Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:53]1([CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][NH:60]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(#N)C.FC(F)(F)C(O)=O.C(Cl)Cl>[C:53]1([CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][N:60]2[C:19]([C:17]2[CH:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15][CH:16]=2)=[O:21])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Reactant: c1ccc(C2CCCCN2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1csc(C2CCNCC2)c1)N1CCCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), HATU (0.35 mmol) and 2-phenylpiperidine (0.35 mmol) were added and the reaction stirred at room temperature for 5 hours. The mixture was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give an oil which was dissolved in trifluoroacetic acid (3 mL) and DCM (5 mL) and stirred for 3 hours. The solvent was evaporated and the residue was purified by flash chromatography on an SCX-2 cartridge, washing with acetonitrile, then methanol and then eluting with 2 M ammonia in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.058 g). LCMS m/z 355.18 [M+H]+ RT=6.59 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.4 (m, 2H), 7.25 (m, 4H), 6.9 (s, 1H), 3.2 (d, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 2.6 (m, 3H), 2.4 (d, 1H), 2.1-1.8 (m, 3H), 1.8-1.4 (m, 6H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl.O>[CH3:28][C:27]([Si:24]([CH3:26])([CH3:25])[N:4]1[CH2:5][CH2:6][CH:2]([CH3:1])[C:3]1=[O:7])([CH3:30])[CH3:29]
Reactant: CC1CCNC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN([Si](C)(C)C(C)(C)C)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
In an oven-dried 500 ml flask under argon was dissolved 3-methyl-2-pyrrolidinone (0.186 mol, 18.4 g) in 200 ml methylene chloride. To this solution was added Triethylamine (0.223 mol, 22.6 g), Dimethylaminopyridine (0.019 mol, 2.27 g), and t-Butyldimethylsilyl chloride (0.204 mol, 30.8 g). This mixture was stirred for 18 hrs at 20° C. after which time it was poured into 500 ml water, the organic layer separated, washed with water (2×100 ml), brine (100 ml), dried with MgSO4 and concentrated. Resulting crude oil was purified on 400 g silica (EtOAc/Hexanes) yielding 35.0 g (88%) of 1-[(1,1-dimethylethyl)(dimethyl)silyl]-3-methyl-2-pyrrolidinone a clear oil. LCMS (ESI+)=214 m/z (MH+). 1H NMR (400 MHz, CDCl3) δ 3.40-3.25 (m, 2H), 2.50-2.40 (m, 1H), 2.30-2.20 (m, 1H), 1.70-1.60 (m, 1H), 1.20-1.18 (d, 3H, J=7.06 Hz), 0.95 (s, 9H), 0.29-0.27 (d, 6H, J=6.70 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([CH3:13])([CH3:14])[O:9]1
Reactant: [H][H]
Reactant: CC1(C)OCC(COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCC(COc2ccc(N)cc2N)O1
Temperature: 5 °C

