Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a solution of N-tert-butyl-2-(p-tolylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 176 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (402 mg, 272 μL, 3.53 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether. Purification by chromatography (silica, 20-40% of a 10:89.5:0.5 methanol:dichloromethane:ammonium hydroxide solution in dichloromethane) gave N-tert-butyl-2-(p-tolylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (17 mg, 52.6 μmol, 30%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.26 (s, 1H), 9.34 (s, 1H), 7.97 (s, 1H), 7.96 (d, J=3.3, 1 H), 7.76 (s, 1H), 7.57 (t, J=8.5, 2 H), 7.09 (d, J=8.1, 2 H), 2.26 (s, 3H), 1.44 (s, 9H); MS (EI/CI) m/z: 324.1 [M+H].
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C@:15]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:16](=[O:17])[C@@H:11]([C@:12]([CH3:42])([CH2:28][CH2:29][CH2:30][C:31]([CH3:41])([O:33][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:32])[C@@H:13]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14]2)[C:10](=[O:43])[C:9]=1[Si:44]([CH3:47])([CH3:46])[CH3:45].[Li]N1C(C)(C)CCCC1(C)C.[C:59](Cl)(=[O:63])[CH:60]([CH3:62])[CH3:61]>CCOC(C)=O.CCCCCC>[C:59]([C@:11]12[C:16](=[O:17])[C@:15]([CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])([CH2:14][C@H:13]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@:12]1([CH3:42])[CH2:28][CH2:29][CH2:30][C:31]([CH3:41])([O:33][Si:34]([CH2:35][CH3:36])([CH2:37][CH3:38])[CH2:39][CH3:40])[CH3:32])[C:8]([O:7][CH3:6])=[C:9]([Si:44]([CH3:47])([CH3:46])[CH3:45])[C:10]2=[O:43])(=[O:63])[CH:60]([CH3:62])[CH3:61]
Reactant: CC(C)C(=O)Cl
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@@H]1C(=O)C([Si](C)(C)C)=C2OC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@]1(C(=O)C(C)C)C(=O)C([Si](C)(C)C)=C2OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
A THF (0.5 mL) solution of 45 (7.0 mg, 11 μmol, 1 equiv.) was cooled to −78° C. in a 10-mL test tube, and a freshly prepared THF solution of lithium tetramethylpiperidide (0.50 M, 113 μL, 57 μmol, 5 equiv.) was added dropwise. The resulting yellow-orange solution was stirred at −78° C. for 10 min and at 0° C. for 10 min. The solution was then cooled to −78° C., and isobutyryl chloride (6.0 μL, 57 μmol, 5 equiv.) was added. The resulting yellow solution was stirred at −78° C. for 50 min, was slowly warmed to 0° C. over 50 min, and subsequently quenched with saturated aqueous NaHCO3. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow residue. Preparatory thin-layer chromatography (3×98:2 hexane:EtOAc) afforded 1.8 mg (2.6 μmol, 24% yield) of 46 as a colorless residue along with 1.7 mg (2.8 μmol, 25% recovery) of 45. TLC Rf 0.47 (95:5 hexane:EtOAc). 1H-NMR (600 MHz; CDCl3): δ 5.00-4.96 (m, 2H), 3.90 (s, 3H), 2.55 (dd, J=14.6, 6.4 Hz, 1H), 2.41 (dd, J=14.5, 7.7 Hz, 1H), 2.08 (d, J=15.0 Hz, 1H), 1.97 (septet, J=6.5 Hz, 1H), 1.92-1.85 (m, 2H), 1.79-1.72 (m, 1H), 1.68 (s, 3H), 1.66 (s, 3H), 1.57-1.56 (m, 3H), 1.55-1.53 (m, 3H), 1.50-1.42 (m, 2H), 1.39-1.31 (m, 3H), 1.30-1.24 (m, 2H), 1.17 (s, 3H), 1.17 (s, 3H), 1.13 (d, J=6.5 Hz, 3H), 1.02 (d, J=6.5 Hz, 3H), 0.98 (s, 3H), 0.92 (t, J=7.9 Hz, 9H), 0.54 (q, J=7.9 Hz, 6H), 0.26 (s, 9H). HRMS-ESI (m/z): [M+Na]+ calculated for C40H70O5Si2, 709.4654. found, 709.4626.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]=[CH2:11])[CH:3](O)[CH2:4][C:5](O)=O.C([O-])(=O)C.[K+].[H-].[Na+].COP([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(OC)=O>C(OC(=O)C)(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:9][C@@H:10]2[C@H:4]([CH:3]=1)[C:5](=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]2
