Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), and 1,1'carbonyldiimidazole (2.9 g, 0.018 mole), in anhydrous tetrahydrofuran (175 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 4 hours. The nitrogen flow was stopped and a solution of dimethylamine in tetrahydrofuran (72 ml of 0.5M) was added. The solution was stirred at room temperature under nitrogen for 1/2 hour. The reaction mixture was filtered, concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from tetrahydrofuran-isopropyl ether, giving 4.5 g (70%). Recrystallization from isopropyl alcohol-isopropyl ether gave 4.0 g of cream colored needles, mp 144°-146° C.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36]O.[CH3:47][O:48][C:49]1[C:54]([O:55][CH3:56])=[C:53]([O:57][CH3:58])[C:52]([O:59][CH3:60])=[CH:51][C:50]=1[CH3:61]>CCCCCC.[N+](C)([O-])=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:60][O:59][C:52]1[C:51]([CH2:36]/[CH:35]=[C:34](\[CH3:38])/[CH2:33][CH2:32]/[CH:31]=[C:30](\[CH3:39])/[CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:40])/[CH2:25][CH2:24]/[CH:23]=[C:22](\[CH3:41])/[CH2:21][CH2:20]/[CH:19]=[C:18](\[CH3:42])/[CH2:17][CH2:16]/[CH:15]=[C:14](\[CH3:43])/[CH2:13][CH2:12]/[CH:11]=[C:10](\[CH3:44])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:45])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])=[C:50]([CH3:61])[C:49]([O:48][CH3:47])=[C:54]([O:55][CH3:56])[C:53]=1[O:57][CH3:58]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Solvent: CCCCCC
Product: COc1c(C)c(C/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)c(OC)c(OC)c1OC
Temperature: 50 °C
Yield: 124.8 %

Procedure:
In a 50 ml four necked flask equipped with a stirrer, thermometer, gas inlet, and a reflux condenser, under argon atmosphere 0.654 g (96.52%, 1 mmol) of solanesol were dissolved in 15 ml of n-hexane and mixed with 1.07 g (5.0 mmol) of 2,3,4,5-tetramethoxy-toluene (TMT) suspended in 7.6 ml of nitromethane. The catalyst, Sc(OTf)3 (2.5 mg, 0.005 mmol), was then added. The two-phase mixture was heated up to 50° C. (internal temperature) under stirring (400 rpm). After 16 hours reaction time the mixture was cooled down to room temperature (21° C.). The hexane layer was separated and washed two times with 4 ml (total 8 ml) of nitromethane. The hexane phase was evaporated and yielded 1.03 g of crude 1,2,3,4-tetramethoxy-5-methyl-6-((2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,27,31,35-nonamethyl-hexatriaconta-2,6,10,14,18,22,26,30,34-nonaenyl)-benzene (tetramethoxy-CoQ9) as a colorless oil, which was purified by column chromatography on 30 g silica (elution with n-hexane/ethyl acetate=99:1, v/v) yielding 280 mg of a colorless oil which crystallized upon standing. Yield:32%; purity 94%.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:18]([CH:26]=[O:27])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.C1COCC1.O.[Na+].[Cl-].C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:8][CH2:9][CH:10]([N:18]([CH:26]=[O:27])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(C=O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(C=O)C(CO)Cc1ccccc1
Yield: 98.4 %

