Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:31]#[C:30][CH2:29][OH:32])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CCO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1 mmol) and propargyl alcohol (84 mg, 1.5 mmol) in toluene (6 mL) was treated with copper(I) iodide (19.2 mg, 0.10 mmol), dichlorobis(triphenylphosphine)palladium(II) (36 mg, 0.05 mmol), and N,N-diisopropylethylamine (2 ml). The resulting mixture was stirred at 25° C. for 1 h and was then heated to 60° C. for 1 h. At this time, the reaction was concentrated in vacuo. The residue was extracted into ethyl acetate from a 1N aqueous hydrochloric acid solution. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-prop-1-ynyl)-pyrazin-2-yl]-propionamide (275 mg, 57%) as a pale yellow solid: (ES)+-HRMS m/e calcd for C22H24ClN3O4S (M+H)+ 462.1249, found 462.1252.
Reaction SMILES: Cl.[C:2]([N:4]=[C:5]([NH:26][CH2:27][CH:28](OC)OC)[NH:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH:11]=1)[CH3:9])#[N:3].C1COCC1.[OH-].[Na+]>O1CCOCC1.O>[F:18][CH:17]([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[CH2:7][N:6]2[CH:28]=[CH:27][NH:26][C:5]2=[N:4][C:2]#[N:3])=[CH:11][C:12]=1[O:20][CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1
Reactant: COC(CNC(=NC#N)NCC(C)c1ccc(OC(F)F)c(OC2CCOC2)c1)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(Cn1cc[nH]c1=NC#N)c1ccc(OC(F)F)c(OC2CCOC2)c1
Yield: 15.7 %

Procedure:
HCl 0.5 N (0.0162 mol) was added dropwise to a solution of intermediate 12 (0.0108 mol) in 1,4-dioxane (20 ml), stirred and cooled in an ice-bath. The reaction mixture was stirred for 2 days at RT. (As an alternative, 1,4-dioxane may be replaced by THF and the reaction mixture may be refluxed for 1 hour instead of stirring 2 days at RT). The reaction mixture was treated with water, alkalized with a dilute NaOH solution, then extracted with ethylacetate. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by open column chromatography over silica gel (eluent: CH2C2 /2-propanone 96/4; CH2Cl2 /CH3OH 96/4) and twice by HPLC over silica gel (1. Eluent: CH2Cl2 /CH3OH 96/4 and 2. Eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 0.64 g (15%) of (±)-[1-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]-propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide (compound 2; mp. 67.8° C.).
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]1[CH2:18][CH2:17][C:16]2[C:19]([CH3:28])=[CH:20][CH:21]=[C:22]([NH:23][NH:24][C:25]([OH:27])=[O:26])[C:15]=2[O:14]1>C(Cl)Cl>[CH3:1][O:26][C:25]([N:24]=[N:23][C:22]1[C:15]2[O:14][CH:13]([CH3:12])[CH2:18][CH2:17][C:16]=2[C:19]([CH3:28])=[CH:20][CH:21]=1)=[O:27]
Reactant: Cc1ccc(NNC(=O)O)c2c1CCC(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)N=Nc1ccc(C)c2c1OC(C)CC2
Temperature: 35 °C