Reactant: C=CCC(C)C(O)CC(=O)O
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methyl-3-hydroxyhept-6-enoic acid (2.21 g, 13.9 mmol) was dissolved in acetic anhydride (14 mL). To the solution, potassium acetate (3.29 g, 33.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was heated to 110 to 120° C. and stirred for 3.5 hours. To the reaction solution, ice water and toluene were then added, and this mixture was stirred at room temperature for 1 hour. The mixture was separated into aqueous and organic layers by the addition of saturated saline and toluene. Then, the organic layer was washed with a 1 N aqueous sodium hydroxide solution and saturated saline in this order, then dried over anhydrous magnesium sulfate, and then filtered. This filtrate was added to a reaction solution prepared by adding sodium hydride (>63% oil, 533.3 mg, 14.0 mmol) to a tetrahydrofuran solution (20 mL) of tert-butyl dimethoxyphosphorylacetate (3.24 g, 14.5 mmol) under ice cooling, and the mixture was further stirred for 1.5 hours. The reaction solution was separated into aqueous and organic layers by the addition of a saturated aqueous solution of ammonium chloride and saturated saline. The aqueous layer was subjected to extraction with ethyl acetate. These organic layers were combined, then washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.21 g, 40%, E/Z mixture).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:6][C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[N+:24]([O-])=O)=[N:4]1)[CH3:2].[H][H]>CO.[Pt]>[NH2:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: [H][H]
Reactant: CCn1nc(Oc2ccc(F)cc2[N+](=O)[O-])cc1-c1cccc(C#N)c1
Agent: [Pt]
Solvent: CO
Product: CCn1nc(Oc2ccc(F)cc2N)cc1-c1cccc(C#N)c1
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
Platinum (3% on carbon, poisoned with 0.6% vanadium, 24 mg, 3.8 mmol, 0.005 equiv) was added to a solution of 3-[1-ethyl-3-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-5-yl]benzonitrile (266 mg, 0.755 mmol, 1 equiv) in methanol (7.6 mL). The reaction flask was capped with a three way valve attached to a vacuum line and a hydrogen balloon. The reaction flask was alternately evacuated and charged with hydrogen for 3 cycles, and finally left under an atmosphere of hydrogen at 22° C. The reaction mixture was stirred for 40 minutes, then filtered through celite with the aid of methanol. Concentrated to afford 3-[3-(2-amino-4-fluorophenoxy)-1-ethyl-1H-pyrazol-5-yl]benzonitrile (243 mg, 90% pure) as a light-yellow solid. Calcd (M+1)+: 323.1. Found: 323.0.
Reaction SMILES: C[O-].[Na+].NC(N)=O.[NH2:8][C:9]([NH:11][N:12]([CH2:28][C:29]([O:31]C)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:14]=1)=[O:10]>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:15]2[CH:14]=[C:13]([N:12]3[CH2:28][C:29](=[O:31])[NH:8][C:9](=[O:10])[NH:11]3)[CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CN(NC(N)=O)c1cccc(OCc2ccc(F)cc2)c1
Agent: C[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CO
Product: O=C1CN(c2cccc(OCc3ccc(F)cc3)c2)NC(=O)N1
Reaction time: 2 h
Yield: 29 %

