Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16](SC)SC)[C:4]=2[CH:3]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[CH:3]=1
Reactant: CCCCCCCC[Mg]Br
Reactant: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a solution of 2,7-dibromo-9-(bis-methylsulfanyl-methylene)fluorene (5.1 g, 12 mmol) in dry THF (100 ml) at 0° C. under nitrogen, was added a solution of lithium tetrachlorocuprate (5 ml of a 0.1 M solution in THF, 5 mol %). A solution of octylmagnesium bromide (13 ml of a 2.0M solution in diethyl ether, 0.026 mol) was added dropwise over 30 min. The reaction was stirred for 2 h at 5° C. The reaction was cooled to 0° C. and further lithium tetrachlorocuprate (1 ml of a 0.1M solution in THF, 1 mol %) was added. The reaction was then stirred for 24 h at 15° C., before quenching and workup as above. Yield (60%). Purity (HPLC>99%). 1H and 13C NMR spectra as expected. M+=560 (t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:38][CH3:39])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:38][CH3:39])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Reaction time: 6 h
Yield: 55.5 %

Procedure:
To a solution of 0.15 g (0.27 mMol) of 4-{4-methoxy-2-[(2-morpholin-4-yl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 6.0 ml of methanol and 6.0 ml THF 50 mg of Pd/C (10%) were added. The reaction mixture was hydrogenated at 60° C. for 6 h, then filtered and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate) to yield 0.083 g (55%) 4-{4-methoxy-2-[(2-morpholin-4-yl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam. ES-MS m/e (%): 554 ([M+H]+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([CH:19]=[O:20])=[CH:17][N:16]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC1C=CC(S([CH2:39][N+:40]#[C-:41])(=O)=O)=CC=1.[OH-].[K+].Cl>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]4[O:20][CH:41]=[N:40][CH:39]=4)=[CH:17][N:16]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(-c2cnco2)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (135 mg, 0.339 mmol), tosmic (73 mg, 0.37 mmol) and potassium hydroxide (38 mg, 0.68 mmol), was added methanol (10 mL). The resulting solution was stirred for 12 hours at 25° C. and then the pH was adjusted to pH=6 with hydrogen chloride (1M aqueous solution). The reaction was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography using silica gel, eluting with 25% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford 5-(4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)oxazole as a yellow oil. LRMS (ESI) calc'd for C21H24N5O4Si [M+H]+: 438, found 438.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].Cl.[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:19][CH3:20])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1
Reactant: COc1cc(CCl)cc(Cl)n1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2cc3ncnc(Oc4ccccc4)c3cc2OC)cc(Cl)n1
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.1 g, 4.1 mmol), (prepared as described for the starting material in Example 13), 2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 3.9 mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (20 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool, diluted with water and the precipitated product collected by filtration, washed with water and dried to give 7-((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (1.38 g, 79%).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[F:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][CH:15]([C:20](=O)[CH3:21])[C:16](OC)=[O:17])=[CH:12][CH:11]=1.O>CO>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[C:16]([OH:17])=[N:4][C:2]([CH3:3])=[N:5][C:20]=2[CH3:21])=[CH:23][CH:24]=1
Reactant: CC(=N)N
Reactant: COC(=O)C(Cc1ccc(F)cc1)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(C)c(Cc2ccc(F)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
To a suspension of acetamidine hydrochloride (0.54 g, 5.71 mmol) in methanol (8 mL) was added a 30% solution of sodium methoxide in methanol (1.1 mL, 5.7 mmol), and the resulting solution was stirred at room temperature for 45 min. Then, a solution of methyl 2-(4-fluorobenzyl)-3-oxobutanoate (0.80 g, 3.57 mmol) in methanol (3 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 22 h. Water (100 mL) was added, and the mixture was extracted with chloroform (4×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to provide 5-(4-fluorobenzyl)-2,6-dimethylpyrimidin-4-ol (0.74 g, 89% yield) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 7.21 (m, 2H), 6.96 (m, 2H), 3.84 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H); MS (EI) for C13H13FN2O: 233 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].C(OC([NH:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C>CS(C)=O>[NH2:30][C@H:31]1[CH2:35][CH2:34][N:33]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C@@H:14]3[CH2:16][C@@H:15]3[F:17])=[C:3]([CH3:22])[C:2]=2[F:1])[CH2:32]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CS(C)=O
Product: Cc1c(F)c(N2CC[C@H](N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 68.6 %

