc2)CC1
Yield: 55.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (5.20 g) as a starting compound, 5-bromo-1-(4-hydroxyphenyl)-1-pentanone (3.60 g) and potassium carbonate (8.7 g) were reacted and purified in the same manner as in Example 172 to give 3.71 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-hydroxyphenyl)-5-oxopentyl)-piperidin-4-yl)methyl)benzamide, m.p. 154°-156° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1)=[O:12].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O.Cl[Pd]Cl>[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Cl)nn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)nn1
Temperature: 80 °C
Yield: 12 %

Procedure:
Na2CO3 (183 mg, 1.73 mmol) was added to a stirred solution of 6-chloro-pyridazine-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (263 mg, 0.57 mmol) in DMF (6 mL). PdCl2 (dppf) (80.4 mg, 0.11 mmol) and phenyl boronic acid (89.9 mg, 0.69 mmol) were then added and the reaction mixture was heated at 80° C. for 2 hrs. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to get the residue. The residue obtained was purified by preparative HPLC afford 34 mg (11% yield) of 6-Phenyl-pyridazine-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.2%. 1H NMR (DMSO-d6): δ 9.3 (t, 1H), 8.5 (d, 1H), 8.3 (t, 3H), 8.0-7.5 (m, 7H), 4.4 (d, 2H), 3.8 (d, 4H), 3.46 (bs, 2H), 3.2 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14]>>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A solution of 5.0 g. of acetonine in 40 g. of acetone was added with 1.6 g. of acetonine formate. The mixture was heated at 60°C. for 10 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 95.8%.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cc([N+](=O)[O-])c(O)c(O)c1Cl
Reaction time: 18 h

Procedure:
1.3 g of 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde are dissolved in 80 ml of methylene chloride, treated with 0.82 ml of boron tribromide, stirred at 23° for 18 hours, the reaction mixture is treated with 5 ml of methanol while cooling with ice, evaporated, the residue is dried in a high vacuum, digested in water, filtered and recrystallized from acetonitrile. There is obtained 2-chloro-3,4-dihydroxy-5-nitrobenzaldehyde of m.p. 193°-195°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:20](=[O:34])[N:19]2[CH3:35])=[CH:11][C:10]=1I)([CH3:7])[CH3:6])[CH3:2].[CH2:38](B(O)O)[CH2:39][CH2:40][CH3:41]>>[CH2:1]([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:20](=[O:34])[N:19]2[CH3:35])=[CH:11][C:10]=1[CH2:38][CH2:39][CH2:40][CH3:41])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCCCB(O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1I
Product: CCCCc1cc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OCC

Procedure:
The titled compound is prepared, according to the procedure of Example 3, Step B, using 2-(2-Iodo-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (0.270 g, 0.430 mmole) and n-butyl boronic acid (0.218 g, 0.215 mmole) to produce an oil (0.115 g, 48%). Mass [EI+] 563 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([SiH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]2N(C)C(C)(C)C[O:22]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.Cl>C(OC)(C)(C)C>[C:1]1([CH:7]([SiH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=[O:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C(c2ccccc2[SiH2]C(c2ccccc2)c2ccccc2)OCC1(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=Cc1ccccc1[SiH2]C(c1ccccc1)c1ccccc1
Yield: 86.2 %

Procedure:
2.35 g of the product of Step (e), above, is heated in a mixture 12 ml of THF and 6 ml of 2N hydrochloric acid, at 60° for 5 hours. The reaction mixture is then diluted with methyl tert.-butyl ether and washed with 2N hydrochloric acid and then brine. The aqueous phases are combined and extracted thrice with methyl tert.-butyl ether. The combined organic extracts are washed with aqueons sodium carbonate, dried and concentrated to give 1.58 g of the title aldehyde product of this step, NMR(CDCl3) δ0.95 (3H, s), 7.2-7.7(13H, m), 7.85-8.05(1H, m), 10(1H, s).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:18]([NH:22][S:1]([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
One equivalent of dansyl chloride (7) was added to a solution containing 2 equivalents of both butylamine and potassium carbonate in 1:1 acetonitrile:water. Solution was stirred at room temperature for 1.5 hrs. Acetonitrile was then removed and water residue extracted with ethyl acetate. The organic solution washed with 5% sodium bicarbonate, 2M citric acid and brine. Solution was dried over magnesium sulfate, filtered and solvent removed by flash evaporation. Crude was dissolved in minimal amount of ethyl acetate and hexane was added until cloudiness. Solution was stored in the refrigerator for 2 hrs. The precipitate was collected by suction filtration, washed with hexane and dried on the pump. ESI-MS and 1H-NMR were consistent with structure 8, which is (n-butyl dansylamide; BDA): 1H-NMR (CDCl3, =ppm): 8.55 (1H, d); 8.30 (2H, dd); 7.55 (2H, m); 7.20 (1H, d); 4.80 (1H, t); 2.90 (8H, m); 1.35 (2H, m). 1.20 (2H, m); 0.70 (3H, t). ESI-MS: Calc. m/z=306.4. Found m/z+H+=307.4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([C:23]#[N:24])[CH3:22])[C:12]([CH2:26][CH3:27])=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pt]=O>[CH2:26]([C:12]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:22])[CH2:23][NH2:24])=[CH:14][C:9]([OH:8])=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:11]=1)[CH3:27]
Reactant: [H][H]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Agent: O=[Pt]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCCC(C)(C)CN
Reaction time: 20 h
Yield: 120.5 %

Procedure:
1-(benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(6-methyl-6-cyanoheptyl)oxy]-benzene (485 mg) was dissolved in ethanol (15 mL) and added to a solution of platinum oxide (20 mg) in 10 mL ethanol in a Parr bottle. The bottle was pressurized to 55 psi with hydrogen and shaken for 20 hours. Additional catalyst (120 mg) was added and bottle shaken at 55 psi of hydrogen for an additional 18 hours. The solution was filtered through Celite and concentrated under vacuum to afford crude 4-ethyl-2-(4-fluorophenyl)-5-[(6,6-dimethyl-7-aminoheptyl)oxy]phenol (475 mg) as an oil. It was purified by chromatography on silica gel with chloroform/methanol eluant. The product fractions were combined and concentrated under vacuum (120 mg). NMR (CDCl3): 1.00, s, (6H); 1.15, t (3H); 1.33, m (2H); 1.44, m (2H); 1.77, m (2H); 2.55, q (2H); 2.74, s (2H); 3.92, t (2H); 6.52, s (1H); 6.96, s (1H); 7.11, d of d (2H); 7.43, d of d (2H). Mass Spec (EI), m/e=374.3 (M+H).