Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H][H]>C(O)C.[Ni]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc(N)cc2)CC1

Procedure:
10.9 g of 4-(1-methyl-4-piperazinyl-carbonyl)-1-nitrobenzene are hydrogenated in 90 ml of ethanol with the addition of 1.1 g of Raney nickel for 35 minutes at ambient temperature under 50 psi of hydrogen atmosphere. The catalyst is removed by suction filtering, the filtrate is evaporated down, the residue is stirred with diethyl ether and dried.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C([O:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:22]=[CH:21]2)=[CH2:15])CCC.O>C1COCC1>[Br:8][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:22]=[CH:21]2)=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCCCC)c1cccc2cnc(C3(c4ccccc4)CC3)nc12
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cccc2cnc(C3(c4ccccc4)CC3)nc12
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 117.2 %

Procedure:
NBS (51.7 mg, 0.290 mmol) was added to a solution 8-(1-butoxyvinyl)-2-(1-phenylcyclopropyl)quinazoline (100.0 mg, 0.290 mmol) in THF (2.2 mL) and water (0.084 mL, 4.65 mmol) at 0° C. and the resulting solution was stirred at 0° C. for 2 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 2-bromo-1-(2-(1-phenylcyclopropyl)quinazolin-8-yl)ethanone (124.8 mg) as a light-yellow oil. NH4OAc (90 mg, 1.161 mmol) and piperidine-2,4-dione (39.4 mg, 0.348 mmol) were added to the resulting oil, and the mixture was taken up in EtOH (2.2 mL) and stirred under argon in a sealed flask at 50° C. for 15.5 h. The reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (2×30 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(1-phenylcyclopropyl)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (35.3 mg, 0.093 mmol, 32% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 11.24 (1H, br. s.), 9.28 (1H, s), 8.16 (1H, d, J=7.6 Hz), 7.66 (1H, d, J=7.8 Hz), 7.52-7.58 (3H, m), 7.46 (2H, t, J=7.3 Hz), 7.39 (1H, t, J=7.2 Hz), 7.11 (1H, d, J=2.2 Hz), 5.45 (1H, br. s.), 3.51 (2H, td, J=7.0, 2.1 Hz), 2.49 (2H, t, J=6.9 Hz), 1.95 (2H, q, J=3.6 Hz), 1.51 (2H, q, J=3.6 Hz). m/z (ESI, +ve) 381.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[C:22]1(=[O:31])[N:1]([CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: CC(C)CC(N)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a stirred solution of d,1-leucine (3.31 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carboethoxyphthalimide (5.65 g, 25.0 mmol). After 1 hour at room temperature, the reaction slurry is filtered, the filtrate stirred, and the pH adjusted to 1-2 with 4N hydrochloric acid. The mixture is stirred overnight, the resulting slurry is filtered, and the solid washed with water and dried in vacuo (60° C., <1 mm) to afford 5.32 g (81%) of the 2-phthalimido-4-methylpentanoic acid as a white powder: mp 134°-137° C.; 1H NMR (DMSO-d6, 250 M Hz) δ 12.50 (br s, 1H), 8.00-7.80 (m, 4H), 4.79 (dd, 1H, J=4.3), 2.28-2.10 (m,1H), 1.94-1.77 (m,1H), 1.51-1.134 (m, 1H), 0.89 (d, 3H, J=4.4), 0.86 (d, 3H, J=4.5); 13C NMR (DMSO-d6) δ 170.8, 167.4, 134.8, 131.1, 123.3, 50.2, 36.7, 24.6, 23.0, 20.8. Anal. Calculated for C14H15NO4. Theoretical: C, 64.36; H, 5.74; N, 5.36. Found: C, 64.18; H, 5.73; N, 5.98.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:18]=O)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(C=O)ccc2C1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CCc2cc(CN3CCCCC3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(6-Formyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (Step D) (0.090 g, 0.33 mmol) was dissolved in N,N-dimethylacetamide (10 mL). Piperdine (0.162 mL, 1.63 mmol) was added and the mixture was stirred at RT for 30 min. NaBH(OAc)3 (0.173 g, 0.817 mmol) was added in one portion and the reaction was stirred at RT until complete consumption of starting material was observed by HPLC analysis. The reaction was in concentrated in vacuo and the residue was diluted with CH2Cl2 and H2O and the aqueous layer was made basic with NaOH. The layers were separated and the organics were dried over MgSO4 and concentrated in vacuo to afford the crude title compound, which was used without further purification. MS (APCI pos) 345 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[N:28]=[C:27]([NH2:29])[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([NH2:29])[N:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1n[nH]c(N)n1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: Nc1nc2ncc3c(n2n1)CC1CCCC3N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3,5-diamino-1,2,4-triazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:13][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]ccc2c1