Procedure:
A solution of 13.8 g of MCPBA in 100 ml of methylene chloride was added drop-by-drop over 10 minutes to a stirred solution of 16.1 g of 1G in 150 ml of methylene chloride at room temperature. The resulting mixture was stirred and refluxed (35° C.) for 30 minutes, then washed with 10% aqueous sodium carbonate solution. The resulting methylene chloride solution was dried (MgSO4), and the solvent was evaporated. The residue was purified by column chromatography over silica gel, using a 1:4:20 v:v:v mixture of THF, ethyl acetate and hexane as eluent, to give 1, as a brick red solid, m.p.: 95°-97° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=O)=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:40][C:41]1[CH:42]=[C:43]([CH:48]=[CH:49][C:50]=1[NH2:51])[C:44]([O:46][CH3:47])=[O:45].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1.O.CO.CN(C)C=O>[NH2:51][C:50]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=1[NH:40][C:31](=[O:33])[C:30]([NH:29][C:27]([C:24]1[CH:25]=[CH:26][C:8]2[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]4[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=43)[C:9]=2[CH:23]=1)=[O:28])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC(C)(C)C(=O)O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(NC(=O)C(C)(C)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CCOc2cc(OC)ccc2-4)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionic acid (0.60 g, 1.26 mmol) in chloroform (18.0 ml) was added a catalytic amount of N,N-dimethylformamide, and thionyl chloride (0.28 ml, 3.78 mmol) was added dropwise under ice-cooling. The mixture was stirred for 2 hr. Then, the reaction mixture was evaporated under reduced pressure to give a yellow solid. Further, the obtained solid was dissolved in chloroform (2.5 ml) and added dropwise to a solution of methyl 3,4-diaminobenzoate (0.29 g, 1.76 mmol) in pyridine (1.5 ml) under ice-cooling. After dropwise addition, the mixture was warmed to room temperature, and the mixture was stirred at overnight. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution, methanol and water. The precipitate was collected by filtration, washed with water, and dried in vacuo to give methyl 4-amino-3-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (0.73 g, yield 93%).
Reaction SMILES: CO.C([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([N+:31]([O-:33])=[O:32])[CH:19]=2)=[CH:14][CH:13]=1)(=O)C1C=CC=CC=1.[OH-].[Li+].Cl>>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)=[CH:19][C:20]=1[N+:31]([O-:33])=[O:32]
Reactant: CC(C)(C)CCOc1ccc(-c2ccc(OC(=O)c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CCOc1ccc(-c2ccc(O)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In synthesizing the liquid crystal material of Formula 1(10), first, benzoyl chloride was dropped into 4,4′-biphenol pyridine solution, and the resultant was subsequently stirred all night at room temperature. The obtained precipitated substance was filtrated, and subsequently 4′-hydroxy-4-biphenyl benzoate was obtained by column chromatography with the use of silica-gel. Subsequently, 4′-hydroxy-4-biphenyl benzoate was dispersed into acetic acid. Thereafter, while temperature was kept at 15 degree centigrade, nitric acid was dropped into the resultant, water was further added thereto, and the resultant was stirred. The obtained precipitated substance was recrystallized by ethanol and acetic acid, and therefore 4′-hydroxy-3′-nitro-4-biphenyl benzoate was obtained. Subsequently, tetrahydrofuran solution composed of 4′-hydroxy-3′-nitro-4-biphenyl benzoate, triphenyl phosphine, and 3,3-dimethylbutyl-1-ol was put into a flask substituted with argon gas (Ar). Thereafter, azodicarboxylic diethyl tetrahydrofuran solution was dropped into the resultant, which was stirred all night at room temperature. Subsequently, after the solvent was volatilized, by using column chromatography, 4′-(3,3-dimethylbutyloxy)-3′-nitro(1,1′-biphenyl)-4-yl benzoate was obtained. Subsequently, 4′-(3,3-dimethylbutyloxy)-3′-nitro(1,1′-biphenyl)-4-yl benzoate methanol solution was added with lithium hydroxide solution, and the resultant was stirred all night at room temperature. Subsequently, after the solvent was volatilized, neutralization was performed by hydrochloric acid, and a target substance was extracted by ethyl ether. Subsequently, dehydration was performed by magnesium sulfate, and the solvent was volatilized. Thereafter, by using column chromatography, 4′-(3,3-dimethylbutyloxy)-3′-nitro(1,1′-biphenyl)-4-ol was obtained. Subsequently, dichloromethane solution composed of 4′(3,3-dimethlbutyloxy)-3′-nitro(1,1′-biphenyl)-4-ol, p-octyloxybenzoic acid, and 4-dimethylaminepyridine was added to 1-(3-(dimethylamino)-propyl)-3-ethylcarbodimide methiodine, and the resultant was subsequently stirred all night at room temperature. Subsequently, after the solution was washed with water, the resultant was separated and dried over sodium sulfate. Finally, after the solvent was volatilized, the liquid crystal material of Formula 1(10) was obtained by using column chromatography.
Reaction SMILES: [F:1][C:2]1([CH3:18])[CH2:6][O:5][CH2:4][CH:3]1[NH:7]C(=O)OCC1C=CC=CC=1.[ClH:19]>[Pd].CO>[ClH:19].[F:1][C:2]1([CH3:18])[CH2:6][O:5][CH2:4][CH:3]1[NH2:7]
Reactant: CC1(F)COCC1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(F)COCC1N
Yield: 99 %