Procedure:
tertbutyl 3-(tert-butyldimethylsilyloxy)-1-oxo-1-phenylpropan-2-lmethylcarbamate (36) (640 mg, 1.6 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by a 1:1 mixture of THF/H2O (8 mL). The mixture was stirred and glacial acetic acid (12 mL) was added to the reaction flask. The reaction stirred for 20 h at rt. The reaction was transferred to a 250 mL separatory funnel with sat. NaCl (50 mL) and sat. NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (3×70 mL) and the combined organic layers were dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 550 mg of crude material. The residue was purified by flash column chromatography (50% EtOAc/hexanes) to give 440 mg (97%) of 37 as a colorless oil. Rf=0.33 (50% EtOAc/hexanes); IR (film) 3451, 2975, 1681, 1149 cm−1; 1H NMR (500 MHz, CDCl3) δ Major rotamer: 7.96 (d, J=7.5 Hz, 1H, Ph-H), 7.90 (d, J=7.5 Hz, 1H, Ph-H), 7.58 (t, J=6.5 Hz, 1H, Ph-H), 7.46 (m, 2H, Ph-H), 5.45 (t, J=6.0 Hz, 1H, Boc-N—CH), 4.24 (m, 1H, CH—CH2), 4.14 (m, 1H, CH—CH2), 2.72 (s, 3H, Boc-N—CH3), 2.50 (m, 1H, CH2—OH), 1.43 (s, 9H, Boc-t-butyl-CH3). Minor rotamer: 4.89 (t, J=6.0 Hz, 1H, Boc-N—CH), 3.94 (m, 1H, CH—CH2), 3.81 (m, 1H, CH—CH2), 2.90 (s, 3H, Boc-N—CH3), 1.38 (s, 9H, Boc-t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 199.9, 199.2, 156.1, 154.6, 135.7, 133.8, 128.9, 128.8, 128.5, 128.3, 81.7, 80.9, 63.5, 61.0, 60.8, 60.7, 33.3, 32.1, 28.4, 28.3; LRMS (ESI-MS m/z): Mass calcd for C15H21NO4Na [M+Na+], 302.32. Found 302.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:6]([C:7]([NH2:9])=O)[CH:5]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:6]([C:7]#[N:9])[CH:5]=1
Reactant: COC(=O)c1cc(OC)cc(C(N)=O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C#N)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
A suspension of 5-methoxy-isophthalamic acid methyl ester (4.0 g, 19.1 mmol) in a dichloromethane (80 mL) at 0° C. was treated with pyridine (6.3 mL, 77.0 mmol) and then trifluoroacetic anhydride drop-wise (6.5 mL, 46 mmol). The reaction was stirred at 0° C. for 20 min. and then stirred overnight at room temperature. The reaction mixture was washed with water, 1.0 N HCl and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 3.6 g (98%) of 3-cyano-5-methoxy-benzoic acid methyl ester as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(NC(C)C)(C)C>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)I.C(OCC)(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: C#Cc1ccccc1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A flame-dried flask was charged with the 5-bromo-2-nitroaniline (2, 300 mg, 1.38 mmol) (scheme 1, Example 1), phenylacetylene (155 mg, 1.52 mmol) and ethyl acetate (13.8 mL). The solution was degassed under vacuum and put under N2 atmosphere. Then, dichlorobis(triphenylphosphine)palladium (48 mg, 0.069 mmol) and copper iodide (26 mg, 0.138 mmol) were added. The yellow solution was degassed again (3 cycles) N,N-diisopropylamine (231 μl, 1.68 mmol) was added and the solution rapidly turned dark. It was degassed twice again and allowed to stir under N2 atmosphere at r.t. over 16 h. Then it was passed through celite and the filtrate was successively washed with dilute aqueous ammonia (NH4OH), saturated NaHCO3, saturated NH4Cl, brine, dried over MgSO4, filtered and concentrated. The resulting dark solid was purified by flash chromatography on silica gel using EtOAc/hexanes as the eluent with increasing polarity (10:90 to 15:85) affording the title compound 124 (242 mg, 74% yield) as a deep yellow solid. 1H NMR: (400 MHz, CD3OD) δ(ppm): 8.04 (dd, J=8.8, 0.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.40-7.37 (m, 3H), 7.11 (dd, J=1.8, 0.4 Hz, 1H), 6.73 (dd, J=8.8, 1.8 Hz, 1H). LRMS: (m/z): 239.3 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32]C1C=CC(C#N)=C(O)C=1.C(O)(=O)C(O)=O.[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[C:51]([O:57][C@@H:58]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:59][CH2:60][CH2:61]NC)[CH:50]=1>O1CCCC1.C1(C)C=CC=CC=1>[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[C:51]([O:57][C@@H:58]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:59][CH2:60][CH2:61][Cl:32])[CH:50]=1
Reactant: CNCCC[C@@H](Oc1cc(Cl)ccc1C#N)c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCCl)c1ccccc1
Yield: 197.8 %