Procedure:
To a solution of 5-indole carboxylic acid (5.08 g, 31.5 mmol) in a 1:1 mixture of methanol/methylene chloride (40 mL) was added (trimethylsilyl)diazomethane (33 mL, 2 M solution in hexanes) in portions over 15 min. The yellow colored solution was concentrated on the rotoevaporator to provide methyl-5-indole carboxylate as a white powder (5.5 g).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>S(=O)(=O)(O)O>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][C:17]=1[CH2:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(NCO)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])cc1CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 43 %

Procedure:
N-hydroxymethyl benzamide (7.55 g; 0.05 mol) is added to a solution of p-nitrotoluene (0.85 g; 0.05 mol) in concentrated sulfuric acid (60 ml). The reaction mixture is stirred for 63 hours at room temperature and then poured onto ice. A colorless precipitate is obtained which is isolated and recrystallized repeatedly from aqueous ethanol to give 4.0 g (i.e., 30% yield) of product. Increasing the reaction time to 7 days gives a 43% yield of product compound. This product has the following characteristics: melting point of 134° to 137° C.; i.r. 3300, 1635, 1655 cm-1 (sh); mass. spec. m/e 270.
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23]([CH2:32][O:33][CH2:34][CH3:35])=[N:22][C:17]=4[CH:18]=[N:19][C:20]=3[CH:21]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:48].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:34]([O:33][CH2:32][C:23]1[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:16]2[C:15]3[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])=[CH:21][C:20]=3[N:19]=[C:18]([NH2:48])[C:17]=2[N:22]=1)[CH3:35]
Reactant: CCOCc1nc2cnc3cc(C=CS(=O)(=O)c4ccccc4)ccc3c2n1CCCOC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(/C=C/S(=O)(=O)c4ccccc4)ccc3c2n1CCCOC(C)C
Reaction time: 0.5 h

