Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]3[C:17](=[O:18])[N:16](C(OC(C)(C)C)=O)[S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].C(OC([C:33]1[C:42](=O)[C:41]2[C:36](=[CH:37]C(Br)=C(F)C=2)[N:35](C2CC2)[C:34]=1SC)=O)C.[C:51]([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:27])=[C:2]([C:42]4[CH:33]=[C:34]([CH3:51])[N:35]=[C:36]([CH3:37])[CH:41]=4)[CH:11]=3)[C:6](=[O:26])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]2=3)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1c(SC)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)n1sc2c(c(=O)c3cc(F)c(Br)cc3n2C2CC2)c1=O
Reactant: O=C([O-])O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)cc(C)n1

Procedure:
A mixture of tert-butyl 7-bromo-9-cyclopropyl-6-fluoro-3,4-dioxoisothiazolo[5,4-b]quinoline-2(3H,4H,9H)-carboxylate (8, 22 mg, 0.048 mmol), 4-(2,6-Dimethylpyridyl)boronic acid (5, 23 mg, 0.12 mmol) and Pd (PPh3)4 (4 mg) in a solution of DMF (1 ml) and 1M NaHCO3 (0.22 ml) is sealed in a microwave reaction vessel with a stirrer. After filling with helium, the mixture is microwaved at 100 W, 130° C. for 10 minutes. The reaction is followed by LC-MS. The reaction mixture is filtered and the filtrate evaporated to dryness. The residue is washed with a solution of methanol and ethyl ether (5:95) (3×3 ml), and dried in vacuum yielding pure product 25. 1H NMR (300 MHz, DMSO-d6) δ 1.1-1.3 (m, 4H, —CH2—), 1.53 (s, 1H, —CH—), 2.47 (s, 6H, —CH3), 7.27 (s, 2H, Ar), 7.93, (d, 1H, Ar), 8.2 (d, 1H, Ar). 19F NMR (350 MHz, DMSO-d6) δ 125 (s, 1F). MS, m/z 382 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C@H:44]([N:46]=[C:47]=[O:48])[CH3:45])=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl>[F:37][C:38]1[CH:39]=[CH:40][C:41]([C@@H:44]([NH:46][C:47]([NH:17][C:15]2[N:14]=[CH:13][C:12]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][NH:10][C:11]=3[CH:16]=2)=[O:48])[CH3:45])=[CH:42][CH:43]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)ccn1
Reactant: C[C@@H](N=C=O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cc(-c2n[nH]c3cc(NC(=O)N[C@@H](C)c4ccc(F)cc4)ncc23)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
A mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (intermediate 5a; 50 mg, 0.107 mmol) and 1-fluoro-4-[(1R)-1-isocyanatoethyl]-benzene (75 mg, 0.454 mmol) in 1,4-dioxane (1 mL) was heated to 60° C. overnight, then cooled down to RT and concentrated in vacuo. The residue was suspended in DCM and purified by chromatography on silica gel (0-50% MeOH/DCM) to yield a solid, which was directly dissolved in DCM (1 mL) and treated with TFA (1 mL). The mixture was stirred at RT for 3 h, then concentrated in vacuo and purified via reverse phase HPLC over a gradient of 20-55% MeCN with 0.1% TFA. The collected fractions were then partitioned between DCM/MeOH and 1N NaOH. The organic layer was dried (Na2SO4) and concentrated in vacuo to provide 1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea as a solid (13 mg, 0.033 mmol, 31%). MS ESI calc'd. for C21H20N6OF. [M+1]+ 391, found 391.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([Cl:10])[N:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C)C=[O:22].N1C=CN=C1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:22][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: CN(C)C=O
Reactant: ClCc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Cl)nc(Cl)c1
Reaction time: 5.5 h

