Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Si](Cl)(Cl)(Cl)Cl.C([C:12]1[CH:17]=[C:16]([C:18]([NH2:20])=O)[CH:15]=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[CH:30][C:31]=2[NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[CH:23][CH:22]=1)#N.[C:39](#[N:41])C>C(Cl)Cl>[C:39]([C:25]1[CH:26]=[C:21]([C:13]2[CH:14]=[CH:15][C:16]([C:18]3[NH:20][N:3]=[N:2][N:1]=3)=[CH:17][CH:12]=2)[CH:22]=[CH:23][C:24]=1[C:27]1[S:28][CH:29]=[CH:30][C:31]=1[NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])#[N:41]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(N)=O)cc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CC#N
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(-c3nnn[nH]3)cc2)cc1C#N
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Add NaN3 (4.5 mmol) and a 1M solution of SiCl4 (1.5 mmol) in DCM to a solution of 2-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid amide (1.5 mmol) in acetonitrile (50 mL). Stir 15 h at 70° C. Concentrate to dryness under reduced pressure. Dissolve resultant residue in 20 ml of NH4Cl and extract with DCM and the aqueous with EtOAc. Concentrate all organic layers to dryness. Purify by HPLC to provide the title compound. MS (ES−):449(M−1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[C:24]([O:27][CH2:28][C:29]([CH2:34][O:35][C:36](=[O:38])[CH3:37])([CH3:33])[C:30]([OH:32])=[O:31])(=[O:26])[CH3:25]>>[C:36]([O:35][CH2:34][C:29]([CH3:33])([C:30]([O:32][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:31])[CH2:28][O:27][C:24](=[O:26])[CH3:25])(=[O:38])[CH3:37]
Reactant: ON=C1CCOCC1
Reactant: CC(=O)OCC(C)(COC(C)=O)C(=O)O
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(=O)OCC(C)(COC(C)=O)C(=O)OC1(N=O)CCOCC1

Procedure:
2-Methyl-2-((4-nitrosotetrahydro-2H-pyran-4-yloxy)carbonyl)propane-1,3-diyl diacetate was prepared from tetrahydro-pyran-4-one oxime and bis(3-acetoxy-2-acetoxymethyl-2-methyl-propionate)iodobenzene (synthesized from iodobenzene diacetate and 3-acetoxy-2-acetoxymethyl-2-methyl-propionic acid which was in turn synthesized using the reported method J. Am. Chem. Soc., 118, 1996, 6388-6395) using conditions of General Method 4. 1H NMR (250 MHz, CHLOROFORM-d) δ 4.32 (4H, s), 3.98-4.17 (2H, m), 3.54-3.74 (2H, m), 2.28-2.46 (2H, m), 2.13 (6H, s), 1.77-1.94 (2H, m), 1.40 (3H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:24])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(OC)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(OC)ccc3nc21
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid (110 g, 0.421 mol) and POCl3 (300 mL) was refluxed overnight and then was allowed to stand at room temperature for about 3 days. The reaction mixture was poured into ice-water and then was basified with NH4OH. The solid which formed was collected by filtration, washed with water and air dried to afford 100.5 g of 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10](O)=O)=[O:7])(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H]3[C@@H](N)CC[C@@H]3C2)=[CH:23][CH:22]=1.F[C:39](F)(F)[C:40]1[N:45]=[C:44](N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=C[CH:41]=1>>[CH3:44][NH:45][C:40]([CH3:41])([C:6]([NH:8][C@@H:9]1[C@@H:13]2[C@@H:14]([CH2:16][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:17][CH2:10]1)=[O:7])[CH3:39]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Product: CNC(C)(C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N,2-dimethyl-L-alanine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.95 (d, J=7.5, 1H), 7.57 (d, J=8.7, 2H), 6.61 (d, J=8.7, 2H), 4.33-4.21 (m, 1H), 3.50 (dd, J=10.2, 3.6, 1H), 3.33 (dd, J=10.1, 8.0, 1H), 3.21 (dd, J=9.7, 8.3, 1H), 3.00 (dd, J=9.9, 4.2, 1H), 2.75-2.65 (m, 1H), 2.65-2.55 (m, 1H), 2.32 (s, 3H), 2.06 (ddd, J=19.3, 7.0, 5.1, 1H), 2.04-1.96 (bs, 1H), 1.98-1.85 (m, 1H), 1.65-1.53 (m, 1H), 1.44 (s, 3H), 1.42 (s, 3H), 1.40-1.30 (m, 1H); MS (ESI+) m/z 370 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[CH:11]([N-]C(C)C)(C)C.[Li+].C1CCCCC1.CI.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: Brc1csc2cnccc12