Procedure:
7-(2-Benzenesulfonylvinyl)-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (0.600 g, 1.22 mmol) was dissolved in chloroform (12 mL). 3-Chloroperoxybenzoic acid (60% purity, 0.351 g, 1.22 mmol) was added. The reaction was stirred for 30 minutes. Ammonium hydroxide (8 mL) was added and the mixture was stirred for 10 minutes. p-Toluenesulfonyl chloride (0.232 g, 1.22 mmol) was added in one portion and the reaction was stirred for an additional 16 hours. The layers were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were sequentially washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using a Horizon HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc.; Charlottesville, Va., USA). The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out with a silica cartridge eluting with a linear gradient of 1-22% CMA in chloroform. The resulting material was subsequently recrystallized from acetonitrile to yield 0.320 g 2-ethoxymethyl-1-(3-isopropoxypropyl)-7-[(E)-2-(phenylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-4-amine as green needles, mp 188.5-190.0° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A 25 mL round bottom flask was charged with ethyl 8-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,2-a]pyrazine-2-carboxylate (1.13 g, 2.47 mmol), trifluoroacetic acid (5 mL) and CH2Cl2 (10 mL). The mixture was stirred at 25° C. for 1 h. Reaction progress was monitored by LC-MS. Work-up: the solvent was evaporated. The residue was mixed with saturated aqueous NaHCO3 and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1:20 MeOH/CH2Cl2, to afford 0.75 g (84%) of the product. 1H NMR (300 MHz, CD3OD) δ: 8.40 (s, 1H), 7.69 (dd, J=5.1, 1.2 Hz, 1H), 7.58 (s, 1H), 7.52 (dd, J=3.9, 1.2 Hz, 1H), 7.28 (dd, J=5.1, 3.9 Hz, 1H), 4.54 (t, J=5.1 Hz, 4H), 4.41 (q, J=7.2 Hz, 2H), 3.39 (t, J=5.1 Hz, 4H), 1.38 (t, J=7.2 Hz, 3H). MS m/z: 358 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:16])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][CH2:6]1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:16][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][CH2:6]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1CCCc2cc(N)cc(F)c21
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-6-amine (222 mg, 0.935 mmol) was stirred to dissolve in ethanol in a round bottom flask. To this solution was added methyl thiophene-2-carbimidothioate hydroiodide (533 mg, 1.87 mmol). The resulting suspension was stirred overnight at room temperature. When TLC analysis showed that the reaction was finished, the mixture was diluted with water and aqueous sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated and the crude product then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in ethyl acetate, then a second time using 20-80% MeCN in an aqueous buffer of ammonium carbonate and ammonium hydroxide adjusted to pH 10.6. Yield: 46 mg, 15%. 1H NMR (DMSO-d6) δ 1.75 (m, 2H), 2.16 (s, 6H), 2.46 (m, 2H), 2.66 (m, 2H), 3.12 (m, 4H), 6.40 (m, 4H), 7.07 (m, 1H), 7.57 (m, 1H), 7.71 (m, 1H). ESI-MS: 347 (MH+, 33), 276 (100), 143 (12).
Reaction SMILES: [CH3:1][O:2][C:3]([O:9][CH3:10])([CH3:8])[C:4](=[N:6][OH:7])[CH3:5].C([Li])CCC.[CH3:16][Si:17]([CH3:31])([CH3:30])[C:18]#[C:19][CH2:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[OH:25][CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH2:20][C:19]#[C:18][Si:17]([CH3:16])([CH3:31])[CH3:30])[CH2:5][C:4](=[N:6][OH:7])[C:3]([O:9][CH3:10])([O:2][CH3:1])[CH3:8]
Reactant: COC(C)(OC)C(C)=NO
Reactant: C[Si](C)(C)C#CCOc1ccccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(C)(OC)C(CC(O)c1ccccc1OCC#C[Si](C)(C)C)=NO
Reaction time: 0.08 h
Yield: 127.2 %

Procedure:
To a solution of 3,3-dimethoxybutan-2-one oxime (270 mg) in tetrahydrofuran (2.7 ml) was added dropwise, at 0° C. under argon, n-butyllithium (2M in tetrahydrofuran, 1.83 ml). After stirring for a further 5 minutes, a solution of 2-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}benzaldehyde (232 mg) in tetrahydrofuran (1 ml) was added dropwise to the reaction mixture, which was stirred for a further 1 hour. Subsequently, concentrated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 1-hydroxyl-4,4-dimethoxy-1-(2-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}phenyl)pentan-3-one oxime (482 mg, 69%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH3:37][C:38](=[O:41])[CH:39]=[CH2:40]>>[O:41]=[C:38]1[CH2:39][CH2:40][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:37]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Yield: 57.2 %

Procedure:
Benzyl 4-formylpiperidine-1-carboxylate (5.17 g, 20.907 mmol) and p-Toluenesulfonic acid monohydrate (0.398 g, 2.091 mmol) were stirred in Benzene (30.0 ml, 334.136 mmol) at 70° C. But-3-en-2-one (3.76 ml, 41.813 mmol) was added and the reaction mixture was refluxed o/n while removing water with dean-stark trap. After cooling the reaction mixture to rt, sat. NaHCO3 soln. was added and the organic layer was dried over Na2SO4 and evaporated. The resulting oil was purified by Biotage (SiO2, 250 g, EtOAc/Hep 10% to 50%) to afford the title compound (3.58 g, 11.96 mmol, 57.2% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]([C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50](O)[CH:49]=[CH:48]2)([C:21]1[N:22]=[CH:23][N:24]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1.O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:50]1[CH:49]=[CH:48][C:47]2[C:52](=[CH:53][CH:54]=[C:45]([C:17]([OH:16])([C:21]3[N:22]=[CH:23][N:24]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)[CH:18]([CH3:19])[CH3:20])[CH:46]=2)[CH:51]=1)(=[O:5])=[O:4]
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (9.1 mL) was added dropwise to a solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthol (27.0 g) in pyridine (200 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C., diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate=1:1). Crystallization from diisopropyl ether gave the titled compound (29.6 g) as a colorless powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Solvent: ClCCl
Product: O=C([C@@H]1CCCN1C(=O)CCCc1ccccc1)N1CCCC1
Temperature: 25 °C