Procedure:
215 ml of methanol are introduced into a 0.7 l autoclave, 85.3 g (0.3 mole) of 4-(2,4-dinitrophenoxymethyl)-2,2-dimethyl-1,3-dioxolane (step a) are dissolved therein and 0.6 g of palladium on active carbon 10% (Degussa) is added. After the autoclave has been closed and blanketed with nitrogen, hydrogenation is carried out under a pressure of 4 bar and at a temperature of 35 to 40° C. until no more hydrogen is taken up. 1.3 g of active carbon is added under nitrogen to the warm solution and the catalyst is filtered off. 42 g of 70% sulfuric acid are added dropwise to the solution while cooling with ice at 5° C. The product precipitated is filtered off under suction, washed with methanol and dried.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:48][N:49]1[CH2:54][CH2:53][N:52]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:51][CH2:50]1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:58]6[CH2:57][CH2:56][CH:55]([N:52]7[CH2:51][CH2:50][N:49]([CH3:48])[CH2:54][CH2:53]7)[CH2:60][CH2:59]6)=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)=[O:33])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C2CCN(C(=O)c3ccc(-c4cc5nccc(Oc6ccc(NC(=O)NC7CC7)cc6F)c5s4)nc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred solution of acid 225 (300 mg, 0.646 mmol) in DMF (10 mL) at 0° C. were added HOBT (198 mg, 1.292 mmol), EDC (248 mg, 1.292 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (118 mg, 0.646 mmol). The reaction mixture was stirred at room temperature overnight, diluted with NaHCO3 saturated solution, and extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified three times by Biotage (MeOH/EtOAc, 0-50%, 25 g column) followed by purification on Gilson [MeOH/H2O, 50-95%, HCOOH (0.05%)] to afford the title compound 234 (50 mg, 0.079 mmol, 12.29% yield) as a mono-formate salt. NMR (400 MHz, CD3OD) δ (ppm): 8.67 (dd, J1=0.8 Hz, J2=2.1 Hz, 1H,), 8.48 (s, 1H), 8.47 (s, 1H), 8.19 (dd, J1=0.8 Hz, J2=8.3 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J1=2.2 Hz, J2=8.2 Hz, 1H), 7.65 (dd, J1=2.4 Hz, J2=13.1 Hz, 1H), 7.29 (t, 1H, J=8.8 Hz, 1H), 7.20-7.18 (m, 1H), 6.65 (dd, J1=0.8 Hz, J2=5.5 Hz, 1H), 3.83 (br. s, 1H), 3.24 (br s, 1H), 3.01 (br. s, 6H), 2.85 (br. s, 3H), 2.76-2.70 (m, 2H), 2.67 (s, 3H), 2.61-2.57 (m, 1H), 2.02 (br. s, 1H), 1.91-1.85 (br. s, 1H), 1.56-1.49 (hr. s, 2H), 0.78-0.74 (m, 2H), 0.55-0.51 (m, 2H). MS: 630.4 (MH)+
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C@@:6]([C:16]([OH:18])=[O:17])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7].[CH3:19]O>>[CH3:19][O:17][C:16](=[O:18])[C@:6]([CH3:5])([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:7]
Reactant: CO
Reactant: C[C@](N)(CCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@](C)(N)CCc1ccccc1
Reaction time: 8.5 h

Procedure:
430 ml methanol are cooled to -10° C. in an ice/sodium chloride mixture and reacted with 21.3 ml thionyl chloride (exothermic reaction). 44.5 g (0.23 mol) α-methyl-homo-phenylalanine are added dropwise at room temperature. Boiling under reflux occurs for 8.5 hours, the mixture is concentrated in a rotary evaporator, taken up with H2O (350 ml) and reacted with 150 ml 25% NH4OH solution. Extraction with dichloromethane occurs 5× and the combined extracts are dried over calcium carbonate and concentrated in a rotary evaporator. Yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]O.C(N(CC)CC)C.CS([Cl:25])(=O)=O.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][Cl:25]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(Br)cc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCOc1ccc(Br)cc1CCl
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
To a solution of 5-bromo-2-methoxymethoxybenzyl alcohol (27.2 g) and triethylamine (23 ml) in dichloromethane (550 ml) was added, at 0° C., methanesulfonyl chloride (13.9 g). The mixture was stirred for 15 hours, while warming up to room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with an aqueous saline solution, which was then dried (anhydrous magnesium sulfate), followed by concentration to give an oily product. The oily product was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-2-methoxymethoxybenzyl chloride (21.6 g) as an oily product.
Reaction SMILES: CC1CC=CCC=1.[CH2:8]([O:10][CH:11]([O:24][CH2:25][CH3:26])[C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)[CH3:9]>[Pd].C(O)C>[CH2:25]([O:24][CH:11]([O:10][CH2:8][CH3:9])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)[CH3:26]
Reactant: CCOC(OCC)c1ccc(/C=C/C(=O)OC)cc1
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: CCOC(OCC)c1ccc(CCC(=O)OC)cc1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
1-Methyl-1,4-cyclohexadiene (10.0 mL, 89 mmol) was added to a suspension of (E)-methyl 3-(4-(diethoxymethyl)phenyl)acrylate (2.41 g, 9.13 mmol) and 10% palladium on carbon (2.4 g) in ethanol (40 mL). The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was filtered through celite and the filter cake washed with further ethanol. The solvent was evaporated at reduced pressure to afford the title compound (2.15 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(F)cc4F)cc3)cc2C1=O