Procedure:
Sodium methoxide (467 mg, 8.6 mmol) was added to a stirred solution of the urea (Intermediate 80, 1 g, 2.88 mmol) in methanol (40 ml) and the mixture was stirred at 20°-25° for 2 h. The mixture was poured into pH6.7 buffer (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating in vacuo to a yellow solid. Trituration with ether gave the title compound as a white solid (265 mg, 29%) m.p. 185°-187° (dec).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[N:10]=2)=[CH:5][CH:4]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[Cl:15][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2ccc(CBr)cc2)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2cccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.8 %

Procedure:
The mixture (5.72 g) obtained in Example 36-2 and potassium phthalimide (2.04 g) were dissolved in DMF (30 ml) and the whole was stirred at room temperature for 24 hours. Then, a solid component was separated by filtration. After the solvent was distilled off, the resultant was dissolved in chloroform and washed with a aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform and dried with anhydrous magnesium sulfate. The solvent was distilled off. The resultant residue was purified through silica gel column chromatography (chloroform), thereby obtaining the subject compound (1.56 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].C1C=CN2CC3C=CC=CC=3NCC=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Agent: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 116.9 %

Procedure:
A suspension of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acid of Step C (0.50 g, 1.78 mmol) in thionyl chloride (3 mL) was heated at reflux for 90 minutes. After cooling, the thionyl chloride was removed in vacuo and the residue dissolved in toluene. The solution was concentrated in vacuo to yield the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.49 g, 2.66 mmol) and N,N-diisopropylethyl amine (0.68 mL, 3.90 mmol) in dichloromethane (15 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was sequentially washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 15 to 25% ethyl acetate in hexane gave a white foam which was crystallized by sonication from ethanol/hexane to provide the title compound (0.55 g) as a white solid, m.p. 127–130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.O([Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CNc1nccc(-c2cc[nH]c2-c2ccc(F)cc2)n1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Product: CNc1nccc(-c2ccn([Si](C(C)C)(C(C)C)C(C)C)c2-c2ccc(F)cc2)n1
Yield: 82 %

Procedure:
In a similar manner to that described in Example 7(ii) above, 2-(4-fluorophenyl)-3-(2-methylaminopyrimidin-4-yl)-1H-pyrrole [prepared as described in step 1(iii) above] was reacted with triisopropylsilyl triflate, to afford the title compound (yield 82%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:21])[S:10][CH2:11][CH2:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][CH:7]=1.[BH4-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:21])[S:10][CH2:11][CH2:12][CH:13]([OH:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: O=C(CCSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OC(CCSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Reaction time: 20 h
Yield: 34.8 %

Procedure:
The procedure of Example 3 is followed, but a suspension of 3-oxo-3-phenylpropyl 5-chloropyrid-2-yldithiocarbamate (28.0 g) in methanol (840 cc) and a solution of potassium borohydride (9.0 g) in distilled water (120 cc) are used as the starting materials at a maximum of 30° C. The reaction is allowed to proceed for 20 hours at between 20° and 25° C. Unreacted starting material (5.5 g) is filtered off from the reaction mixture. The filtrate is evaporated to dryness. The residue (20.0 g) is dissolved in chloroform (200 cc). The solution is chromatographed on silica (0.063-0.2 mm, 400 g) contained in a column of diameter 5 cm. Elution is carried out with chloroform (2 liters), this eluate being discarded, and then with chloroform (4.5 liters). The eluate which is collected is evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. The chromatographed product (14.4 g) is recrystallised from acetonitrile (40 cc). 3-Hydroxy-3-phenylpropyl 5-chloropyrid-2-yldithiocarbamate (9.8 g), which melts at 91° C., is obtained.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[N:5]2[C:20](=[O:25])[C@H:21]([C@H:22]([OH:24])[CH3:23])[C@H:4]2[CH2:3]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[C:66](/[CH:69]=[CH:70]/[Sn](CCCC)(CCCC)CCCC)(=[O:68])[NH2:67]>C(#N)C.CN1CCCC1=O.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[C:66](/[CH:69]=[CH:70]/[C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:8])(=[O:68])[NH2:67]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CCCC[Sn](/C=C/C(N)=O)(CCCC)CCCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(/C=C/C(N)=O)C[C@H]12
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of 128 mg (0.367 mmol) of 4-nitrobenzyl (5R,6S)-2-oxo-6-((1R)-1-hydroxyethyl) -1-carbapenam-3-carboxylate in acetonitrile (3ml) was added 0.065 ml (0.37 mmol) of diisopropylethylamine at -45° C., followed by 0.062 ml (0.37 mmol) of trifluoromethanesulfonic anhydride, and the mixture was stirred at -40°-30° C. for 30 minutes. To the reaction mixture was added ethyl acetate (3 ml), and the organic layer was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed. The residual triflate was used the next reaction without purification. To this crude product was added 113 mg (0.83 mmol) of zinc chloride, 5.3 mg (0.0091 mmol) of bis(benzylideneacetone)palladium(0), and 4.4 mg (0.0185 mmol) of tri(2-furyl)phosphine. Under a nitrogen atmosphere, a solution of 157 mg (0.436 mmol) of (E)-2-carbamoylvinyl (tri-n-butyl)tin in N-methylpyrrolidinone (6 ml) was added, and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added ethyl acetate, and the organic layer was washed with water followed by saturated aqueous sodium chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography (elution with methanol-chloroform system) to give 50.5 mg (yield: 34.3 %) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.Cl[CH2:11][C:12]1[C:17]([CH3:18])=[C:16]([S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>CC(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:11][C:12]2[C:17]([CH3:18])=[C:16]([S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=4)[N:29]=3)[CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(C)nc(SCc2nccc(SCCCSc3ccc4ncc([N+](=O)[O-])n4n3)c2C)n1
Temperature: 0 °C

