Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#C[Si](C)(C)C)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 90 °C
Reaction time: 0.02 h
Yield: 82.5 %

Procedure:
To a mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol), [1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) CH2Cl2 complex (7.9 mg, 0.01 mmol, 5 mol %) and copper(I) iodide (3.7 mg, 0.019 mmol, 10 mol %) in DMF (2 mL) under an argon atmosphere was added trimethylsilylacetylene (0.08 mL, 0.58 mmol, 3.0 equiv) and triethylamine (0.13 mL, 0.96 mmol, 5.0 equiv). The resulting mixture was heated at 90° C. for 1 h in a microwave apparatus, then concentrated under reduced pressure. The remaining material was separated between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material (112 mg) was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 99% CH2Cl2/1% MeOH for 1 min., gradient to 90% CH2Cl2/10% MeOH over 10 min.; 90% CH2Cl2/10% MeOH for 5.2 min.) to give {1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (84 mg, 82%):
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13]C(=O)C)=[CH:8][N:7]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H-]>O1CCCC1>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(COC(C)=O)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(CO)nc1
Reaction time: 1 h

Procedure:
2,5-Di(acetoxymethyl)pyridine (0.05 mole) is reduced with lithium aluminum hydride (0.025 mole) in tetrahydrofuran (50 ml.) at 0° C. with stirring. After one hour, water is added to decompose excess hydride, and the mixture is concentrated to dryness. The residue is extracted with hot isopropanol (2×60 ml.) and the extract is concentrated to dryness to give 2,5-di(hydroxymethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18](Cl)[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)[OH:27].O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:27])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: O
Solvent: ClCCl
Product: CCCC1(CCC(C)=O)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-[6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]propionic acid (6.8 g, 0.0168 mole) dissolved in methylene chloride (65 ml) was added over 15 minutes to a mixture of sulfuric acid (75 ml) and methylene chloride (35 ml) at 5° C., stirred at 5° C. for 1 hour, poured over ice and water, and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from butyl chloride to obtain the product mp 131°-3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCCN1CC=C(c2ncco2)CC1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: OC(CCCN1CCC(c2ncco2)CC1)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
A 0.32 g. portion of 3,6-dihydro-α-(p-fluorophenyl)-4-(2-oxazolyl)-1(2H)-pyridinebutanol, prepared as described in Example 15, is dissolved in 10 ml. of ethanol and 0.1 g. of palladium on carbon catalyst is added. The mixture is reduced at room temperature and pressure for 4 hours and then filtered. The filtrate is evaporated giving an oil which solidifies to a white solid. This solid is recrystallized twice from acetonitrile, m.p. 99°-100°C.
Reaction SMILES: [OH:1]O.[F:3][C:4]([F:29])([CH:26]([F:28])[F:27])[CH2:5][O:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1>CO>[F:3][C:4]([F:29])([CH:26]([F:28])[F:27])[CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([OH:1])=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CC1(C)OB(c2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)OC1(C)C
Reactant: OO
Solvent: CO
Product: Oc1cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Hydrogen peroxide (1.29 mL, 13.33 mmol, 35% solution) was added to a solution of 2-(2,2,3,3-tetrafluoropropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine (Preparation 261, 4.45 g, 11.04 mmol) in methanol (50 mL) at 0° C. (ice-bath) and the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction was quenched with 1M solution of sodium thiosulfate and then methanol was removed in vacuo. The residue was partitioned between ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 30% heptane in ethyl acetate to give the title compound as a oil (2.95 g, 91%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:19][CH:18]=1.Cl>C1COCC1.CCCCCC>[C:17]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=[CH:19][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A dispersion of sodium hydride in a mineral oil (60%) (0.22 mol) was treated with hexane under N2 flow to remove the oil and then dispensed in THF (100 ml) under N2 flow. Ethyl (diethylphosphono)acetate (0.22 mol) was added dropwise. The mixture was stirred for 30 minutes until the gas development has stopped. A mixture of (1,1′-biphenyl)-4-ylphenylmethanone (0.2 mol) in THF (100 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, then stirred and refluxed for 17 hours, cooled, poured out into HCl 10% and ice and extracted three times with DCM. The combined organic layer was washed once with a saturated K2CO3 solution, twice with H2O and once with a saturated NaCl solution, then dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc/hexane 1/1/98). Two pure fractions were collected and their solvents were evaporated. Fraction 2 was crystallized from 2-propanol. The precipitate was filtered off and dried. The mother layer was evaporated and combined with fraction 1, yielding 45 g of ethyl 3-[(1,1′-biphenyl)4-yl]-3-phenyl-2-propenoate (interm. 18).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]1([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH2:19]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+].O>CO>[C:10]1([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH2:19][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Solutions of dimethyl malonate (1.32 g) in dry methanol (5 ml) and 3-phenylbenzyl bromide (2.47 g) in dry methanol (5 ml, hot solution) were added successively to a stirred solution of sodium methoxide [from sodium (0.23 g) and dry methanol (20 ml)]. The resulting mixture was stirred for 2 hours at room temperature and for 2 hours under reflux, then poured into water and extracted with ether. The extracts were washed with water, dried, concentrated and purified by column chromatography using a 1:1 mixture of dichloromethane and 40°-60° C. petrol as eluant to give dimethyl (m-phenylbenzyl)malonate (1.77 g, 59%) as a yellow oil, lR (film) : 1 755 and 1 740 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N([O-])=O.[Na+].[I:19]I>C(O)(=O)C.Cl.O>[I:19][C:11]1[CH:13]=[CH:14][C:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Ic1ccc(Cc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
A solution of 4-(pyridin-4-ylmethyl)aniline (679 mg, 3.7 mmol) in acetic acid (1.84 mL) and concentrated hydrochloric acid (0.787 mL) was cooled to 0° C. NaNO2 (280 mg, 40.7 mmol) in water (1.23 mL) was added dropwise and the reaction mixture was allowed to stir for 30 min. A solution of KI (737 mg, 4.44 mmol) and iodine (563 mg, 2.22 mmole) in water (3.7 mL) was added dropwise to the above solution. The solution stirred for 30 min at 0° C. and for 1 h at rt. The reaction was quenched by the addition of aq. NaS2O4 and the solution was extracted with EtOAc. The combined organic solutions were washed with sat. NaHCO3, brine and 1% NaOH, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (140 mg, 18%). LCMS: (FA) ES+ 296.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:13])[CH3:12].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:13][CH2:11][CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCNC(C)c1ccc(Cl)nc1
Reaction time: 8 h
Yield: 80 %

