Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30]>>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reactant: CCOC(=O)CCCCCBr
Product: O=C(O)CCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
This compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Example 4.1 step 1) and ethyl 6-bromohexanoate analogously to 7-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid (Example 1 step 1 and step 2. Step 1 was carried out using microwave radiation).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[N:27]([CH3:28])[C:26]([CH3:29])=[N:25][CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:22])(=[O:21])[NH:16]C(C)(C)C)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([C:23]2[N:27]([CH3:28])[C:26]([CH3:29])=[N:25][CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:21])(=[O:22])[NH2:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(S(=O)(=O)NC(C)(C)C)cc3)ncc2Cl)n1C
Solvent: COc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(-c2nc(Nc3ccc(S(N)(=O)=O)cc3)ncc2Cl)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
A mixture of 5-chloro-4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(t-butyl)sulphamoyl]anilino}pyrimidine (Example 60; 116 mg, 0.267 mmol), trifluoroacetic acid (2.7 ml), water (0.3 ml) and anisole (145 μl, 1.34 mmol) was stirred at ambient temperature for 72 hours. The mixture was then concentrated by evaporation and the residue treated with water and ether. The precipitated solid was collected by filtration, washed with water and ether, and dried to give the title compound (87 mg, 86%) as a white solid. NMR: 2.4 (s, 3H), 3.78 (s, 3H), 7.15 (s, 2H), 7.65 (s, 1H), 7.73 (d, 2H), 7.83 (d, 2H), 8.6 (s, 1H), 10.11 (s, 1H); m/z 3.78 (M−H)−.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[C:3](=[N:8][O:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:11][C:2](=[O:1])[C:3](=[N:8][O:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: CON=C(C(C)=O)C(=O)OC
Solvent: ClC(Cl)Cl
Product: CON=C(C(=O)CBr)C(=O)OC
Temperature: 40 °C
Yield: 87.4 %

Procedure:
In 150 ml of chloroform is dissolved 40 g of methyl 3-oxo-2-methoxyiminobutyrate and the solution is heated to 40° C. Then, a solution of 40 g bromine in 50 ml chloroform is added dropwise over a period of an hour. Thereafter, the reaction is continued under stirring at room temperature for an hour. The reaction mixture is washed with a 5% aqueous solution of sodium hydrogen carbonate and water in the order mentioned, and the organic layer is dried. The solvent is then distilled off to obtain 52.1 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])O1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:27][C:23]1[N:22]=[CH:21][N:26]=[C:25]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH:24]=1
Reactant: COC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccnc(Cl)n1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccccc1-c1cc(Cl)ncn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A mixture of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.0 g), 2,6-dichloropyrimidine (1.4 g), sodium carbonate (2.4 g), tetrakis(triphenylphosphine)palladium(0) (0.44 g), water (2.0 mL) and DME (10 mL) was stirred at 150° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.60 g).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:9]([C:10](OCC)=[O:11])=[CH:8][N:7]([CH3:15])[N:6]=1.C(O)(C)C.N.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:10]([C:9]2[C:5]([NH:4][C:3]3[CH:16]=[CH:17][C:18]([C:20]([F:22])([F:21])[F:23])=[CH:19][C:2]=3[NH2:1])=[N:6][N:7]([CH3:15])[CH:8]=2)=[O:11])[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1cn(C)nc1Nc1ccc(C(F)(F)F)cc1N
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: CC(C)O
Solvent: COc1ccccc1
Product: CN1CCN(C(=O)c2cn(C)nc2Nc2ccc(C(F)(F)F)cc2N)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(2-amino-4-trifluoromethylanilino)-1-methylpyrazole-4-carboxylate (4.75 g) was stirred in a mixture of N-methylpiperazine (25 ml) and anisole (65 ml). A solution of titanium tetrachloride (4.2 ml) in anisole (20 ml) was added and the mixture was stirred under nitrogen at 65° C. for 30 minutes. A mixture of isopropanol (25 ml) and 0.88 ammonia solution (25 ml) was added and the stirred mixture cooled to 25° C. The precipitate was removed by filtration, washing with ethyl acetate. The combined filtrates were washed with water (3X), dried over magnesium sulphate, the solvent evaporated and the residue crystallised from acetonitrile to give the title compound m.p. 170° C.