Procedure:
The compound of example 83 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 2,4-difluorobenzene sulfonyl chloride. The compound of example 83 was used directly without isolation for the preparation of compound of example 84.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([O:20]CC)=[O:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([OH:20])=[O:19])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(=O)O)cnn2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixed solution of the compound (2.86 g, 9.46 mmol) obtained in step 1 in THF (15 mL) and ethanol (15 mL) was added 1N aqueous sodium hydroxide solution (14.19 mL, 14.19 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added thereto. The precipitate was collected by filtration to give 1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid (2.59 g, 9.44 mmol, 100%) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Br:10]N1C(=O)CCC1=O.O>O1CCCC1.N1C=CC=CC=1>[Br:10][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1c[nH]c(Br)c1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A solution (30 mL) of methyl 1H-pyrrole-3-carboxylate (3.06 g) in tetrahydrofuran was cooled to −78° C., N-bromosuccinimide (4.38 g) and then pyridine (3 drops) were added, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=5:1) to give the title compound as a pale-yellow solid (yield 3.08 g, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5](=O)[CH2:6][C:7](=[O:20])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=1[F:19])[CH3:2].C([O-])(=O)C.[NH4+:27]>CCO>[CH2:1]([O:3][C:4](=[O:22])/[C:5](/[NH2:27])=[CH:6]/[C:7](=[O:20])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=1[F:19])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)c(OC)c1F
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)c(OC)c1F
Yield: 102.2 %

Procedure:
Using the procedure of Example 4, (E)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (5; 37.8 g, 0.115 mol) and ammonium acetate (15.4 g, 0.2 mol) were allowed to react in EtOH (200 mL) to yield (2Z,5E)-2-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (10; 38.5 g, 92%, 90% pure by 1H NMR spectroscopy) as a dark orange solid. Treatment with silica gel (50 g) followed by eluting with 40% EtOAc/hexanes (400 mL) gave a yellow solid (25.3 g, 67%): mp 103-104° C.; 1H NMR (400 MHz, CDCl3) δ 9.44 (br s, 1H), 7.63 (d, J=16.1 Hz, 1H), 7.23 (dd, J=8.6, 7.0 Hz, 1H), 7.16 (dd, J=8.6, 1.6 Hz, 1H), 6.87 (d, J=16.1 Hz, 1H), 6.15 (s, 1H), 6.04 (br s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.98 (d, J=1.2 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C15H15ClFNO4, 327.067. found, 327.068.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:20])=[O:19]
Reactant: NCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.4 %

Procedure:
To a 10° C. solution of phenethylamine (12.1 g, 0.100 mol) and triethylamine (11.1 g, 0.110 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at room temperature for 1.5 h and was then washed with 1N HCl (5×20 mL). The organic phase was directly concentrated to provide the intermediate title compound, (methylsulfonyl)(2-phenylethyl)amine, (21.2 g, 93.3%) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:3][CH2:2]1.[H][H]>[C].[Pd].O1CCCC1>[NH2:18][C:9]1[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=1[NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1NC1CCOCC1
Yield: 73.5 %