Procedure:
6-chloro-3-acetylpyridine (1.03 g, 0.3 mmol) and a 30% ethylamine-methanol solution (1.0 mL) were mixed with 8 mL of chloroform, and the mixture was subjected to refluxing. After 8 hours, 1 mL of 30% ethylamine-methanol solution was added and stirring was continued for 12 hours at the same temperature. The chloroform was distilled off and the residue was dissolved in 10 mL of methanol, then ice-cooled. Sodium borohydride (1 g) was added a little at a time, and the system was stirred overnight. The methanol was distilled off, and the residue was extracted with acetonitrile. The extract was then concentrated under reduced pressure. Acetonitrile extraction and concentration under reduced pressure were each repeated another two times, following which the residue was dissolved in chloroform, washed with 1% aqueous NaOH, and the chloroform phase was dried over solid KOH. The chloroform was distilled off under reduced pressure, giving 790 mg of crude N-[1-(6-chloro-3-pyridyl)ethyl]-N-ethylamine product (purity, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:18][NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: N#Cc1c[nH]nc1N
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2n[nH]cc2C#N)cc1OC1CCCC1
Reaction time: 24 h

Procedure:
A solution of 3-amino-4-cyanopyrazole (5.0 g, 0.16 mol), 3-cyclopentyloxy-4-methoxybenzaldehyde (10.0 g, 0.045 mol) and sodium acetate (0.2 g, 2.4 mol) in methanol (70 mL) was placed in a stirred reaction flask equipped with a pH stat controlling a syringe pump and syringe filled with 3 N acetic acid in methanol. The pH stat was set to maintain pH 7. After 24 hours, more 3-cyclopentyloxy-4-methoxybenzaidehyde (7.0 g, 0.031 mol) was added and the reaction was continued. After 48 hours, more 3-cyclopentyloxy-4-methoxybenzaldehyde (4.0 g, 9.0 mmol) and sodium cyanoborohydride (0.5 g, 7.9 mmol) was added and the reaction was continued. After 72 hours, more sodium cyanoborohydride (0.5 g, 7.9 mmol) was added and after 96 hours, the reaction was stopped log and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (75mL) and water (50 mL). The ethyl acetate layer was washed with water (2×50 mL) and evaporated. The crude product was chromaotgraphed over 200 g of flash chromatography silica gel. Elution with 2% methanol/methylene chloride removed some impurities including 3-cyclopentyloxy-4-methoxybenzyl alcohol. Continued elution with methanol/methylene chloride mixtures of increasing methanol concentration afforded 8 g (56%) of nearly pure title compound. Pure 3-(3-cyclopentyloxy-4-methoxy-benzylamino)-4-cyanopyrazole, mp 159-160° was obtained by recrystallization from methanol.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:6]([CH2:8][CH2:9][O:10]C2CCCCO2)[CH:7]=1)[CH3:2].[Cl:30]CCl.[ClH:33]>CO>[ClH:30].[ClH:33].[CH2:1]([C:3]1[N:4]=[C:5]([CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1cn(CCOC2CCCCO2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CO
Product: CCc1cn(CCO)c(C2CCNCC2)n1
Reaction time: 8 h
Yield: 100 %

Procedure:
Combine tert-butyl 4-(4-ethyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (4.70 g, 11.53 mmol), dichloromethane (100 mL), and methanol (50 mL). Add hydrogen chloride (20 mL) (4 M in dioxane) slowly. Stir overnight under nitrogen. Concentrate in vacuo to give the title compound (3.40 g, 100%). MS (ES) m/z=224 [M]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14]Br)[CH2:2][CH2:3][CH3:4].[CH:16]([NH:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].C1(C)C=CC=CC=1>O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:19]([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccccc1OCCBr