Procedure:
A mixture of 100 mg of 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 120 mg of (S)-3-t-butoxycarbonylaminopyrrolidine, and 3 ml of anhydrous dimethyl sulfoxide was heated at 100° to 120° C. for 1 hour with stirring, and dimethyl sulfoxide was removed under reduced pressure. Water was added to the residue, and the precipitated yellow crystals were collected by filtration. Three milliliters of trifluoroacetic acid was stirred under ice-cooling, and the above-obtained yellow crystals were slowly added thereto, followed by stirring at room temperature for 30 minutes. The trifluoroacetic acid was removed under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution (pH 12). The solution was neutralized with 1N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and aqueous ammonia. The resulting crystals were collected by filtration, washed with ethanol, and dried to yield 83 mg of the titled compound as a pale yellow crystal.
Reaction SMILES: C([C:4]1[C:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])=[N+:12]([O-:19])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:20])(=O)C.Cl.[CH3:22]O>>[CH3:22][O:18][C:16]1([CH3:17])[C:4]2=[N+:5]([O-:20])[C:6]3[C:11]([N+:12]([O-:19])=[C:13]2[CH2:14][O:15]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CO
Reactant: CC(=O)OCc1c(C(C)=O)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: Cl
Product: COC1(C)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Yield: 63 %

Procedure:
A suspension of 30.0 g. (0.11 mol.) of 2-acetyl-3-acetoxymethylquinoxaline 1,4-dioxide in 300 ml. of methanol, saturated with dry hydrogen chloride, was stirred at ambient temperature for 2 days. The tan solid was collected by filtration, and then it was recrystallized from methanol, to give 17.0 g. (63% yield) of 1-methoxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide, m.p. 201°-202° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[S:12][CH:13]=2)=[CH:5][CH:4]=1.CC(=CC)C.Cl([O-])=[O:24].[Na+].P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([C:14]([OH:24])=[O:15])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (intermediate 37, 1.23 g), t-butanol (20 ml) and 2-methyl-2-butene (10 ml) was cooled to 0° C. To this was added drop-wise, a solution of sodium chlorite (3.8 g) and sodium dihydrogen phosphate (4.03 g) in water (15 ml). After the addition was complete, the mixture was allowed to warm to room temperature and was stirred for 4 hours. The solution was then concentrated and partitioned between water and ethyl acetate. The aqueous layer was washed with a second ethyl acetate portion and the organic liquors were combined, washed with brine, then dried (MgSO4). The solution was then absorbed onto silica and loaded onto a SPE (Si) cartridge. The product was eluted with neat ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Br:10])=[O:4].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][Br:19])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: COC(=O)c1sc(C)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)cc1Br
Yield: 44.7 %

Procedure:
A mixture of 3-Bromo-5-methyl-thiophene-2-carboxylic acid methyl ester (1.66 g, 7.06 mmol), NBS (1.63 g, 9.18 mmol), and Benzoyl peroxide (0.085 g, 0.35 mmol) in CCl4 (15 ml) was refluxed in a pressure tube 15 h. The reaction mixture was cooled and evaporated. The residue was purified by column (0-15% EtOAc in hexane) to give 0.99 g (45%) yellow oil product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[C:10]1([C:16](=O)[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: NNc1ccccc1Cl
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Product: O=C(C(=NNc1ccccc1Cl)c1ccccc1)c1ccccc1

Procedure:
1,2-Diphenylethane-1,2-dione (2-chlorophenyl)hydrazone was prepared from 2-chlorophenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS m/z 335;
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][NH:14][C:13]2=[O:20].[H-].[Na+]>CN(C=O)C>[CH2:1]([N:14]1[C:13](=[O:20])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[N:16]=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2ncn1Cc1ccccc1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
Benzyl bromide (0.264 mL, 2.22 mmol) was added to a solution of 6-bromoquinazolin-4(3H)-one (0.5 g, 2.22 mmol) and NaH (0.08 g, 3.33 mmol) in DMF (5 mL) at 0° C. The reaction mixture was heated to 80° C. for 4 h. The reaction mixture was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford title compound (0.4 g, 48.1%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J=1.6 Hz, 1H), 8.09 (s, 1H), 7.83 (dd, J1=2.0 Hz, J2=8.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.4-7.2 (m, 5H), 5.2 (s, 2H); ESI-MS m/z=315 (M+H)+; LCMS purity: 84.2%
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(C#N)cc4)ccc(F)c32)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
(1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 146 mg, 0.41 mmol), 4-fluorobenzonitrile (55 mg, 0.45 mmol), and cesium carbonate (145 mg, 0.45 mmol) are suspended in dry dimethylformamide (10 mL) and stirred for 3 hours at 100° C. followed by room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, filtered and the solvent removed. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (Yield 62 mg). LC (METHOD 5): tR=1.54 min; Mass spectrum (ES+): m/z=458 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:4]=1.Cl.Cl.[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][CH:33]=[C:32]([NH:38][CH2:39][CH2:40][NH2:41])[N:31]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][CH:33]=[C:32]([NH:38][CH2:39][CH2:40][NH:41][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:4]=2)[N:31]=1
Reactant: N#Cc1ccc(NCCN)nc1N
Reactant: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)[1,2,4]triazolo-[1,5-c]-pyrimidine hydrochloride (Example 49A), 32 mg (0.15 mmol) of 2-amino-6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.13 ml (0.75 mmol) of N,N-diisopropylethylamine were initially charged in 1.5 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 43 mg (64% of theory) of the product as a solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][N:10]=[CH:11][CH2:12]Cl)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:14][C:15]([F:45])([F:44])[C:16]1[CH:17]=[C:18]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]1[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:20].C(N(C(C)C)CC)(C)C>C(#N)C>[N:1]1([CH2:7][CH2:8][O:9][N:10]=[CH:11][CH2:12][N:24]2[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]3[CH:17]=[C:16]([C:15]([F:14])([F:45])[F:44])[CH:39]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:37]=3)[C@H:22]([CH2:27][C:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][CH:29]=3)[CH2:23]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCC=NOCCN1CCOCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC=NOCCN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A mixture of 2-chloroethanal O-[2-(morpholin-4-yl)ethyl]oxime (0.13 g), (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.29 g), diisopropylethylamine (0.11 mL), and acetonitrile (10 mL) was heated under reflux overnight. After cooling to room temperature the solvent was removed in vacuo, and the residue treated with dichloromethane and K2CO3 (aq). The layers were separated, the organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 92/7.5/0.5) to afford 2-{(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-ethanal O-[2-(morpholin-4-yl)ethyl]oxime 0.38 g (95%) as an E/Z mixture. MH+ 626, Rf 0.53+0.66 (E+Z isomer) (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:33][NH:34][S:35]([CH2:38][CH2:39][CH2:40]Cl)(=[O:37])=[O:36])[CH2:10][O:11][C:12](=[O:32])[NH: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][CH2:28][CH2:29][CH2:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4].C(SCC(OC)CNS(CCC[I:69])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:33][NH:34][S:35]([CH2:38][CH2:39][CH2:40][I:69])(=[O:37])=[O:36])[CH2:10][O:11][C:12](=[O:32])[NH: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][CH2:28][CH2:29][CH2:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OCCCC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(=O)OCCCC