Procedure:
0.30 g of 2,6-dichloro-4-chloromethylpyridine and 0.25 g of tert-butyldimethylsilyl chloride were added to 4.0 ml of dimethylformamide, and were dissolved. The solution was cooled in an ice bath. After 0.14 g of imidazole was added, stirring was conducted at room temperature for 5.5 hours. Ethyl acetate was added to the reacted solution. The organic phase was washed with water, and was dried by adding sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 0.41 g of 2,6-dichloro-4-((1,1-dimethylethyl)dimethylsilyl)oxymethylpyridine (Compound No. 96).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7](I)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.O>CN(C=O)C.C(NCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(OC)cc1
Reactant: CC(C)(C)c1ccc(O)c(I)c1
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(C(C)(C)C)ccc3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-t-butyl-2-iodophenol [38941-98-9] (1.09 g, 3.6 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with MeOH, filtered to give 84 as a solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a cooled (0° C.), stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 ml) was added DIAD (11.4 ml, 0.06 mol), and the reaction mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (30 ml) and TFA (30 ml). The solution was stirred at room temperature for 30 min. and the solution was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaRCO3, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3—MeOH (9:1, v/v) as eluent to give benzyl (S)-4-(2-amino-1-propoxy)benzoate (6.63 g, 2 steps, 60%) as a yellow oil. 1H-NMR (CDCl3) δ1.18 (d, J=6.3 Hz, 3 H), 3,35-3.39 (m, 1 H), 3.71-3.75 (m, 1 H), 3.90-3.93 (m, 1 H), 5.34 (s, 2 H), 6.90-6.93 (m, 2H), 7.32-7.46 (M, 5H), 8.01-8.04 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14](O)=[O:15])=[CH:6][CH:5]=1)([OH:3])=O.[C:18](O)(=O)/[CH:19]=[CH:20]\[C:21](N)=O.[C:26]([O-])(=O)[CH3:27].[Na+]>C(OC(=O)C)(=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:17])[CH:12]=[CH:13][C:14]2=[O:15])=[CH:6][CH:5]=1)(=[O:3])[C:18]1[CH:27]=[CH:26][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)[O-]
Reactant: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Reactant: NC(=O)/C=C\C(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(c1ccccc1)c1ccc(N2C(=O)C=CC2=O)cc1

Procedure:
The method of Example 2 was employed, but, in place of the product of Example 1 the maleamic acid from Example 3 (15.0 g, 0.0508 mol) and anhydrous sodium ethanoate (3.00 g) in ethanoic anhydride (150 ml) were used. The maleimide was obtained. 1H-n.m.r (DMSO): δ 7.91 (4H, m, N-Ph); 7.52 (5H, m, Ph); 6.89 (2H, s, CH=CH), H.p.l.c. 100%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:18][CH2:19][CH2:20]Br.[CH2:22](OCC)C>C(#N)C>[Br:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:22])=[O:10])=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: CCOCC
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cc1ccc(OCCBr)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2 L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2 L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2), 2.61 (m, 1H); ES-MS (m/z) 458 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=O.[PH2:12]([OH:14])=[O:13]>C1(C)C=CC=CC=1>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:1]([P:12]([CH:6]2[C:5]3[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:1](=[O:3])[O:7]2)(=[O:14])[OH:13])[O:3]1
Reactant: O=[PH2]O
Reactant: O=Cc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Product: O=C1OC(P(=O)(O)C2OC(=O)c3ccccc32)c2ccccc21
Yield: 91.5 %

Procedure:
Into a suspension of 30.1 grams (0.2 moles) of 2-carboxybenzaldehyde in 220 mL of toluene is added 10.4 mL (0.1 moles) of 50% aqueous hypophosphorous acid. The resultant mixture is heated to reflux and 9 mL of water is collected by azeotropic distillation using a Dean-Stark receiver. Upon cooling the reaction mixture, the precipitated white solid is collected by filtration and dried to give 30.2 grams (91% yield) of bis-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-phosphinic acid as a white powder, mp 280-285° C.
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=[N:12][OH:13])[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([N:24]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([N:12]=[O:13])[C:9]([CH3:10])=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)C(=NO)C(=O)c1ccccc1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1nn(Cc2ccccc2)c(-c2ccccc2)c1N=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a 0° C. solution of 2.32 g of 1-phenyl-butane-1,2,3-trione 2-oxime in 31 mL of EtOH was added a suspension of 2.43 g benzyl hydrazine dihydrochloride in 9 mL EtOH. The reaction mixture was warmed to rt and stirred for 96 h. The reaction mixture was concentrated under reduced pressure and purified by means of MPLC (120 g SiO2, 45% EtOAc:Heptane) to obtain 1-benzyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole. A suspension of 2.55 g 1-benzyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole, 34 mL EtOAc and 500 mg 10% Pd/C was reacted under 40 psi H2 atmosphere using a Parr apparatus. After 4 h, the suspension was filtered through Celite (EtOH eluting) and the filtrate was concentrated under reduced pressure and purified by means of MPLC (120 g SiO2, 60% EtOAc:Heptane) to give the title compound as an orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-])=O.Cl.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N:18]1[CH:19]=[CH:20][C:15]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)=[CH:16][CH:17]=1
Reactant: Clc1ccncc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2c(ccn2-c2ccncc2)c1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
To a solution of 5-nitroindole (7.0 g, 43.2 mmol) and 4-chloropyridine hydrochloride (7.8 g, 51.8 mmol) in DMF (43 mL) was added potassium tert-butoxide (12.1 g, 108.0 mmol), portionwise. The reaction was heated at 100° C. for 48 h. The mixture was allowed to cool to room temperature and poured into water (400 mL). The resulting solid was removed by filtration and dried under vacuum. Desired compound (6.04 g, 25.3 mmol; 58% yield); 1H NMR (DMSO-d6) δ 8.76 (dd, J=1.7, 4.5, 2H), 8.68 (d, J=2.2, 1H), 8.06-8.13 (m, 2H), 7.92 (d, J=9.2, 1 H), 7.75 (dd, J=1.5, 4.6, 2H), 7.07 (dd, J=0.9, 3.5, 1H); ES MS [M+H]+=240. Step 2. Preparation of 1-(4-pyridinyl)-1H-indol-5-amine
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>ClCCl>[Cl:13][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(Cl)c1
Yield: 73.9 %