Procedure:
A 3-neck flask (200 mL) was charged with 1-(tetrahydropyran-4-yl)amino-2-nitro-4-trifluoromethylbenzene (see Synthesis Example 4-1) (1.00 g, 3.45 mmol) and tetrahydrofuran (17 mL), and this was shaken to give a homogeneous solution. To this was added palladium-carbon (Pd: 10%, 0.09 g), and this was again shaken. Hydrogen was substituted in by successively reducing the pressure and purging with hydrogen gas 3 times, and after vigorous shaking at room temperature under these conditions for 4 h, this was purged with nitrogen, distilled water (40 mL) was added and this was shaken for 10 minutes, then insoluble material was filtered off through a Celite layer (20 mm thickness), and this same layer was further washed with ethyl acetate. The filtrate and wash solutions were combined and the solvent was distilled off under reduced pressure to yield the title compound (0.66 g, 73.6% yield) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([C@@H:4]1[N:13]2[C:14]([C@@:16]([NH:21][C:22]([C@@H:24]3[CH:39]=[C:38]4[C@@H:27]([CH2:28][C:29]5[C:33]6[C:34]4=[CH:35][CH:36]=[CH:37][C:32]=6[NH:31][CH:30]=5)[N:26]([CH3:40])[CH2:25]3)=[O:23])([CH:18]([CH3:20])[CH3:19])[O:17][C@@:12]2([OH:41])[C@H:11]2[N:7]([CH2:8][CH2:9][CH2:10]2)[C:5]1=[O:6])=[O:15])[CH3:3].[CH3:42][CH:43]([CH2:45][C@@H:46]1[N:55]2[C:56]([C@@:58]([NH:63][C:64]([C@@H:66]3[CH:81]=[C:80]4[C@@H:69]([CH2:70][C:71]5[C:75]6[C:76]4=[CH:77][CH:78]=[CH:79][C:74]=6[NH:73][CH:72]=5)[N:68]([CH3:82])[CH2:67]3)=[O:65])([CH:60]([CH3:62])[CH3:61])[O:59][C@@:54]2([OH:83])[C@H:53]2[N:49]([CH2:50][CH2:51][CH2:52]2)[C:47]1=[O:48])=[O:57])[CH3:44].[CH3:84]C([C@@H]1N2C([C@@](NC([C@@H]3C=C4[C@@H](CC5C6C4=CC=CC=6NC=5)N(C)C3)=O)(C(C)C)O[C@@]2(O)[C@H]2N(CCC2)C1=O)=O)C.CC(C[C@@H]1N2C([C@@](NC([C@@H]3C=C4[C@@H](CC5C6C4=CC=CC=6NC=5)N(C)C3)=O)(C(C)C)O[C@@]2(O)[C@H]2N(CCC2)C1=O)=O)C>>[CH3:44][CH:43]([CH2:45][C@@H:46]1[N:55]2[C:56]([C@@:58]([NH:63][C:64]([C@@H:66]3[CH:81]=[C:80]4[C@@H:69]([CH2:70][C:71]5[C:75]6[C:76]4=[CH:77][CH:78]=[CH:79][C:74]=6[NH:73][CH:72]=5)[N:68]([CH3:82])[CH2:67]3)=[O:65])([CH:60]([CH3:61])[CH3:62])[O:59][C@@:54]2([OH:83])[C@H:53]2[N:49]([CH2:50][CH2:51][CH2:52]2)[C:47]1=[O:48])=[O:57])[CH3:42].[CH3:84][CH2:3][C@@H:2]([C@H:4]1[N:13]2[C:14]([C@@:16]([NH:21][C:22]([C@@H:24]3[CH:39]=[C:38]4[C@@H:27]([CH2:28][C:29]5[C:33]6[C:32](=[CH:37][CH:36]=[CH:35][C:34]=64)[NH:31][CH:30]=5)[N:26]([CH3:40])[CH2:25]3)=[O:23])([CH:18]([CH3:19])[CH3:20])[O:17][C@@:12]2([OH:41])[C@H:11]2[N:7]([CH2:8][CH2:9][CH2:10]2)[C:5]1=[O:6])=[O:15])[CH3:1]
Reactant: CC(C)[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Agent: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Product: CC[C@H](C)[C@@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12