Reaction SMILES: [NH:1]1[C:52](=[O:53])[C@H:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH:46][C:44](=[O:45])[C@@H:40]([CH:41]([CH3:43])[CH3:42])[NH:39][C:37](=[O:38])[C@@H:36]2[CH2:54][CH2:55][CH2:56][N:35]2[C:33](=[O:34])[C@@H:21]([CH2:22][C:23](=[O:32])[O:24]CC2C=CC=CC=2)[NH:20][C:18](=[O:19])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C)=[O:15])[CH:5]=1.[OH-].[Na+]>CO>[NH:1]1[C:52](=[O:53])[C@H:47]([CH2:48][CH:49]([CH3:50])[CH3:51])[NH:46][C:44](=[O:45])[C@@H:40]([CH:41]([CH3:43])[CH3:42])[NH:39][C:37](=[O:38])[C@@H:36]2[CH2:54][CH2:55][CH2:56][N:35]2[C:33](=[O:34])[C@@H:21]([CH2:22][C:23](=[O:24])[OH:32])[NH:20][C:18](=[O:19])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1
Reactant: COC(=O)Cn1cc(C[C@H]2NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC(=O)OCc3ccccc3)NC2=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)NC(=O)[C@@H]2CCCN2C(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2cn(CC(=O)O)c3ccccc23)NC1=O

Procedure:
cyclo(-DTrp(CH2COOCH3)-DAsp(OBzl)-Pro-DVal-Leu-) prepared in Example 90 was hydrolized with 1N NaOH in methanol to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:20].[Na+].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([I:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCCC(I)C1
Temperature: 25 °C

Procedure:
A solution of 3-(tert-butyldimethylsilyl)oxy-1-(methylsulfonyloxy)cyclohexane (15.9 g) and sodium iodide (8.5 g) in N,N-dimethylformamide (80 ml) was heated at 100° C. for 3 hours with stirring. After cooled to ambient temperature, a reaction mixture was poured into a mixture of ethyl acetate (250 ml) and n-hexane (150 ml), and insoluble material was removed by filtration. Mother liquor was washed in turn with water (100 ml×3), 5% sodium thiosulfate in water (50 ml), and saturated sodium chloride in water (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with 10% ethyl acetate in n-hexane to give 3-(tert-butyldimethylsilyl)oxy-1-iodocyclohexane (cis and trans mixture).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:19][CH2:18][C@H:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=3)[C:16]2=[O:31])[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[O:31]=[C:16]1[C@@H:17]([O:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)[CH2:18][CH2:19][N:15]1[CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cn1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Concentrated aqueous HCl (2 mL) was added to a suspension of (S)-methyl 5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinate (0.19 g, 0.45 mmol) in MeOH (4 mL). The mixture was stirred at ambient temperature overnight and then concentrated. The residue was concentrated from MeOH twice to afford (S)-methyl 5-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)picolinate hydrochloride (0.19 g, 0.44 mmol, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C[O-].[Na+].[CH2:13](Cl)[C:14]#[CH:15]>CO.C(Cl)Cl>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])[C:14]#[CH:13]
Reactant: OCc1cccc(O)c1
Reactant: C#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C#CCOc1cccc(CO)c1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A 20.0 L flange flask was charged with 3-hydroxybenzyl alcohol (97%, ex. Aldrich, 903 g, 7.28 mol, 1 eq.) in methanol (MeOH)(9.1 L, dried over 3 A molecular sieves) to give a clear solution, into which sodium methoxide (25% in methanol, ex. Aldrich, 1.746 L, 7.63 mol, 1.05 eq.) was slowly added with vigorous stirring. After stirring for 10 min. the propargyl chloride (70 wt % in toluene, ex. Aldrich, 542.6 g, 805 ml, 7.29 mol, 1 eq) was added slowly with vigorous stirring over a period of 30 minutes. The reaction mixture was heated under reflux for 40 h (isomantle set to 76° C. with an internal temp. of 64° C.). TLC-examination (10% MeOH in DCM) showed that the reaction was not complete. The reaction was nevertheless worked-up at this stage. The MeOH was removed by rotary evaporation, and the residue dissolved in DCM (10.2 L) to give a clear solution, which was washed with water (5.82 L×3), and dried over sodium sulfate. The solvent was removed in vacuo, to give the title compound (706 g, 60%) as an orange gum.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([Cl:12])[C:5]=1[Cl:13])([O-])=O.N[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O1CCOCC1>[Cl:11][C:8]1[C:9]([Cl:10])=[C:4]([NH:1][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:5]([Cl:13])=[C:6]([Cl:12])[N:7]=1
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)nc(Cl)c1Cl
Reactant: NCC1CCNCC1
Solvent: C1COCCO1
Product: Clc1nc(Cl)c(Cl)c(NCc2ccncc2)c1Cl
Yield: 24.3 %

Procedure:
1 g 4-nitro-2,3,5,6-tetrachloropyridine, 0.65 g 4-aminomethylpiperidine and 20 ml absolute dioxane were stirred for 1 hour at room temperature. Subsequently the dioxane was removed by distillation, the residue was admixed with water, separated from undissolved material and the aqueous phase was extracted several times with dichloromethane. After drying and evaporating the solvent, the residue can be crystallized from a small amount of diethyl ether. 0.3 g 4-(2,3,5,6-tetrachloropyridin-4-ylaminomethyl)pyridine is obtained as colourless crystals. TLC (mobile solvent: toluene/dioxane/water 90:20:0.2), Rf=0.8.
