Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:42]1[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]1>ClCCl>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:17]3([C:15]([NH:14][C:12]4[S:13][C:9]([CH:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[N:42]5[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]5)=[CH:10][N:11]=4)=[O:16])[CH2:18][CH2:19]3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O[C@@H]1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33333.3 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-[(2-chloro-phenyl)-hydroxy-methyl]-thiazol-2-yl]-amide (0.500 g, 1.17 mmol) was placed in 10 mL of anhydrous dichloromethane containing trieihylamine (984 μL, 7.02 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (364 μL, 4.68 mmol) was added, immediately followed by (R)-pyrrolidin-3-ol (945 μL, 11.7 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The crude product was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column, chromatography (20-90% ethyl acetate in hexanes on silica gel) to yield the product as a white solid (194.2 mg, 0.390 mol, 33.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.15 (m, 2H), 1.41-1.44 (m, 2H), 1.54-1.63 (m, 1H), 1.93-2.77 (m, 5H), 4.20 (S, 1H), 4.72-4.77 (m, 1H), 4.96 (d, J=7.0 Hz, 1H), 6.00 (s, 2H), 6.85 (d, J=0.9 Hz, 2H), 6.95 (s, 1H), 7.24-7.29 (m, 1H), 7.37-7.43 (m, 3H), 7.76-7.80 (m, 1H), 11.03 (s, 1H. ESI-MS m/z calc. 497.1, found; 498.1 (M+1)+; Retention time 2.36 minutes.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=O.[CH:9]1([CH:12]=O)C[CH2:10]1.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1.N1C=CC=CC=1>[CH:9]1([C:2](=[CH2:3])[C:1]([O:7][CH3:8])=[O:6])[CH2:12][CH2:10]1
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=CC1CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=C(C(=O)OC)C1CC1
Yield: 88 %

Procedure:
To a solution of monomethyl malonate (14.16 g, 1.2 eq based on the cyclopropanecarboxaldehyde) and ammonium acetate (0.3 g) in benzene (20 ml) was added dropwise a solution of cyclopropanecarboxaldehyde (7.1 g, 101.3 mmol) in pyridine (11 ml) at 0±5° C. After addition, the solution was refluxed to remove water outside. To the reaction mixture was added 1N hydrochloric acid to acidify. After separation, the aqueous layer was extracted with diisopropyl ether (70 ml) twice. The combined organic layer was concentrated under reduced pressure to give methyl cyclopropylacrylate (11.1 g, yield 88%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)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.O>[CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[C:28]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:29][C:30]3[O:35][CH2:34][O:33][C:31]=3[CH:32]=2)=[N:24][C:18]2[C:17]1=[N:22][CH:21]=[N:20][C:19]=2[NH2:23])([CH3:11])[CH3:9]
Reactant: OB(O)c1cccs1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2cccs2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 45.2 %

Procedure:
2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 12.5:1) to give 12.4 mg (45%) of DZ2-395. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.33 (dd, J=1.4, 4.9 Hz, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 7.00-7.02 (m, 2H), 6.09 (s, 2H), 4.12 (t, J=6.6 Hz, 2H), 2.95 (septet, J=6.6 Hz, 1H), 2.62 (t, J=6.8 Hz, 2H), 2.00 (m, 2H), 1.19 (d, J=6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.2, 152.0, 151.1, 149.4, 148.8, 148.4, 140.5, 132.9, 127.8, 126.9, 126.3, 119.2, 119.0, 114.6, 111.8, 102.3, 49.6, 42.5, 40.6, 27.8, 20.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O2S2, 469.1480; found. 469.1461; HPLC: method A Rt=6.38, method B Rt=7.18.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[O:3]1.[N:12]([O-:14])=[O:13].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[C:4]=2[O:3]1
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)C[C@@H](C)O2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c([N+](=O)[O-])c1)O[C@H](C)C2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A mixture of (R)-2,5-dimethyl-2,3-dihydrobenzofuran (3d) (2.0 g, 13 mmol) in TFA (40 mL) was cooled to 0° C., NaNO2 (1.7 g, 23 mmol) was added thereto. It was stirred at ambient temperature for 12 h. The mixture was concentrated, poured into water (50 mL), extracted with EtOAc (150 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1) to give the title compound (3e).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21](O)=[O:22])[CH2:19][OH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH:6][C:19](=[O:20])[C@@H:18]([CH2:21][OH:22])[NH:17][C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Product: COC(=O)[C@H](CS)NC(=O)[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
L-Cysteine methyl ester hydrochloride was acylated with N-(tert-butoxycarbonyl)-D-serine by using in an analogous manner the procedure described in Example 1(e) to yield N-[N-(tert-butoxycarbonyl)-D-seryl]-L-cysteine methyl ester as white crystals of m.p. 105°-106° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: CS(=O)(=O)c1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cc32)cc1