Procedure:
According to the spectrum of the produced alkaloids, the new strain belongs to the chemical rage ergocornine-ergocryptine. Ergocornine and ergocryptine in the weight ratio of approximately 1:1 are the main alkaloids contained in both the parasitic ergot sclerotia and the mycelium of saprophytic culture. The ergocryptine component is formed by α-ergocryptine and β-ergocryptine in parasitic sclerotia in a weight ratio of approximately 2:1 to 1:1, and in saprophytic mycelium without precursoring in a weight ratio of approximately 5:1. Customary ergometrine and futher a small amount of ergosine and traces of ergocristine, ergotamine, lysergylvaline amide, ergoxine (ergostine, ergonine, ergoptine) and of further three nonidentified alkaloids are the components of the alkaloid spectrum besides the above set forth main alkaloids.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[Br:6][C:7]1[CH:8]=[C:9]([C:15]2([OH:18])[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(N(CC)CC)C>C1COCC1.O>[Br:6][C:7]1[CH:8]=[C:9]([C:15]2([O:18][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(C2(O)CC2)cc1Br
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(O[Si](C)(C)C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Trimethylsilyl chloride (6.54 ml) was added to a solution of 1-(3-bromo-4-methoxyphenyl)cyclopropanol (5.0 g) and triethylamine (8.61 ml) in THF (100 ml). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (3.84 g).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([N:21]2[CH2:25][CH2:24][C@H:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)[C:15](Br)=[C:14]([CH3:30])[C:11]=1[C:12]#[N:13].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>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.O1CCOCC1>[NH2:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([N:21]2[CH2:25][CH2:24][C@H:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)[C:15]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:14]([CH3:30])[C:11]=1[C:12]#[N:13]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)c(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])c(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(C#N)c(N)c([N+](=O)[O-])c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Yield: 90.2 %

Procedure:
Potassium phosphate (115 mg, 0.54 mmol) and Pd(PPh3)4 (16 mg, 5 mol %) were added to a dioxane (3 ml) solution of 2-amino-5-bromo-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-methyl-3-nitrobenzonitrile (I-267) (100 mg, 0.27 mmol) and phenylboronic acid (40 mg, 0.33 mmol), followed by purging with nitrogen and heating under reflux for 18 hours. After cooling, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform/methanol (2:1, v/v) to obtain the entitled compound (89 mg, 90%) as a dark red solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:15][CH2:16][CH2:17][CH2:18][NH2:19])(C)(C)C>>[CH2:1]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Product: NCCCNCc1ccccc1

Procedure:
Example 20 was prepared in a similar fashion to Example 18 (CZ-25) from benzaldehyde and tert-butyl(3-aminopropyl)carbamate. 1H NMR (500 MHz, D2O) δ 7.49 (quint, J=3 Hz, 5H), 4.26 (s, 2H), 3.17 (t, J=8 Hz, 2H), 3.07 (t, J=8 Hz, 2H), 2.09 (quint, J=7.5 Hz, 2H). 13C NMR (125 MHz, D2O) δ 130.6, 129.9, 129.8, 129.4, 51.4, 44.1, 36.7, 23.9. LRMS [M+H]+291.3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH:27]([Br:30])[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)Cc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 40.4 %

Procedure:
A mixture of 1.12 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde and 0.49 g of N-bromosuccinimide in 40 mL of CCl4 was irradiated (UV-lamp, pyrex filter) for 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) afforded 0.54 g of 1-[(2'-carbomethoxybiphenyl-4-yl)-methyl]-2-(2-bromobutyl)-4-chloroimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3) δ 9.87 (s, 1H); 7.86 (d, 1H); 7.54 (t, 1H); 7.46 (t, 1H); 7.30 (m, 3H); 7.11 (d, 2H); 6.16 (d, 1H); 5.32 (d, 1H); 4.79 (t, 1H); 3.65 (s, 3H); 2.32 (m, 2H); 1.34 (sext., 2H); 0.83 (t, 3H).