Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]3[N:28]([CH:29]=2)[CH2:27][CH2:26][S:25]3)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Cl.NO.[CH3:33][N:34](C)C=O>C(Cl)CCl.N1C=CC=CC=1>[C:33]([C:29]1[N:28]2[C:24]([S:25][CH2:26][CH2:27]2)=[N:23][C:22]=1[C:13]1[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]([OH:17])=[C:11]([C:7]([CH3:8])([CH3:9])[CH3:10])[CH:12]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Agent: Cl
Agent: NO
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)c1cc(-c2nc3n(c2C#N)CCS3)cc(C(C)(C)C)c1O

Procedure:
To a mixed solution of 0.5 g of dimethylformamide and 10 ml of ethylene dichloride was added dropwise a solution of 0.9 g of oxalyl chloride in 5 ml of ethylene dichloride under ice-cooling. After allowing to stand the mixture for 15 minutes at room temperature, a solution of 2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole dissolved in a mixture of 3 ml of dimethylformamide and 10 ml of ethylene dichloride was added dropwise to the solution and the resultant mixture was stirred for 2 hours. Then, a solution of 0.5 g of hydroxylamine hydrochloride dissolved in a mixture of 1.5 ml of dimethylformamide and 0.6 ml of pyridine was added to the reaction mixture and the resultant mixture was refluxed overnight. The reaction mixture was washed with 30 ml of an aqueous 5% sodium hydrogen carbonate solution, dried, and then concentrated. The residue thus formed was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.33 g of 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CN(C)CCCO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCCN(C)C)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (100 mg, 0.234 mmol) in DMF (5 mL) were added 3-(dimethylamino)-1-propanol (121 mg, 1.170 mmol), EDC (90 mg, 0.468 mmol) and DMAP (2.86 mg, 0.023 mmol). The resulting mixture was stirred at room temperature overnight, the reaction mixture was concentrated in vacuo, dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (HpH). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(dimethylamino)propyl 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (23 mg, 19%) as a colourless oil. LCMS (Formate, 2 min), Rt=0.70 min, MH+=513.
Reaction SMILES: Cl.N[N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]#[N:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20].C(O)CCC>>[CH3:20][C:19]1[N:22]=[C:8]([NH2:9])[C:4]2=[CH:5][CH:6]=[CH:7][N:3]2[N:21]=1
Reactant: N#Cc1cccn1N
Reactant: CC(=N)N
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1nc(N)c2cccn2n1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carbonitrile hydrochloride (2.77 g, 19.3 mmol), potassium phosphate (21.11 g, 96.5 mmol), acetamidine hydrochloride (9.6 g, 96.5 mmol) and 1-butanol (166 mmol) was refluxed under nitrogen atmosphere. After 166.5 h of reflux, the mixture was allowed to cool to rt, and was then partitioned between ethyl acetate and water. The phases were separated, and the organic phase was extracted with 1N aqueous hydrochloric acid. The acid extracts were made basic (pH>7) and extracted with ethyl acetate. After washing the organic layers with water and brine, drying (anhydrous sodium sulfate) and concentration afforded 1.63 g (57%) of solid. 1H-NMR (CD2Cl2): δ 7.51 (m, 1 H), 6.40 (m, 2 H), 6.72 (br s, 2 H), 2.32 (s, 3 H). MS: LC/MS (+esi), m/z=149 [M+H]. RT=1.12 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(O)c1ccc(O)c(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCC=Cc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Hydroxy-5-(1-hydroxyoctadecyl)benzoic acid (100 mg) was dissolved in 20 ml of benzene and a trace of p-toluenesulfonic acid monohydrate added. The solution was refluxed for 10 minutes, then 10 ml of solvent was distilled. Reflux was continued for about 18 hours. Upon cooling to room temperature, the solution was extracted with 1% sodium bicarbonate solution and the solvent removed under a stream of nitrogen gas to give crystals. The material was recrystallized from methanol to give the title compound, m.p., ca. 95° C. ##STR11##