Reactant: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccccc1OCCN(C(C)C)C(C)C
Yield: 53.5 %

Procedure:
The thus obtained 1-n-butoxy-2-(2'-bromoethoxy)-benzene (2.73 g, 10 mmole) was heated under reflux for 160 hours with diisopropylamine (4.0 g; 40 mmole) and toluene (25 ml). The reaction mixture was shaken with water until the precipitated salt had dissolved. The toluene phase was then extracted with an excess of dilute hydrochloric acid. The extracts were washed twice with ether and then made alkaline with sodium hydroxide solution. The precipitated base was taken up in ether and the aqueous phase extracted once more with ether. The ether extracts were washed once with water and then dried over potassium carbonate. The solvent was evaporated and the residue distilled to yield 1.57 g (53.5%) of product with b p 104°-105° C at 0.02 mm Hg; nD25 = 1.4936.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=1)=[O:27]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: Cc1cccc(CNC(=O)C(C)C(=O)O)c1
Product: Cc1cccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
The title compound, MS: m/e=468.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3-methyl-benzyl)-malonamic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl>ClCCl>[CH3:27][O:28][CH2:29][O:1][CH:2]1[CH2:3][CH2:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(O)CC1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C(=O)OCC)CCC(OCOC)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
12.3 g of diethyl 4-hydroxycyclohexane-1,1-dicarboxylate was dissolved in 160 ml of dichloromethane and 26.3 ml of diisopropylethylamine was added thereto followed by ice-cooling. Next, 9.6 ml of chloromethyl methyl ether was added thereto and the reaction mixture was stirred at room temperature for 15 hours. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 11.10 g of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:10]2[NH:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[O:24][CH3:25])[CH2:7]1)=O)[CH3:2].[O-]S([O-])(=O)=O.[Na+].[Na+].CS(O)(=O)=O>C1COCC1.CC(C)=O>[CH2:39]([N:3]([CH2:4][CH:6]1[CH2:7][N:8]2[CH2:13][CH2:12][CH:11]1[CH:10]([NH:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])[CH:9]2[CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:1][CH3:2])[CH3:40]
Reactant: CCN(CC)C(=O)C1CN2CCC1C(NCc1cc(OC)ccc1OC)C2C(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCN(CC)CC1CN2CCC1C(NCc1cc(OC)ccc1OC)C2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A solution of 19 (300 mg, 0.55 mmole) in dry THF (2 ml) was added to a suspension of LiAIH4 (105 mg, 2.75 mmole) in 5 ml of dry THF at 5° C. and stirred at room temperature for 1 hour. Na2SO4 /10H2O (2 g) was added to the reaction mixture and stirred for 15 hours at room temperature. The suspension was filtrated, and the solids were washed with dry THF. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in 2 ml of acetone, and CH3SO3H (159 mg, 1.65 mmole) was added to the solution of the crude oil in acetone (2 ml). The resulting precipitate was collected by filtration and dried in vacuo to give 20 (254 mg, 0.31 mmole, 57%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18]C(OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:33]1[CH:34]=[N:35][N:36](C2CCCCO2)[CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][C:45](O)=O>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:44]([CH3:45])=[N:18][N:17]=3)[C:11]=2[CH:10]=[C:9]1[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cnn(C4CCCCO4)c3)n2Cc2ccccc2)n1
Reactant: CC(=O)O
Product: Cc1nnc2ccc3c(cc(-c4cn[nH]c4)n3Cc3ccccc3)n12