Procedure:
Diethyl azodicarboxylate (1.86 g) was added dropwise to a solution of triphenylphosphine (2.81 g), 4-chloro-2-hydroxybenzonitrile (1.49 g) and the product from step (a) (1.79 g) in tetrahydrofuran (5 ml) and toluene (60 ml) at 0° C. and stirred at 0° C. for 4hand at 20° C. for 18 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica eluting with hexane-diethyl ether (4:1) to give the title compound as a colourless oil (2.80 g).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:28][NH2:29]>CCO>[CH2:1]([O:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:28][NH2:29])=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NN
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-{[4-(hexyloxy)benzoyl]amino}benzoate (856 mg, 2.41 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 681 mg of the title compound (80%) as a white solid in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl-].[CH:6]([NH:9][P:10]([CH2:13][CH2:14][Cl:15])(=[O:12])[OH:11])([CH3:8])[CH3:7]>C1C=CC=CC=1>[CH:6]([NH-:9])([CH3:8])[CH3:7].[CH2:2]([O:3][P:10]([CH2:13][CH2:14][Cl:15])(=[O:11])[OH:12])[CH3:1]
Reactant: CC[O-]
Reactant: CC(C)NP(=O)(O)CCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)[NH-]
Product: CCOP(=O)(O)CCCl
Reaction time: 2 h

Procedure:
87 ml (0.2 mole) ethanolic sodium ethylate solution are added to 41 g (0.2 mole) 2-chloroethanephosphonic acid N-monoisopropylamide chloride in 200 ml benzene at room temperature. Stirring was afterwards effected for 2 hours; the salts were then filtered off with suction, the reaction solution was washed with water, and drying with sodium sulfate was effected. After the solvent had been drawn off, slight distillation was carried out. There remained behind a colourless oil, nD26 = 1.4580, yield: 27 g (64%) 2-chloroethanephosphonic acid ethyl ester N-monoisopropylamide.
Reaction SMILES: CC(C)(OC([NH:7][CH2:8][CH2:9][C@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=O)C.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([OH:26])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:10]([OH:15])(=[O:26])[C:11]([OH:13])=[O:12].[NH2:7][CH2:8][CH2:9][C@@H:10]([O:15][C:24]1[CH:25]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[C:22]#[N:23])[CH2:11][O:13][CH3:14]
Reactant: COC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@@H](CCN)Oc1cc(Cl)ccc1C#N
Product: O=C(O)C(=O)O
Temperature: 0 °C
Reaction time: 48 h
Yield: 148.7 %

Procedure:
The product of step (b) (3.25 g, 13.9 mmol), 4-chloro-2-hydroxybenzonitrile (2.14 g, 13.9 mmol) and triphenylphosphine (4.38 g, 16.7 mmol) were dissolved in anhydrous tetrahydrofuran (80 ml) and the solution cooled to 0° C. Diethyl azodicarboxylate (2.91 g, 16.7 mmol) was added dropwise and the solution allowed to warm to room temperature, then stirred for 2 days. The solvent was removed in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (3:1), to afford the title compound as a white solid (3.562 g, 69%).
Reaction SMILES: [CH2:1](Br)[C:2]#C.[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:13][C:12]1[CH:14]=[CH:15][C:7]([CH:6]=[O:5])=[CH:8][C:9]=1[O:10][CH2:11][C:1]#[CH:2]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Reactant: C#CCBr
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(C=O)ccc1OC
Yield: 80.7 %