Procedure:
The title compound, white solid (12 mg, 14%), MS (ISP) m/z=433.4 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methylsulfonyl-phenyl)-1H-benzo[d]imidazole (intermediate O) (70 mg, 199 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (49.2 mg, 239 μmol).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([C:7]([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27].O>CN(C=O)C>[CH3:24][N:25]([CH3:30])[S:26]([N:11]1[CH:12]=[N:13][C:9]([C:7](=[O:8])[C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)=[N:10]1)(=[O:28])=[O:27]
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1nc[nH]n1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(C(=O)c2ccc(C(F)(F)F)cc2)n1
Yield: 69.2 %

Procedure:
0.31 g of 3-(4-trifluoromethylbenzoyl) -1,2,4-triazole was dissolved in 3 ml of DMF, 0.21 g of potassium carbonate was added thereto, and then 0.22 g of dimethylsulfamoyl chloride was added at room temperature with stirring. After stirring the reaction mixture for 1.5 hours at room temperature, water was added to precipitate crystals, and the crystals were collected by filtration and washed with diethyl ether. Drying of the mixture under reducing pressure afforded 0.31 g of the titled compound.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Mg].[CH:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1Br
Reactant: CCCCCC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccccc1C(O)CCCCC
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A third of a solution of 11 g of 2-nonylbromobenzene [cf. EP-OL 0 123 543] in 15 ml of tetrahydrofuran is added to a mixture, stirred under an argon atmosphere, of 1.1 g of magnesium turnings, 8 ml of tetrahydrofuran and 3 drops of carbon tetrachloride, and the whole is heated at the boil, under reflux, for 30 minutes. The remainder of the solution of 2-nonylbromobenzene (cf. EP-OL 0 123 543) is then added dropwise over a period of 35 minutes and the reaction mixture is maintained under reflux for 2 hours. After dilution with 15 ml of tetrahydrofuran, the suspension is cooled to -10° C. and added in portions to a solution, cooled to -70° C., of 4.6 g of hexanal in 12 ml of tetrahydrofuran. After stirring for 1 hour at -70° C., 200 ml of saturated aqueous ammonium chloride solution are added to the reaction mixture, the organic layer is separated off and the aqueous layer is extracted three times with ether. The residue that remains after the combined ethereal extracts have been dried and concentrated by evaporation is purified by chromatography on silica gel with mixtures of petroleum ether with an increasing amount of methylene chloride, yielding the desired 1-(2-nonylphenyl)-1-hexanol in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([NH:12][C:13]2[O:14][C:15]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[O:11])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH3:24]>>[C:8]([C:6]1[CH:5]=[C:4]([C:10]([NH:12][C:13]2[O:14][C:15]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[O:11])[CH:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:23][CH3:24])=[CH:30][CH:29]=3)=[CH:32][CH:33]=2)[CH:7]=1)#[N:9]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: N#Cc1cc(Br)cc(C(=O)Nc2nnc(-c3ccco3)o2)c1
Product: CCc1ccc(-c2ccc(-c3cc(C#N)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-5-cyano-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 41 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)[NH2:2].O=[C:17]1[CH2:21][S:20][CH2:19][CH:18]1[C:22](OC)=[O:23]>>[O:23]=[C:22]1[N:1]([C:3]2[N:8]=[CH:7][C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)[NH:2][C:17]2[CH2:21][S:20][CH2:19][C:18]1=2
Reactant: COC(=O)C1CSCC1=O
Reactant: CC(C)(C)OC(=O)c1ccc(NN)nc1
Product: CC(C)(C)OC(=O)c1ccc(-n2[nH]c3c(c2=O)CSC3)nc1
Yield: 61.1 %

Procedure:
According to the process described in Example 1, starting with 0.75 g of tert-butyl 6-hydrazinopyridine-3-carboxylate and 0.58 g of methyl 4-oxotetrahydrothiophene-3-carboxylate, 0.7 g of tert-butyl 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-carboxylate is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10]([C:19]([O:21]CC)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10]([C:19]([OH:21])=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Yield: 78.2 %

Procedure:
Part C: To a stirred suspension of ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (23.0 gram, 0.07 mol) in methanol (200 ml) is added water (15 ml) and concentrated NaOH (10 ml) and the resulting solution is heated at reflux temperature for 2 hours. The methanol is partly removed by evaporation and the residue is dissolved in a mixture of water and ethyl acetate. Ice, concentrated HCl (20 ml) and ethyl acetate are successively added, the ethyl acetate layer collected, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is washed with diethyl ether (100 ml) and diisopropyl ether respectively, to give 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid (16.46 gram, 78% yield). Melting point: 177-179° C.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CCOC(C)=O>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(NS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
To a solution 100 mg of 8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20), (0.28 mmol) in 2 ml of pyridine chilled in an ice/water bath was added 22 μL of methanesulfonyl chloride (0.28 mmol), 30% completion after 24 h at 10° C. Two more aliquots (22 μL and 50 μL) of methanesulfonyl chloride were added to drive the reaction to completion. The reaction mixture was concentrated in vacuo to afford a yellow oil which was taken up in EtOAc (10 ml) and washed twice with sat'd NaHCO3 (5 ml), once with 0.5N HCl and once with brine. The organic layer was dried over NaSO4 and conc'd to an oil. Crystallized from acetonitrile to afford 27 mg (22%) as a white solid (MH+=438.08). The following compounds were prepared in an analogous manner:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH:24]([CH:25]=[O:26])[CH:23]2[CH:27]([CH2:28][O:29][CH3:30])[CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH:24]([CH:25]([OH:26])[CH:8]([N+:9]([O-:11])=[O:10])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]2[CH:27]([CH2:28][O:29][CH3:30])[CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C(O)C(Cc1ccccc1)[N+](=O)[O-]
Yield: 51.4 %