Procedure:
A mixture of 8.26 g of ethyl 4-aminobenzoate, 8.26 g of N-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight. The mixture is washed with saturated NaHCO solution and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated and hexane added. Chilling gives 7.38 g of ethyl 3-chloro-4-aminobenzoate, m.p. 82°-83° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16](O)[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[CH:10]=[CH:9]2>>[ClH:3].[CH3:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]([Cl:3])[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[CH:10]=[CH:9]2
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2cc(C(O)Cn3ccnc3)ccc2c1
Product: Cc1ccc2cc(C(Cl)Cn3ccnc3)ccc2c1
Product: Cl

Procedure:
Thionyl chloride (5 ml.) and 2.0 g. of 1-[2-(6-methyl-2-naphthyl)-2-hydroxyethyl]imidazole are stirred at room temperature for about 20 minutes. Thereafter, the solution is evaporated to dryness and the residue is treated with ethyl acetate and filtered to yield 1-[2-(6-methyl-2-naphthyl)-2-chloroethyl]imidazole hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][N:22]4[CH:26]([C:5]=3[C:4]=2[CH:3]=1)[CH2:25][CH2:24][CH2:23]4.[C:27](O)(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[O:13][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:6]3[CH2:20][CH2:21][N:22]4[CH:26]([C:5]=3[C:4]=2[CH:3]=1)[CH2:25][CH2:24][CH2:23]4
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Reactant: O=C(O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)CCC(=O)O)c2ccncc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
2-(10-Methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol (350 mg, 1 mmol), succinic acid (118 mg, 1 mmol) and dimethylaminopyridine (122 mg, 1 mmol) in DCM (20 mL) were stirred at RT. Dicyclohexylcarbodiimide (206 mg, 1.6 mmol) in DCM (20 mL) was added dropwise and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated to obtain the crude product that was purified by reverse phase HPLC to yield 4-(2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethoxy)-4-oxobutanoic acid (96 mg). 1H NMR (CD3OD, freebase) δ (ppm): 8.46 (d, 2H), 7.33 (d, 2H), 7.27 (d, 1H), 7.23 (s, 1H), 7.01 (d, 1H), 6.07 (t, 1H), 4.8 (t, 2H), 4.5 (m, 2H), 3.55 (m, 2H), 3.45 (m, 1H), 3.0 (q, 2H), 2.7 (m, 1H), 2.54 (m, 2H), 2.39 (s, 3H), 2.37 (m, 1H), 2.1 (m, 4H). Separation by chiral HPLC provided diastereomers V-18a-d.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10](O)[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:4][C:3]=2[O:2]1>C(OCC)(=O)C.[Pd](Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(CCCC(O)c2ccc3c(c2)OCO3)cc(OC)c1OC
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Product: COc1cc(CCCCc2ccc3c(c2)OCO3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
Dissolved in 20 ml of ethyl acetate were 500 mg (1.39 mmol) of 1-(3,4-methylenedioxyphenyl)-4-(3,4,5-trimethoxyphenyl)butan-1-ol, followed by the addition of 5 mg of palladium chloride. The resulting mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere of 1 atm. Insoluble matter was removed by filtration and the filtrate was then concentrated. The concentrate thus obtained was purified by column chromatography (silica gel: "MERCK #9385", 50 g, eluent: 1:5 mixed solvent of ethyl acetate and hexane), whereby 388 mg of the title compound were obtained as colorless oil (yield: 81%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](=[O:20])[CH2:11][P:12]([CH3:19])(=[O:18])[O:13]CC(C)C)=O)(C)(C)C>Cl>[NH2:8][CH2:9][C:10](=[O:20])[CH2:11][P:12]([CH3:19])(=[O:13])[OH:18]
Reactant: CC(C)COP(C)(=O)CC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Product: CP(=O)(O)CC(=O)CN
Temperature: 25 °C