Procedure:
Propargyl bromide (2.90 mL, 80% w/v, 19.7 mmol) was added to a suspension of vanillin (2.00 g, 13.1 mmol) and potassium carbonate (5.46 g, 39.4 mmol) in acetone (20 mL) and treated according to Procedure 3. 4-Methoxy-3-propargyloxybenzaldehyde (2.01 g, 80%) was obtained as a colourless crystalline solid; mp 66-67° C.; δH (400 MHz, CDCl3) 2.54 (t, J=2.4 Hz, 1H, C≡CH), 3.95 (s, 3H, OCH3), 4.81 (d, J=2.4 Hz, 1H, OCH2), 7.00 (d, J5,6=8.4 Hz, 1H, H5), 7.50-7.53 (m, 2H, H2, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.1, 56.6, 76.4, 77.6, 110.9, 111.9, 127.3, 129.9, 147.3, 154.9, 190.6; HRMS (ESI) Calculated for C11H10O3 [M+H]+ 191.0703. found 191.0704; vmax 1014, 1130, 1261, 1584, 1678, 2119, 2841, 2932, 3262 cm−1.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH:22]([NH:24][OH:25])[CH3:23].C(N(CC)CC)C.Cl>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH:22]([N:24]([OH:25])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CC(Cc1ccc(Cl)cc1Cl)NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cc1ccc(Cl)cc1Cl)N(O)C(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (2.10 g; 11.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxylamine (2.0 g; 9.10 mmol), prepared as described in example P17, triethylamine (3.10 ml; 22 mmol) in dichloromethane (15 ml) at 0° C. The reaction mixture was stirred over night at ambient temperature. The reaction mixture was poured onto 1M HCl (50 ml), extracted with dichloromethane (3×20 ml) and then dried over Na2SO4. After removal of the solvent the residue (5.08 g) was purified by flash chromatography over silica gel (eluant: c-hexane/ethyl acetate 7:3). 1.51 g (43.8% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxy-amide (compound 1.028) was obtained in form of a white solid (m.p. 162-167° C.).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:32])=[O:31]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (120 mg, 0.36 mmol) in DCM (6 ml), were sequentially added triethylamine (79 μl, 1.08 mmol) and methanesulfonyl chloride (33.4 μl, 0.43 mmol). The reaction was stirred at RT for 3 hours, and then the volatiles were evaporated. The crude was taken up with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(methylsulfonamido)-2-phenylacetate (38.9 mg; 32% yield).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][S:7]([NH2:10])(=[O:9])=[O:8]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]1([CH:4]=[N:10][S:7]([CH3:6])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: CS(N)(=O)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N=CC1CC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopropanecarbaldehyde (0.374 mL, 5 mmol) and methanesulfonamide (0.523 g, 5.5 mmol) in toluene (15 mL) was added titanium(IV) isopropoxide (2.93 mL, 10 mmol), and the mixture was heated to 100° C. for 1 day. The mixture was cooled to room temperature and concentrated in vacuo. The residue was placed under high vacuum for 30 min to give a biphasic mixture. The top layer was discarded. The residue was used in next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>>[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)[CH:19]=1)=[O:17])[CH3:13]
Reactant: CN1CCN(CCCCl)CC1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=O)c1cn(CCCN2CCN(C)CC2)c2ccccc12
Yield: 53 %

Procedure:
The general procedure 1 was then followed using 1-(3-chloropropyl)-4-methylpiperazine (12.5 mmol, 2.2 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (10 mmol, 2.17 g) and K2CO3 (10.8 mmol, 1.5 g). The purification was achieved by column chromatography (petrolether:ethylacetate:diethylamine 5:5:1) to yield ethyl-2-{1-[3-(4-methylpiperazin-1-yl)propyl]-1H-indol-3-yl}-2-oxoacetate (5.3 mmol, 42%). IR {tilde over (ν)} [cm−1]=2936; 2790; 1727; 1638. FD-MS m/z (rel. int.)=359.9 (2.05%; M+•). 1H NMR (300 MHz, CDCl3) 8.40 (m; 2H; indole-H); 7.36 (m; 3H; indole-H); 4.38 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.25 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.44 (m; 8H; 4′piperazin-CH2); 2.30 (s; 3H; CH3); 2.26 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.00 (m; 2H;
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[C:23]2[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]3)=[N:21][CH:20]=[N:19][C:18]=2[S:17][C:16]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(O)C.CS(C)=O>[OH:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:22]2[C:23]3[C:15]([CH3:14])=[C:16]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:25][CH2:26]1
Reactant: OCc1cccc(OCC2CO2)c1
Reactant: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(N)CC3)c12
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(NCC(O)COc4cccc(CO)c4)CC3)c12
Yield: 36 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 35 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 36% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:48]=1)C(O)=O)C1C=CC=CC=1.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:48]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:17])([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: O=C(C[C@H](C(=O)O)c1ccn(-c2ccc(F)cc2)c1)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C
Yield: 82 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-succinic acid 4-benzyl ester and L-t-leucine N-methylamide (see Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861) were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 as gradient eluant provided in 82% yield N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid benzyl ester as a crisp foam. 1H NMR: δ 7.34-7.26 (m, 7H), 7.10 (t, 2H, J=8.6 Hz), 6.95 (t, 1H, J=2.4 Hz), 6.89 (t, 1H, J=2.0 Hz), 6.49 (d, 1H, J=8.8 Hz), 6.23 (dd, 1H, J=1.8, 3.0 Hz), 5.76-5.74 (m, 1H), 5.11 (s, 2H), 4.12 (d, 1H, J=9.2 Hz), 4.00 (t, 1H, J=7.2 Hz), 3.20 (dd, 1H, J=7.7, 16.5 Hz), 2.84 (dd, 1H, J=6.6, 16.6 Hz), 2.75 (d, 3H, J=4.8 Hz), 0.95 (s, 9H). Anal. Calculated for C28H32N3O4F: C, 67.89; H, 6.55; N, 8.48. Found: C, 67.78; H, 6.52; N, 8.50.