Procedure:
2-Butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane IIIe2 is allowed to react and worked up by the same procedure as described in (5). m.p. 96°-98° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+].CO.O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][OH:13])=[NH:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(Cc1ccc(Br)cc1)NO
Yield: 85.6 %

Procedure:
4-Bromophenylacetonitrile (5.0 g, 25.5 mmol), hydroxylamine hydrochloride (3.9 g, 56.1 mmol), and sodium bicarbonate (5.1 g, 61.2 mmol) were dissolved in MeOH (250 mL, 6.2 mol) and water (40 mL, 2 mol). The mixture was heated at reflux overnight, cooled, and then concentrated to ˜50 mL. The residue was dissolved in DCM, washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to yield 2-(4-bromophenyl)-N-hydroxyacetamidine (5.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1[CH3:18].C=O.[BH3-][C:22]#N.[Na+].C(O)(=O)C>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:22])[CH2:13][C@@H:12]1[CH3:18]
Reactant: [BH3-]C#N
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Temperature: 0 °C
Yield: 100 %

Procedure:
Racemic-1-(2-Fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine (5.71 g, 24.3 mmol) and formalin (24 mL) are dissolved in 70 mL of acetonitrile. The solution is cooled to 0° C. and 2.44 g of NaBH3CN (38.8 mmol) is added in small portions. Acetic acid (2 mL) is added until no further effervescence is observed. The crude reaction mixture is then filtered through a thick plug of silica gel that is rinsed with 10% MeOH in CH2Cl2. Concentration in vacuo gives a yellow solid that is further purified by addition of ethyl acetate and filtration. Concentration in vacuo of the filtrate gave 6.1 g of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine as an off-white solid (24.3 mmol, 100%). 1H NMR (300 MHz, CDCl3) δ 1.04 (d, J=4.9 Hz, 1H), 1.07 (d, J=5.2 Hz, 1H), 2.20 (dd, J=11.5, 8.8 Hz, 1H), 2.32 (s, 3H), 2.41-2.50 (m, 1H), 2.65 (dd, J=11.6, 8.9 Hz, 1H), 2.90 (dd, J=11.5, 3.3 Hz, 1H), 3.25 (dd, J=11.8, 3.0 Hz, 1H), 3.44-3.53 (m, 1H), 7.10 (t, J=8.5 Hz, 1H), 7.90 (dd, J=11.5, 2.7 Hz, 1H), 7.95-8.00 (m, 1H). LCMS-ESI (m/z): calcd for C13HBFN3O2, 267.14; [M+H]+ found, 268.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH:13]([OH:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40].Cl>CN(C)C=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH:13]([O:21][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(Cc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
3.50 g (9.32 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid in 14 ml dimethylformamide were added at 0° C. to 0.86 g (19.8 mmol) sodium hydride (55%) in 2 ml dimethylformamide. The suspension was stirred for 2 hours and then 2.25 ml (20.5 mmol) 2,5-difluoro-nitrobenzene in 3.4 ml dimethylformamide were added. After stirring overnight at 0° C. the mixture was poured on ice/water. The pH was adjusted to 1 by adding aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol (100:0 to 95:5) yielded 2.95 g (62%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-4-phenyl-butyric acid as yellow oil, MS m/e (%): 515.3 (M+H+, 100).