Procedure:
A solution of 0.5 g of isobutyl P-(3-tert.-butoxycarbonylamino-2-oxo-propyl)-P-methyl-phosphinate in 10 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 4 hours. The mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and coevaporated twice with 20 ml of water. The crude product is dissolved in 20 ml of ethanol, 1 ml of propylene oxide is added, and the mixture is stirred until the precipitated solid is free of halogen. The solid is filtered and dried to give P-(3-amino-2-oxo-propyl)-P-methyl-phosphinic acid, m.p. 148°-149°, 31P-NMR spectrum: δ=32.8 ppm (D2O).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:38][CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NC1CCc2ccccc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCc4ccccc43)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (25 mg) was reacted with 2,3-dihydro-1H-inden-1-amine via General Procedure E to give 10.6 mg of 271 following reverse phase purification. MS (Q1) 495.2 (M)+
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=O)(=[O:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:15]=[C:14]([C:11](=[O:13])[CH3:12])[CH:22]=[CH:21][CH:20]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-acetylbenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.72 (s, 3H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.80 (t, J=8.1 Hz, 1H), 8.31 (ddd, J=8.1, 1.4, 1.2 Hz, 1H), 8.47 (ddd, J=8.1, 1.4, 1.2 Hz, 1H), 8.59 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.75 (dd, J=5.2, 1.6 Hz, 1H), 8.81 (t, J=1.4 Hz, 1H), 9.32 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 266 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][OH:13])[C:9]#[N:10])=[C:4]([CH3:14])[CH:3]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O.[BH4-].[Na+].NCCNCCN>CO>[C:19]([O:18][C:16](=[O:15])[NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:14])[CH2:11][CH2:12][OH:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(Br)ccc1C(C#N)CCO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NCCNCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)ccc1C(CCO)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To a solution of 2-(4-bromo-2-methyl-phenyl)-4-hydroxy-butyronitrile (27.3 g, 0.1074 mol) in MeOH (750 mL) at 0° C. was added (BOC)2O (46.9 g, 0.2149 mol), followed by NiCl2.6H2O (2.55 g, 0.01074 mol) and sodium borohydride (27.83 g, 0.7359 mol). The mixture was stirred at room temperature for 24 hours, and diethylenetriamine (12 mL, 0.1074 mol) was added. The reaction mixture was stirred for 30 minutes, then solvent was evaporated under reduced pressure. The resulting crude material was partitioned between NaHCO3 (10% aqueous solution) and EtOAc. The organic phase was washed with water and brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 6/4) to give 30.3 g (79% yield) of [2-(4-bromo-2-methyl-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([NH2:11])[CH2:10][CH:4]([CH2:5]2)[CH2:3][CH:2]1[CH2:9]3.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CN(P(N(C)C)(N(C)C)=O)C>O>[C:8]12([NH:11][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[CH2:10][CH:4]3[CH2:5][CH:6]([CH2:1][CH:2]([CH2:3]3)[CH2:9]1)[CH2:7]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A mixture of 1.51 g. (0.01 mole) of 1-adamantamine, 1.41 g. p-fluoronitrobenzene and 1.38 g. K2CO3 in 10 ml. HMPA was stirred overnight in an oil bath at 135°. The mixture was allowed to cool, diluted with H2O and extracted thoroughly with C6H6. The organic layer was washed in turn with H2O and brine and taken to dryness. The waxy residue was recrystallized twice from Me2CO:cyclohexane to give 1.82 g. (67%) of N,1-adamantyl-p-nitroaniline, m.p. 188°-189°.