Procedure:
di-tert-Butyl 1-{1-benzyl-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-5-yl}hydrazine-1,2-dicarboxylate (68 mg, 0.12 mmol, from Step 2) in AcOH (4 mL) was heated in the microwave to 180° C. for 9 minutes. The acetic acid was removed in vacuo, and the residue was reconstituted in MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (17 mg, 45%).
Reaction SMILES: N[C:2]1[C:3]([I:21])=[C:4]([C:9]([I:20])=[C:10]([N:13](CCO)C(=O)C)[C:11]=1[I:12])[C:5]([NH:7][CH3:8])=[O:6].[Cl-].O.C[C:25]([N:27](C)[CH3:28])=[O:26]>>[NH2:13][C:10]1[C:9]([I:20])=[C:4]([C:5]([NH:7][CH3:8])=[O:6])[C:3]([I:21])=[C:2]([C:11]=1[I:12])[C:25]([NH:27][CH3:28])=[O:26]
Reactant: CNC(=O)c1c(I)c(N)c(I)c(N(CCO)C(C)=O)c1I
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Solvent: O
Product: CNC(=O)c1c(I)c(N)c(I)c(C(=O)NC)c1I
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-amino-5-[N-(2-hydroxyethyl)acetamido]-2,4,6-triiodo-N-methylbenzamide (II; 50.32 g.; 0.08 mole) dissolved in dimethylacetamide (252 ml.) was added in one portion 2,3,4,5,6-O-pentaacetylgluconyl chloride (101.88 g.; 0.24 mole; prepared by the method of C. E. Braun and C. D. Cook, Org. Syn., 41, 79 (1961)). After being stirred for six days at room temperature, the reaction mixture was poured into a mixture of dimethylacetamide (510 ml.) and water (680 ml.). The mixture was stirred for 2 hours, after which it was extracted with chloroform (3×340 ml.). The combined chloroform extracts were washed with 5% aqueous bicarbonate (2×340 ml.) and water (340 ml.), dried over sodium sulfate and evaporated under reduced pressure to give III as an oil, 132.75 g. (>100% due to the presence of dimethylacetamide as shown by the nuclear magnetic resonance spectrum). The product was homogeneous by thin-layer chromatography (ethyl acetate-acetic acid, 98:2), and the nuclear magnetic resonance spectrum was consistent with the assigned structure. The product was hydrolyzed without further purification.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[C:7]([C:3]1[N:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: Nn1cccc1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccccc1
Yield: 95.6 %

Procedure:
To a mixture of 1-amino-2-benzoylpyrrole (12.3 g, 66 mmol) and sodium bicarbonate (13.9 g, 165 mmol) in 250 ml of dichloromethane was added a solution of ethyl chloroformate (8.2 g, 75 mmol) in 50 ml of dichloromethane. This mixture was stirred at reflux for 5 hours and then quenched with 150 ml of ice. The dichloromethane layer was separated, washed with water, dried over anhydrous Na2SO4, filtered and evaporated to an oil. This oil solidified upon trituration with hexane to give 16.3 g (96%) of powder, m.p. 68°-70°.