Procedure:
A mixture of crude benzyl 4-fluoro-4-methyltetrahydrofuran-3-ylcarbamate (0.597 g, from Step 5), 10% palladium on carbon (0.200 g), 1 N hydrochloric acid (5 mL, 5.00 mmol) and methanol (20 mL) was purged with hydrogen and reacted with 40 psi hydrogen using a Parr Shaker for 2.5 h. The mixture was filtered through a celite pad and the pad rinsed with methanol. The filtrate was concentrated to give crude 4-fluoro-4-methyltetrahydrofuran-3-amine hydrochloride as a tan solid (363 mg). 1H and F NMR showed patterns consistent with the desired product, as a ca. 2:1 mixture of two diastereomers. This material was taken to the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:28][OH:29])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1CCC[CH2:31]1>C(O)=O>[CH2:1]([O:8][CH2:9][CH:10]([N:28]([OH:29])[CH:31]=[O:30])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=S(=O)(CC(COCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: O=CO
Product: O=CN(O)C(COCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine (29.5 g) in tetrahydrofuran (150 ml) and formic acid (25 ml), was added in portions to the above solution at 25° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in methanol (70 ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water-bath temperature 30° C.). The residual foam was stirred in ethanol (250 ml), solid separated and the mixture was stirred for 18 hours. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[2-(benzyloxy)1-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide (25.5 g). mp 118-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:12]1[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[CH:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(S(C)(=O)=O)n1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-4-(6-(5-fluoropyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 6) (132 mg, 0.19 mmol) was heated in phosphorus oxychloride (8 mL) overnight at 95° C. The reaction mixture was allowed to cool to room temperature and then portion wise added to ice water (100 mL) and left to stir for 1 hour. Carefully, NaOH pellets were added to basify the mixture. The resulting aqueous layer was extracted with DCM (100 mL), passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a brown gum (110 mg) used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])=[O:3].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][S:2]([C:4]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])=[O:3]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1S(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 1 h

Procedure:
Combine methyl 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoate (0.46 g, 1.73 mmol) and a 1 M aqueous solution of sodium hydroxide (30 mL, 30 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). After 1 hour, adjust the pH to about 2 using a 1 M aqueous hydrochloric acid solution and extract with ethyl acetate and then dichloromethane. Dry the combined organic layers over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.15 (silica gel, 10% methanol/85% dichloromethane/5% acetic acid).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:32])=[C:12]([CH2:14][C:15]([NH:17][C:18]2([C:28]([O:30]C)=O)[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[O:16])[CH:13]=1.Cl>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:32])=[C:12]([C:14]2[C:15](=[O:16])[NH:17][C:18]3([C:28]=2[OH:30])[CH2:19][CH2:20][C:21]2([O:25][CH2:24][CH2:23][O:22]2)[CH2:26][CH2:27]3)[CH:13]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1C1=C(O)C2(CCC3(CC2)OCCO3)NC1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1.92 g (17.08 mmol) of potassium tert-butoxide were added to 3.64 g (8.54 mmol) of methyl 8-{[(5-bromo-2-methylphenyl)acetyl]amino}-1,4-dioxaspiro[4.5]decane-8-carboxylate (Example 27A) in 43 ml of N,N-dimethylformamide. The reaction mixture was stirred at 80° C. for 30 minutes. For work-up, the cold reaction mixture was poured into 500 ml of ice-water and acidified to pH=4 with aqueous hydrochloric acid. The crude product was filtered off. Drying gave 2.49 g (74% of theory) of the title compound which was used without further characterization in the next step.
Reaction SMILES: C([C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:5][CH:4]=1)=O.OO.[OH:32]S(O)(=O)=O.C([O-])(O)=O.[Na+]>CO>[OH:32][C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(O)cc2)c1