Procedure:
A suspension of 4,6-dimethyl-pyrimidine-2-thiol (0.35 g, 2.5 mmol) and 6-[3-(2-chloromethyl-3-methyl-pyridin-4-ylsulfanyl)-propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.03 g, 2.5 mmol) in 2-propanol (50 ml) is heated under reflux for 4 h under a nitrogen atmosphere. After cooling, the mixture is treated with ice water (100 ml), adjusted to pH 10 with 40% strength sodium hydroxide solution, and extracted with ethyl acetate. The combined extracts are washed with sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from acetonitrile to give the title compound as a colourless solid, 0.93 g (76%). M.p. 145-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:31])[NH:28][O:29][CH3:30])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:31])[NH:28][O:29][CH3:30])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:51])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbamoyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (25 mg, 0.042 mmol) and Lawesson's reagent (33 mg, 0.084 mmol) in THF (1 mL) was stirred at room temperature for 1 h, and then diluted with toluene (10 mL). The mixture was concentrated and the residue was washed with DCM twice. The DCM solutions were combined and concentrated. The residue was purified by flash column to give the title compound as white solid (10 mg).
Reaction SMILES: C([NH:8][CH2:9][C@:10]1([OH:17])[CH2:15][CH2:14][CH2:13][C@H:12]([CH3:16])[CH2:11]1)C1C=CC=CC=1>[Pd].CO>[NH2:8][CH2:9][C:10]1([OH:17])[CH2:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH2:11]1
Reactant: C[C@H]1CCC[C@@](O)(CNCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC1CCCC(O)(CN)C1
Reaction time: 72 h
Yield: 90.5 %

Procedure:
A mixture of (1S,3S)-1-[(benzylamino)methyl]-3-methylcyclohexanol (4.5 g) and 5% palladium on carbon (500 mg) in methanol (40 ml) was stirred under a hydrogen atmosphere of 4 bar for 72 hours. The reaction was filtered through celite, washed with methanol (2×) and concentrated in vacuo to afford 1S,3S)-1-(Aminomethyl)-3-methylcyclohexanol as a colourless oil (2.5 g).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)[CH3:19]>>[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1)[CH3:19]
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: CCc1ccccc1B(O)O
Product: CCc1ccccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-ethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N+:6]([O-:20])[CH:7]=1
Reactant: COC(=O)c1ccc(F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
Methyl 5-fluoropicolinate (440 mg, 2.836 mmol) was dissolved in CHCl3 (10 ml), followed by addition of mCPBA (954 mg, 4.254 mmol), and then the resulting mixture was stirred at room temperature for 15 hours. A saturated aqueous Na2S2O3 solution (15 ml) was added to the resulting reaction liquid, followed by extraction with 5% MeOH/MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (2% MeOH/MC), to obtain 318 mg of colorless oil (66%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=1[F:38])=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=1[F:38])=[O:27])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1F
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C(=O)NCc1cc(F)cc(F)c1F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=509.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(2,3,5-trifluoro-benzyl)-malonamic acid.