Reaction SMILES: B(Br)(Br)Br.Br.[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][O:26]CC)[N:19]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:15]=2[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.Cl.[OH-].[Na+]>ClCCl.CO>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][OH:26])[N:19]([CH2:20][C:21]([CH3:22])([OH:23])[CH3:24])[C:15]=2[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)O
Agent: Br
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cccnc3c21
Reaction time: 16 h
Yield: 48.7 %

Procedure:
A solution of boron tribromide in dichloromethane (11.8 mL of 1 M) was added to a chilled (0° C.) suspension of 1-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol hydrobromide (1.24 g, 3.93 mmol) in dichloromethane (30 mL). The reaction mixture was allowed to come to ambient temperature with stirring for 16 hours. Methanol (15 mL) and hydrochloric acid (10 mL of 6 N) were added and the reaction mixture was heated at reflux for 2.5 hours. The reaction mixture was made basic with sodium hydroxide and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined extracts were washed sequentially with water and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to provide a white solid. This material was crystallized from ethyl acetate and then dried under vacuum at 95° C. for 16 hours to provide 0.55 g of 1-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol as a white powder, mp 235-237° C. Anal. calcd for C14H17N5O2: % C, 58.52; % H, 5.96; % N, 24.37. Found: % C, 58.40; % H, 5.82; % N, 24.45.
Reaction SMILES: CN1C(=O)CCC1.[CH2:8]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18][C:17]([NH2:27])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[N:39]=2)=[CH:31][CH:30]=1>CCOC(C)=O>[CH2:8]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18][C:17]([NH:27][C:37]([C:38]([NH:39][C:35](=[O:36])[C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)([CH3:41])[CH3:40])=[O:42])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)N=C(c2ccc(F)cc2)OC1=O
Reactant: Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 5 mL Biotage microwave vial were added NMP (1 ml), 1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-amine (150 mg, 0.559 mmol), 2-(4-fluorophenyl)-4,4-dimethyloxazol-5(4H)-one (116 mg, 0.559 mmol,), under N2. Then it was placed in 100° C. oil bath and stirred for 2.5 h. It was cooled to r.t. and diluted with 2 ml of EtOAc. It was stirred for 10 min that resulted precipitation of the desired product. Then 2 mL of water was added and it was stirred for additional 10 min followed by addition of a couple drops of heptane. The precipitates were collected by filtration and dried under vacuum overnight. This afforded the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 1.50 (s, 6H) 5.40 (s, 2H) 7.08-7.14 (m, 2H) 7.24-7.39 (m, 7H) 7.63-7.71 (m, 2H) 7.96-8.04 (m, 2H) 8.33 (s, 1H) 10.17 (s, 1H). MS (m/z) 476.2 M(+1), tR=1.36, Method A.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[NH:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A solution of 10.00 g of BOC-Tyr(Bzl)-OH dissolved in 50 ml of dichloromethane was mixed with 6.53 g of H-Pro-OBzl.HCl. To this mixture, under cooling at -5° C., 4.93 ml of WSC was added, followed by stirring at -5° C. for one hour and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was mixed by shaking with ethyl acetate and 1N hydrochloric acid and separated into liquid layers. The ethyl acetate layer was washed successively twice with 1N hydrochloric acid, twice with saturated aqueous sodium chloride, three times with 5% aqueous sodium hydrogen carbonate and twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 14.46 g (yield: 96.1%) of BOC-Tyr(Bzl)-Pro-OBzl as oily product. Rf1 =0.71.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Cl-].[Ca+2].[NH2:9][C:10]1[C:11](=[O:26])[NH:12][CH:13]=[C:14]([CH3:25])[C:15]=1[S:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:25][C:14]1[C:15]([S:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[C:10]([NH:9][C:1](=[O:4])[CH2:2][CH3:3])[C:11](=[O:26])[NH:12][CH:13]=1
Reactant: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2N)c1
Reactant: CCC(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1c(Sc2cc(C)cc(C)c2)c(C)c[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