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3C(OC)=O)=[O:14])[CH2:4][CH2:3]1.O>[OH-].[Na+].CO>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([NH:12][CH:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCN(C)c4ccccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCC(NC(=O)Nc2cccc3[nH]ncc23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in example 95B was dissolved in 2 mls of 5N NaOH in methanol and stirred for 2 hours at ambient temperature. Water was added to the reaction mixture and the precipitate was collected. The precipitated compound was redissolved in 10% methanol in dichloromethane and purified by flash chromatography on silica using a gradient from dichloromethane to 20% methanol in dichloromethane with a few drops of NH4OH as the solvents to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.99 (s, 1 H) 8.53 (s, 1 H) 8.01 (s, 1 H) 7.70 (d, J=7.46 Hz, 1 H) 7.21 (t, J=7.97 Hz, 1 H) 7.11-7.17 (m, 2 H) 7.07 (t, J=8.48 Hz, 1 H) 6.58-6.72 (m, 3 H) 4.76-4.85 (m, 1H) 3.15-3.29 (m, 2 H) 2.89 (s, 3 H) 1.99 (s, 2 H). MS (DCI/NH3) m/z 322.0 (M+H)+.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of toluene (20 ml), diphenyl phosphite (2.07 g, 6.7 mmole), imidazole (1.09 g, 16 mmole) and o-chlorophenyldiphenylmethanol (2.95 g, 10 mmole) obtained in Example 1 (A) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was washed with a 5% aqueous potassium hydroxide solution (20 ml). The toluene layer was separated, washed with water, dried and evaporated to give a crystalline mass. Recrystallization from acetonitrile gave 2.57 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 74.5%. M.P., 142°-143° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:4][CH:3]([CH2:2][CH3:6])[CH2:5][O:7][C:6](=[O:8])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH:1][C:18](=[O:19])[CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)COC(=O)[C@@H](NC(=O)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 136.4 %

Procedure:
To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0° C. was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22](O)=[O:23].C(OC(=O)C)(=O)C>CN(C=O)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][CH:22]=[O:23]
Reactant: O=CO
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 1 mmol of phenylalanine methyl ester hydrochloride and 2 mmol of triethylamine in 1 mL of DMF at 0 ° C. was added 2 mL of formic acid and 0.7 mL of acetic anhydride. After stirring for 16 h at rt, extractive isolation provided N-formylphenylalanine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]([N:18]2[CH2:17][CH2:16][N:15]([C:9]3[C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:2]([Cl:1])=[C:3]4[C:8]=3[N:7]=[CH:6][CH:5]=[CH:4]4)[CH2:20][CH2:19]2)=[O:31])[CH2:28][CH2:29]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCN(C(C)=O)CC2)CC1
Reaction time: 2 h
Yield: 67.7 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 1-acetylpiperidine-4-carbonyl chloride (0.029 g, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (30 mg, 65%). LCMS calculated for C23H28ClN4O3 (M+H)+: m/z=443.2; Found: 443.2.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:17])[CH:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18](=O)[CH2:19][CH2:20][CH3:21]>CO>[ClH:1].[CH2:19]([C@H:18]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH2:7][C@@H:5]([C:4]([O:3][CH3:2])=[O:17])[NH:6]1)[CH2:20][CH3:21]
Reactant: COC(=O)C(N)Cc1c[nH]c2ccccc12
Reactant: CCCC=O
Agent: Cl
Solvent: CO
Product: CCC[C@@H]1N[C@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Yield: 38.5 %

Procedure:
A mixture of DL-tryptophan methyl ester hydrochloride (33 g), n-butyraldehyde (21.0 g) and methanol (450 ml) is refluxed for 48 hours. After the reaction, the reaction mixture is concentrated to about 1/3 in volume and allowed to stand. The precipitated crystals are collected by filtration and recrystallized from methanol to give methyl (1RS, 3RS)-cis-1-n-propyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride (15.4 g, 38.4%) as colorless prisms, m.p. 205°-207° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Temperature: 85 °C
Reaction time: 36 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzonitrile (5.5 g, 22 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (7.04 g, 22 mmol), potassium carbonate (7.6 g, 55 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.300 g, 0.25 mmol) were combined in DME (40 mL) and H2O (20 mL). The mixture was purged with N2, and then stirred at 85° C. for 36 hours. After standard work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.[OH-].[K+].[I:13]I>CN(C=O)C>[I:13][C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[NH:1][N:2]=1
Reactant: II
Reactant: c1n[nH]c2c1CCCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2c1CCCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of 1,4,5,6,7,8-hexahydrocycloheptapyrazole (500 mg, 3.67 mmol) in DMF (8 ml) at room temperature was added powdered potassium hydroxide (618 mg, 11.0 mmol) and iodine (1.86 g, 7.34 mmol). The maroon reaction mixture was stirred at room temperature for 1 h then quenched with aqueous 10% Na2S2O3, diluted with water, and extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography with 20% to 50% EtOAc/hexanes to afford 600 mg (62%) of 3-iodo-1,4,5,6,7,8-hexahydrocycloheptapyrazole as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 2.75-2.84 (m, 2H), 2.46-2.55 (m, 2H), 1.80-1.91 (m, 2H), 1.63-1.77 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:45])[CH2:21][NH:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>>[OH:45][CH:20]([C:12]1[C:13]2[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=2[C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:21][NH:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][N:26]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]1=[O:42]