Procedure:
2.3 g (6 mmol) of 1-(4-formylphenoxy)-2-(3-methoxyphenyl)-6-methoxynaphthalene was suspended in 15 mL of MeOH and 1.7 mL (9 mmol) of 30% H2O2 was added. To the stirring mixture, 0.76 mL of conc. H2SO4 was slowly added. An additional 30 mL of MeOH was added and the reaction was allowed to proceed for forty-eight hours. The reaction was neutralized with NaHCO3 solution and extracted with CHCl3. The CHCl3 was washed with brine, dried with Na2SO4, and chromatographed on a silica gel column eluted with CHCl3. This yielded 1.6 g of the title compound as a tan amorphous powder, mp 125–126° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:9]1([CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.Cl[C:20]1[N:24]([CH3:25])[C:23]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]2)=[O:27])=[CH:22][N:21]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:34]([N:31]1[CH2:32][CH2:33][N:28]([C:26]([C:23]2[N:24]([CH3:25])[C:20]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH3:18])=[N:21][CH:22]=2)=[O:27])[CH2:29][CH2:30]1)([CH3:36])[CH3:35]
Reactant: CC(C)N1CCN(C(=O)c2cnc(Cl)n2C)CC1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ncc(C(=O)N2CCN(C(C)C)CC2)n1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A reaction vessel is charged with Pd2(dba)3 (0.0183 g, 0.02 mmol), P(t-Bu)3HBF4 (0.0116 g, 0.04 mmol), K3PO4 (0.127 g, 0.60 mmol), o-tolylboronic acid (0.0408 g, 0.30 mmol) and (2-chloro-3-methyl-3H-imidazol-4-yl)-(4-isopropyl-piperazin-1-yl)-methanone (0.0542 g, 0.20 mmol). Toluene (2.4 mL, anhydrous) is added and the reactor is flushed and sealed under argon. The reaction is stirred at 100° C. for 16 hr; then at rt water (2 mL) and isopropyl acetate (1 mL) are added. The organic layer is removed and the aqueous layer is reextracted with isopropyl acetate. The combined organic extracts are passed through a plug of celite with EtOAc as the eluent. The filtered solution is concentrated to ˜⅓ volume in vacuo and the resulting solution is purified via SCX solid phase extraction. Purification of this crude product via preparative LC-MS gives (4-isopropyl-piperazin-1-yl)-(3-methyl-2-o-tolyl-3H-imidazol-4-yl)-methanone. LC-MS (M+1) 327.3.
Reaction SMILES: [CH3:1][CH:2]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:22])=[C:19]([OH:21])[CH:20]=1)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.OCC(CO)(CO)N.[OH-].[Na+].OS([O-])=O.[Na+].CC(NCCC1C=CC(O)=C(O)C=1)CCC1C=CC(O)=CC=1.Cl.[C:61]([OH:70])(=[O:69])[CH:62]([CH:64]([C:66]([OH:68])=[O:67])[OH:65])[OH:63].C(C(C(C([O-])=O)O)O)([O-])=O>O>[CH3:1][CH:2]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:22])=[C:19]([OH:21])[CH:20]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C@@H:62]([OH:63])([C:61]([OH:70])=[O:69])[C@H:64]([OH:65])[C:66]([OH:68])=[O:67]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(CCc1ccc(O)cc1)NCCc1ccc(O)c(O)c1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O

Procedure:
A preferred method of preparing dobutamine free base involves the use of tris(hydroxymethyl)methylamine in place of aqueous sodium hydroxide. A typical preparation using this procedure is carried out as follows: 500 ml of deoxygenated water for injection (WFI) are placed in a 2 1 3-neck round-bottom flask equipped with N2 inlet, dropping funnel, stirring means and a probe leading to a pH meter. A nitrogen sweep is maintained throughout the operation. 50 mg of NaHSO3 are added and the mixture stirred till solution occurs. 80.16 g of dobutamine hydrochloride are added via a y-tube adapter, and any salt remaining in the addition tube is washed in with an additional 500 ml of deoxygenated water (WFI). The resulting slurry is stirred for 15-20 minutes. 250 ml of 1M aqueous tris(hydroxymethyl) methylamine [30.3 g in 250 ml of deoxygenated water (WFI)] are added in dropwise fashion over a 1-2 hr. period at such a rate that the pH of the solution does not rise above pH=8.5. After the addition is completed, the neutralization mixture is chilled to a temperature in the range 0°-10° C. The chilled solution is then vacuum filtered under N2. The filter cake comprising dobutamine free base is washd with 1200 ml of deoxygenated water (WFI) (in three 400 ml portions). Next, a solution is prepared in a 2 1 beaker by dissolving 35.56 g of (+)-tartaric acid and 1.3 g of NaHSO3 in 1 1 of deoxygenated water (WFI). The filter cake is added with stirring to this solution under N2. After the dobutamine free base has all dissolved, the solution is assayed for dobutamine by UV and the volume of solution now containing the (+)-tartrate salt is adjusted by adding deoxygenated water (WFI) such that the final dobutamine concentration is 50 mg./ml. Five milliliter aliquots are then transferred under N2 to a series of vials. The vials under N2 can be sealed as such or lyophilized and then sealed.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 43 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 43% of theory, C35H42N6O5 (626.8) Rf value: 0.40 (silica gel; dichloromethane/ethanol=19:1) ##EQU68##
Reaction SMILES: [I-].C[S+](C)C.[C:6]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:14]C(C)([O-])C.[K+]>CS(C)=O>[O:13]1[C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:14]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCCCC1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: C1CCCC2(CC1)CO2

Procedure:
To a mixture of trimethylsulfonium iodide (35.7 g) in 300 mL dry DMSO was added 11.2 g of cycloheptanone with stirring. A solution of potassium tert-butoxide (16.83 g) in 200 mL dry DMSO was slowly added. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of water (600 mL), and extracted with diethyl ether (3×200 mL). The combined organic layers were washed with water (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product.