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1sc2cnccc2c1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a cooled (−78° C.) solution of 3-bromothieno[2,3-c]pyridine (250 mg, 1.17 mmol) in THF (10 mL) was added 1.5 M lithium diisopropylamide in cyclohexane (0.86 mL, 1.28 mmol) and the mixture stirred at −78° C. for 15 min. Methyl iodide (80 μL, 1.28 mmol) was added at −78° C. The mixture was stirred from −78° C. to room temperature and stayed at room temperature for 30 min. Saturated aqueous NH4Cl solution was added and the mixture extracted with DCM. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The crude product was purified by ISCO chromatography (0 to 25% EtOAc:heptane) to afford 178 mg (67%) of the title compound as a white solid. 1H NMR (400 MHz, CD3Cl): δ 8.81 (s, 1 H), 8.39 (d, J=5.6 Hz, 1 H), 7.36 (dd, J=5.3, 0.8 Hz, 1 H), 2.41 (s, 3 H); MS (ESI): 228.30, 230.30 [M+H]+; HPLC tR=0.68 min (HPLC: Analytical—2 min).
Reaction SMILES: C(O)(=O)C.C([BH3-])#N.[Na+].O1CCCC1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:36][CH2:37][CH3:38])[N:27]([CH2:28][CH2:29][CH2:30][O:31][N:32]=[C:33]([CH3:35])[CH3:34])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>CO>[CH:33]([NH:32][O:31][CH2:30][CH2:29][CH2:28][N:27]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:14])[C:24]=2[N:25]=[C:26]1[CH2:36][CH2:37][CH3:38])([CH3:34])[CH3:35]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCON=C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCONC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Acetic acid (10 mL) followed by 1 M sodium cyanoborohydride in tetrahydrofuran (11.05 mL, 11.05 mmol) was added to a stirred solution of acetone O-[3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]oxime (1.50 g, 4.42 mmol) in methanol (10 mL). The reaction was stirred overnight at room temperature and then was concentrated under reduced pressure. The residue was diluted with water (100 mL) and the pH was adjusted with solid sodium hydroxide to pH 6. The mixture was extracted with chloroform (2×100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 1.31 g of 1-{3-[(isopropylamino)oxy]propyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:24]#[N:25])=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C1C(=O)N([Br:33])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:33])[C:9]([C:24]#[N:25])=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C#N)cc3c(N)ncnn23)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#N)c(Br)c3c(N)ncnn23)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of tert-butyl 4-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (54 mg, 0.158 mmol) in DMF (2 mL), NBS (28.07 mg, 0.158 mmol) was added. The mixture was stirred at 0° C. for 2 h. The mixture was concentrated to dryness. Trituration with acetone afforded product (60 mg, 90%). 1H NMR (400 MHz, DMF-da) 7.52 (s, 1H), 4.42-4.38 (m, 4H), 4.88-4.78 (m, 1H), 2.20-2.08 (m, 4H), 1.62 (s, 9H); LC-MS m/z [M+H]+ 420.9% 422.9, LC-MS RT 3.24 min.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([F:25])=[CH:18][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:22][C:20]1[C:19]([F:25])=[CH:18][C:3]([CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[C:2]([F:1])[CH:21]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)c([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(F)c(N)cc2F)CC1

Procedure:
A mixture of tert-butyl 4-(2,5-difluoro-4-nitrobenzylidene)piperidine-1-carboxylate (4.52 mmol, 1.6 g) and palladium on carbon (10%) (0.135 mmol, 0.144 g) in ethyl acetate was hydrogenated at 3 bar until the desired amount of hydrogen was consumed. The reaction was filtered through celite and concentrated under reduced pressure to give the intermediate tert-butyl 4-(4-amino-2,5-difluorobenzyl)piperidine-1-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH2:29][CH2:28][C:27]5([CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:26]=4)=[C:19]([O:34][CH3:35])[CH:18]=3)[CH2:14]2)=[O:12])[CH:6]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>C(Cl)(Cl)Cl>[CH3:43][S:44]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH2:29][CH2:28][C:27]5([CH2:30][CH2:31][CH2:32][CH2:33]5)[CH:26]=4)=[C:19]([O:34][CH3:35])[CH:18]=3)[CH2:14]2)=[O:12])[CH:6]=1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C2CN(C(=O)c3cc(OCCO)ccn3)C2)ccc1OCC1=CC2(CCCC2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C2CN(C(=O)c3cc(OCCOS(C)(=O)=O)ccn3)C2)ccc1OCC1=CC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [4-(2-hydroxyethoxy)-pyridin-2-yl]-{3-[3-methoxy-4-(spiro[4.4]non-1-en-2-ylmethoxy)phenyl]-azetidin-1-yl}-methanone (0.040 g) prepared in Example 11 (3) in chloroform (3.0 mL) were added triethylamine (0.028 mL) and methanesulfonyl chloride (0.014 mL). The reaction mixture was stirred at RT for 30 minutes. Water was added to the reaction mixture. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give the crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[S:20])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br.CCO[CH2:30][CH3:31]>O1CCOCC1>[CH2:22]([S:20][C:10]1[NH:11][C:12]([C:31]2[CH:30]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH2:23][CH2:24][CH2:25][S:20][C:10]1[NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: BrCCCCBr
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)cc1
Reactant: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(-c2nc(SCCCCSc3nc(-c4ccc(F)cc4)c(-c4ccc(F)cc4)[nH]3)[nH]c2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 4,5-bis(4-fluorophenyl)-1H-imidazole-2-thione (5.8 g, 0.02 mol) and 1,4-dibromobutane (4.3 g, 0.02 mol) in dioxane (75 ml) was refluxed one hour. After cooling, ether was added and the solid which formed was removed by filtration. This product was air dried and recrystallized from isopropanol to give the title compound as its dihydrobromide salt (hydrate), m.p. 172°-174°.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]=12)([O-:5])=[O:4].S(O[CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(C1C=CC(C)=CC=1)(=O)=O.O>C1COCC1>[N+:3]([C:6]1[CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][CH2:32]3)[C:10]=12)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cnn2c1NCC2
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCn3ncc([N+](=O)[O-])c32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added portionwise to a stirred solution of 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.125 g, 0.81 mmol) in anhydrous THF (10 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 min. before a solution of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (0.31 g, 0.81 mmol) in THF (5 mL) was added portionwise over 10 min. The reaction was stirred for 6 hr at room temperature followed by 18 hr at 50° C. Further sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added and stirring continued at 60° C. for a further 24 h. The reaction was cooled and water was added dropwise. The mixture was extracted with EtOAc and the combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 4-(2-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)ethyl)piperidine-1-carboxylate as a yellow oil (50 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 4.24-4.16 (m, 2H), 4.25-3.97 (m, 2H), 3.83-3.77 (s, 2H), 3.27 (s, 2H), 3.22 (t, J=6.8 Hz, 2H), 2.72-2.62 (s, 2H), 1.73-1.65 (m, 3H), 1.46-1.44 (m, 9H) 1.40-1.05 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][Mg]Br)=[CH:5][CH:4]=1.CO[C:15]1[CH:23]=CC(CCBr)=C[CH:16]=1.[Mg]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][CH2:23][CH:15]=[CH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: COc1ccc(CC[Mg]Br)cc1
Agent: [Mg]
Product: C=CCCCc1ccc(OC)cc1

Procedure:
This compound was prepared as in Example 35a using 4-methoxyphenethyl magnesium bromide prepared from 4-methoxyphenethyl bromide and magnesium turnings. The crude oil isolated after work-up was distilled to give the title compound (b.p. 65° C., 0.3 mm.Hg), as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:4]=[C:3]1[SH:12].[Cl:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26](=[O:29])[CH2:27][CH3:28])[CH:23]=2)[CH2:18]1>>[ClH:13].[CH3:1][N:2]1[C:6]([C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:4]=[C:3]1[S:12][CH2:14][CH2:15][CH2:16][N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26](=[O:29])[CH2:27][CH3:28])[CH:23]=2)[CH2:18]1
Reactant: CCC(=O)c1ccc2c(c1)CN(CCCCl)C2
Reactant: Cn1c(S)nnc1-c1ccc[nH]1
Product: CCC(=O)c1ccc2c(c1)CN(CCCSc1nnc(-c3ccc[nH]3)n1C)C2
Product: Cl

Procedure:
The title compound was prepared in analogy to method 1.5 from 4-methyl-5-(1H-pyrrol-2-yl)-4H-1,2,4-triazole-3-thiol (1.43 mmol, 0.26 g) and 1-[2-(3-chloropropyl)-2,3-dihydro-1H-isoindol-5-yl]propan-1-one (1.43 mmol, 0.36 g; preparation in analogy to 1.4 from isoindoline as disclosed in WO 0125200). Yield: 0.11 g.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH:31]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:25]1([C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:3]([OH:32])=[O:2])=[O:14])=[CH:31][C:21]=3[N:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A solution (R)-2-(2-phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenylpropionic acid methyl ester 59 (374 mg, 0.8 mmol) in dioxane (8 ml) was treated with a solution of lithium hydroxide hydrate (55 mg, 1.3 mmol) in water (4 mL) under an atmosphere of N2 and stirred for 3 hrs at room temperature. The mixture was acidified with 1 N HCl, then extracted with ethyl acetate (25 ml). The ethyl acetate extract was washed, and dried. Evaporation of the solvent afforded the product which was recrystallized to yield 220 mg (60%) of (R)-2-(2-phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenyl propionic acid 60, mp. 220.0-221.4° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:18]([C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)=[O:19])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)c3ccco3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole and furan-2-carboxylic acid chloride in pyridine the title compound was obtained as a tan solid (400% yield), MS: m/e=274.1 (M+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:12](O)=[O:13]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=CNc1ccc(C(F)(F)F)cc1

Procedure:
Was prepared according to Example 2 from 4-(trifluoromethyl)aniline and formic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH3:10][C:11]1([CH3:20])[O:15][C@H:14]([CH2:16][CH:17]=O)[C:13](=[O:19])[O:12]1.C(O)(=O)C.[BH4-].[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:17][CH2:16][C@H:14]2[O:15][C:11]([CH3:20])([CH3:10])[O:12][C:13]2=[O:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Reactant: Nc1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(C)OC(=O)[C@@H](CCNc2cc(F)cc(F)c2)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (4.0 g, 31.0 mmol), (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (4.9 g, 31.0 mmol) and acetic acid (1.7 ml, 31.0 mmol) in 1,2-dichloroethane (100 mL) under nitrogen at 0° C. was added sodium borohydride (1.17 g, 31.0 mmol mol) in portions over 10 minutes. The resulting mixture was stirred at RT for 2.5 hours. After cooling to 0° C. the reaction mixture was quenched by the careful addition of saturated aqueous NaHCO3 (100 mL) followed by DCM (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to provide the crude (R)-5-[2-(3,5-difluorophenylamino)ethyl]-2,2-dimethyl-1,3-dioxolan-4-one as a yellow oil (8.07 g, 29.7 mmol, 96% yield) which was used without any further purification in the next reaction step. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=272.3; tR=1.76 min.