Reactant: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OCC(=O)N3)c2ccccc21
Agent: Cl
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(O)c3c2OCC(=O)N3)c2ccccc21

Procedure:
The product is prepared analogously to Example 12b starting from 1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one. Yield: 30 mg (19%, hydrochloride); HPLC-MS: Rt=13.0 min. (method A); ESI-MS: [M+H]+=526.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=1)[C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17](C)[C:18](=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:29][CH:28]=1)[C:5](=[O:26])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH3:18])[CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (31) (450 mg, 0.86 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise. The reaction mixture was stirred at rt for 1 h and then concentrated. The residue was purified by column chromatography (silica gel, 0 to 10% methanol in methylene chloride (0.3% Et3N)) to give 6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (32) (364 mg, 100%). LC-MS (ESI): m/z (M+1) 425.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:21]#[N:22].[SiH](CC)(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([OH:16])=[O:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:21]#[N:22]
Reactant: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
1,1-Dimethylethyl (4-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)acetate (0.032 g, 0.1 mmol) and Et3SiH (0.116 mg, 1 mmol) were combined in CH2Cl2/TFA (1:1; 6 mL) and stirred at rt for 5 h. Concentration was followed by pH adjustment to ca. 7 in H2O. Extraction with EtOAc, washing with brine, drying (Na2SO4), filtration, and concentration were followed by purification (SiO2, EtOAc/hexanes) to afford the title compound (0.017 g): MS (ESI) m/z 264 (M+1).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][Mg]Br>C1COCC1>[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[CH3:20]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (8.17 g, 30 mmol) was dissolved in THF (100 mL) and cooled to 0° C., methylmagnesium bromide (3.0 M in Et2O, 11 mL, 33 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. After quench with saturated NH4Cl, the reaction mixture was extracted with EtOAc, dried and concentrated. The crude product was column purified with mixture of hexane and EtOAc to give tert-butyl 3-acetylpiperidine-1-carboxylate (4.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[C:36]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:10]2=[O:28])[CH2:27][CH2:26]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCNCC2)c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCN(C(=O)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
30 mg of 3-(2-cyanophenyl)-1-(piperidin-4-yl)methyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 2 ml of chloroform. Under ice-cooling, 0.04 ml of triethylamine and 19 mg of benzoyl chloride were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, and then evaporated and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 25 mg of the title compound.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([O:28][C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1)[CH2:26][CH3:27].OC1C=C(C(OC)=O)ON=1.BrCCC.[Li+].[OH-].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.ClCCl>[CH2:25]([O:28][C:29]1[CH:33]=[C:32]([C:34]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:35])[O:31][N:30]=1)[CH2:26][CH3:27]
Reactant: CCCOc1cc(C(=O)O)on1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Solvent: CCCBr
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3cc(OCCC)no3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.7 g of 3-propyloxy-isoxazole-5-carboxylic acid (prepared as described by Xue et al., Bioorg. Med. Chem. Letters 8 (1998) 3499 by reacting methyl 3-hydroxy-isoxazole-5-carboxylate, which is commercially available, with 1-bromopropane at 60° C. in dimethylformamide/potassium carbonate followed by hydrolysis with LiOH in tetrahydrofuran) and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals having the phase sequence X 91 SA 109 N 126 I.