Procedure:
When the reaction was over, the mixture was extracted twice with ethyl ether to remove the unreacted acid chloride. The water phase was acidified by addition of hydrochloric acid. The resulting precipitate was extracted three times with ethyl acetate and the solvent was removed under vacuum, whereby N-(γ-phenyl)butyryl-L-proline was obtained. N-(γ-phenyl)butyryl-L-proline (1 equivalent) was then dissolved in dry methylene chloride (ca. 100 ml) together with pyrrolidine (1 equivalent), WSCD (1 equivalent) was added thereto and the mixture was continuously stirred at room temperature for one whole day and night. After the reaction, the product was washed successively with 1N hydrochloric acid, brine, saturated sodium bicarbonate and brine in that order and was then dried over anhydrous magnesium sulfate. The solvent was distilled off under vacuum and the residue was purified by column chromatography on silica gel, whereby the titled compound was obtained.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>N1C=CC=CC=1.C(N(CC)CC)C>[S:18]1[C:19]2=[N:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21](=[O:22])[NH:15]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccnc1S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=c1[nH]sc2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of diphenylphosphoryl azide (39.41 g, 0.139 mol) in pyridine (160 ml) and triethylamine (19 ml) was added 2-mercaptonicotinic acid (21.57 g, 0.139 mol) portionwise at 0° C. The reaction mixture was stirred overnight at room temperature and afterwards concentrated in vacuo. Ethanol (15 ml) was added at 30° C. to the crude product. Filtration at room temperature afforded a yellow solid which was washed with ethanol (15 ml) and dried in vacuo (10 mbar). 17.04 g (89%) of the title compound were obtained as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14](Br)[C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(C(Br)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Yield: 88.6 %

Procedure:
(S)-2-[bromo-(6-methoxy-pyridin-3-yl)-methyl]-morpholine-4-carboxylic acid tert-butyl ester (290 mg, 0.75 mmol) was dissolved in methanol (5 mL) and hydrogenated at 0.25 bar in the presence of 50 mg 10% Pd/C. Reaction mixture was diluted with ethyl acetate and filtered through Dicalite. The filtrate was washed with 1M sodium hydroxide. The aqueous phase was extract 2 times with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford (R)-2-(6-Methoxy-pyridin-3-ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester (205 mg, 88%) as a light yellow oil. Chiral HPLC (Chiralpak-AD) indicated that product was 98.3% pure. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 2.53-2.79 (m, 3H) 2.86-3.00 (m, 1H) 3.38-3.58 (m, 2H) 3.73-3.89 (m, 3H) 3.91 (s, 3H) 6.68 (d, J=8.33 Hz, 1H) 7.39-7.49 (m, 1H) 8.00 (d, J=2.15 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17][O:18][CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC>O1CCOCC1.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>[CH3:19][O:18][CH2:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:21]=[CH2:22])[C:3]1=[O:20]
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2COC)c1=O

Procedure:
94 g (277 mmol) of the compound from Example 28A are dissolved in 1.2 l of anhydrous dioxane, and 8 g (6.9 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. At room temperature, 105 g (333 mmol) of tributylvinyltin are added slowly, and after the addition has ended, the mixture is heated at reflux for 21 h. The reaction solution is allowed to cool and filtered through kieselguhr. The filter cake is washed with ethyl acetate and the combined organic filtrates are concentrated to dryness under reduced pressure. The residue that remains is dissolved in dichloromethane and applied to kieselguhr. The product is chromatographed on 1.2 kg of silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 23 g (29% of theory) of the desired product.