Procedure:
Add 1-phenyl-2-nitroethane (0.350 g, 2.23 mmol) to a solution of 3-formyl-7-methoxymethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.400 g, 1.48 mmol) in anhydrous tetrahydrofaran (5 mL) cooled in an ice bath. Add tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.48 mL, 1.48 mmol) and stir the mixture in an ice bath for 1 h. Dilute the mixture with ethyl acetate, and wash the solution with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (0.320 g, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(-c3cccc(Cl)c3)ccc2F)c1

Procedure:
The phenyl bromide (141) (100 mg, 0.26 mmol) was coupled to 3-chloro-phenylboronic acid (40 mg, 0.26 mmol) using Method E. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([OH:23])=O.C(Cl)(=O)C([Cl:27])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([Cl:27])=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)/C2=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccccc1

Procedure:
(Z)-5-methoxy-2-methyl-1-benzylidene-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: Cl.[O:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([N:21]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[O:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([NH2:21])=[N:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(OCc2ccccc2-c2cnc(N=C(c3ccccc3)c3ccccc3)s2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ncc(-c2ccccc2COc2ccccc2)s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
150 ml of an aqueous hydrochloric acid solution (1 M) are added to 35 g of 5-{2-[(phenoxy)methyl]phenyl}-N-(diphenylmethylene)-1,3-thiazol-2-amine, obtained in step 1.4, in solution in 250 ml of methanol, and the mixture is stirred for 18 hours at 20° C. The mixture is evaporated to dryness, the residue is taken up in diethyl ether and washed with an aqueous sodium hydroxide solution (0.5 M). The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a silica gel column, eluting with a dichloromethane/methanol 98/2 (v/v) mixture, to give 15 g of a beige solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl.[C:13]([N:17]1[CH:21]=[C:20]([CH2:22]Cl)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].O>CN(C)C=O>[C:13]([N:17]1[CH:21]=[C:20]([CH2:22][CH:2]([C:1]#[N:5])[C:3]#[N:4])[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CCC#N
Reactant: CC(C)(C)n1cc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1cc(CC(C#N)C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
5.95 g of malononitrile was dissolved in 30 ml of N,N-dimethylformamide, and 12.44 g of potassium carbonate was then added under ice-cooling. Thereto a solution of 6.27 g of 1-t-butyl-4-(chloromethyl)-1H-pyrazole hydrochloride in 30 ml of N,N-dimethylformamide was added dropwise over 1 hour. After completion of the addition, the mixture was stirred at room temperature for 8 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.12 g of [(1-t-butyl-1H-pyrazol-4-yl)methyl]malononitrile.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=1)([CH3:3])[CH3:2].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15](OCC)=[O:16])[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[N:7]2[N:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[C:6]2[NH:9][CH:20]=1)=[O:24])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)c1cc(N)[nH]n1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C(C)C)nn2c1=O
Temperature: 120 °C
Yield: 64.2 %

Procedure:
To a solution of 5-isopropyl-2H-pyrazol-3-ylamine (2.5 g, 20 mmol, 1 eq) in acetic acid (20 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (4.4 mL, 22 mmol, 1.1 eq). The mixture was heated at 120° C. for 3 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol to afford the expected compound as beige powder (3.2 g, 65% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])=[CH:7][C:6]=2[CH:18]=1.C([Li])(C)(C)C.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][C:6]=2[CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
Agent: [Li]C(C)(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1

Procedure:
As shown in Scheme 13, (2R)-1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2-methylpyrrolidine is treated with tert-butyl lithium and tributylstannyl chloride at −78° C. to provide (2R)-2-methyl-1-{2-[5-(tributylstannyl)-1-benzofuran-2-yl]ethyl}pyrrolidine. (2R)-2-Methyl-1-{2-[5-(tributylstannyl)-1-benzofuran-2-yl]ethyl}pyrrolidine is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides in the presence of a palladium catalyst, like palladium (II) acetate, and a trivalent phosphine, like tri(2-furyl)phosphine, in an organic solvent such as dimethylformamide at 25° C. to 120° C. to provide compounds of formula (50). Compounds of formula (50) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (50) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.