Freshly distilled propionyl chloride (0.04 ml, 0.41 mmole) (the receptacle is fitted with a trap containing CaCl2) was added to a solution of amine 8a (0.10 g, 0.40 mmole) and triethylamine (0.04 ml, 0.38 mmole) in dichloromethane (5 ml) at 0° C. The mixture was agitated at ambient temperature for 5 hours. The solvent was evaporated, water was added and the solid was isolated by filtration. The residue was purified by column chromatography using a mixture of dichloromethane and ethanol (94:6) as eluant and at the end ethyl acetate in order to obtain the compound 11c (0.10 g, 90%) in the form of a white powder: melting point 186-188° C.; NMR-1H (DMSO-d6) δ 11.86 (1H, s, NH-1), 8.60 (1H, s, NH-3), 7.21 (1H, s, H-6), 6.88 (1H, s, H-4'), 6.80 (2H, s, H-2' and 6'), 4.04 (2H, q, J=7 Hz, COCH2CH3), 2.22 (6H, s, CH3 -3' and 5'), 1.82 (3H, s, CH3 -5), 1.20 (3H, t, J=7 Hz, COCH2CH3). Anal. C17H20N2O2S . 1.25H2O (C, H, N, S).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH2:24]([O:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCCOc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: CCCCOc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-butoxyphenyl)-5-phenylbenzoxazole (174 mg, 0.49 mmol) and 1,2,4-benzenetricarboxylic anhydride (94 mg, 0.49 mmol) the title compound was obtained (146 mg, 56%). 1H NMR (DMSO) δ 8.44(dd, 1H), 8.32(s, 1H), 8.18(d, 1H), 8.12(d, 1H), 8.05(d, 1H), 7.82(d, 1H), 7.71(m, 4H), 7.48(m, 3H), 7.39(t, 1H), 4.25(t, 2H), 1.83(m, 2H), 1.58(m, 2H), 1.00(t, 3H). MS 533 m/z (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([CH3:38])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:5]1=[O:37])[CH:2]=C.I([O-])(=O)(=O)=[O:40].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O.O.CCOC(C)=O>[CH:24]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:9]1[C:10](=[O:11])[C:4]([CH3:38])([CH2:1][CH:2]=[O:40])[C:5](=[O:37])[N:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]1=2)([CH3:26])[CH3:25]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC1(C)C(=O)N(CC(=O)N(c2ccc(OC)cc2)C(C)C)c2ccccc2N(c2cccnc2)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(CC=O)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 4 h
Yield: 103.5 %

Procedure:
To a stirring solution of 1.5 g (2.93 mmol) of 2-(3-Allyl-3-methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-[4-methoxyphenyl]acetamide, prepared as in Part C, in 10 mL of dioxane and 10 mL of H2O at 0° C. is added 3.13 g (14.63 mmol, 2 equiv.) of sodium periodate followed by the addition of 2 drops of osmium tetroxide solution (4% in H2O). The resulting suspension is stirred for 4 h and then diluted with 200 mL H2O and 200 mL of EtOAc. The organic phase is washed with H2O (2×250 mL) and a solution of Na2S2O3 (10%) and then dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 1.56 g of N-Isopropyl-N-[4-methoxyphenyl]-2-[3-methyl-2,4-dioxo-3-(2-oxo-ethyl)-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl]acetamide as an oil: 1H NMR (CDCl3, 300 MHz) δ8.51 (m, 2H), 7.68 (d, 1H, J=9), 7.39-6.93 (m, 8H), 6.71 (d, 1H, J=8), 5.78-5.64 (m, 1H), 5.08-5.00 (m, 2H), 4.72 (d, 1H, J=16), 4.39 (d, 1H, J=17), 4.08 (m, 1H), 3.85 (s, 3H), 3.81-3.79 (m, 1H), 2.11 (d, 1H, J=8), 1.77 (s, 1H), 1.60 (s, 2H), 1.21-1.07 (m, 6H); low resolution MS (FAB)m/e 513 (MH+).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:18][C:12]=2[O:11][C@@H:10]([CH3:25])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH3:25][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:18][C:12]=2[O:11]1
Reactant: C[C@H]1CN(Cc2ccccc2)Cc2ncc(N3CCOCC3)nc2O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CNCc2ncc(N3CCOCC3)nc2O1
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
A mixture of (6S)-8-benzyl-6-methyl-3-(morpholin-4-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (70 mg), 20% Pd(OH)2/C (70 mg) and methanol (2 mL) was stirred under a hydrogen atmosphere at 50° C. for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 20→100% ethyl acetate/hexane) and recrystallized (ethyl acetate-hexane) to give the title compound (11.1 mg, 21%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[NH:25][C:26](=[O:28])[CH3:27])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)Nc1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC(=O)Nc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.