Reaction SMILES: [CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([Si:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH2:29]>C1(C)C=CC=CC=1>[CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][C:12]=1[CH2:29][CH2:28][Si:30]([O:31][CH2:32][CH3:33])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Reactant: C=C[Si](OCC)(OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1cc(N2CCOCC2)ccc1C(=O)C(CC)(Cc1ccccc1)N(C)C)(OCC)OCC
Yield: 98.8 %

Procedure:
14.6 g (40 mmol) of 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl) -1-butanone, 750 mg (0.8 mmol) of RuH2 (CO) (PPh3)3 and 18.4 ml (88 mmol) of vinyltriethoxysilane were dissolved in 50 ml of toluene and degased using argon. After heating for 29 hours with stirring at reflux, the solvent was distilled off and the product was chromatographed (silica gel, heptane/CH2Cl2 /ethyl acetate). 22 g (100%) of a brown oil were obtained which were purified by boiling in heptane with active charcoal followed by filtration to give a yellow, viscous oil in a quantity of 20.6 g (95%). 1H-NMR (CDCl3): 0.64 ppm (3H, t, Bu-H4, 3JH,H =7.0 Hz); 1.10 ppm (2H, mc, Et-H2); 1.26 ppm (9H, t, CH3 of Si(OEt)3, 3JH,H =6.8 Hz); 1.88 ppm (2H, mc, Bu-H3); 2.36 ppm (6H, s, N(CH3)2); 2.72 ppm (2H, mc, Et-H1); 3.15 ppm (2H, mc, CH2 -Ph); 3.24 ppm (4H, mc, morpholine-N-CH2); 3.85 ppm (4H, mc, morpholine-o--CH2); 3.88 ppm (6H, q, SiOCH2); 6.60 ppm (1H, dd, Ph-H5, 3JH5,H6 =8.6 Hz, 4 JH3,H5 =2.6 Hz); 6.77 ppm (1H, d, Ph-H3); 7.12-7.28 ppm (5H, m, Ph'-H); 8.38 ppm (1H, d, Ph-H6).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH3:2].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:7]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2]
Reactant: CCOC(=O)Nc1c(I)cccc1OC(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1c(C#C[Si](C)(C)C)cccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.6 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.6 mmol) and copper(I) iodide (0.3 g, 1.6 mmol) were added to triethylamine (600 mL) and heated with stirring for 20 min. The mixture was cooled to room temperature and (2-iodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl ester (60.2 g, 160 mmol) was added. After stirring for 30 min at room temperature trimethylsilylacetylene (21.1 g, 152 mmol) was added and the mixture was stirred for another 2 h at room temperature. Triethylamine was removed in vacuo and the residue was partitioned between water and diethyl ether. The organic phases were washed with 1N HCl, brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 57 g of brownish solid, which was purified by chromatography on silica gel with hexane/ethyl acetate (9:1). This yielded the title compound, (52.8 g, 95%) as a beige amorphous solid. (EI-MS: m/e=345.0 (M+))
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH3:7].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-:17].[Na+]>O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:17][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(O)c1cccs1
Reactant: BrCCCCCCBr
Agent: [Na+]
Solvent: O
Product: BrCCCCCCOCCc1cccs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-thienylethanol (10.0 g), 1,6-dibromohexane (57.10 g) and TAB (1.3 g) in 40% sodium hydroxide solution (40 ml) was stirred vigorously under nitrogen at room temperature for 5 h. The mixture was diluted with water (400 ml) and extracted with diethyl ether (2×300 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (100:0→95:5) gave the title compound as a colourless oil (19.28 g), t.l.c. (hexane-ether 9:1) Rf 0.39.