Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([CH:16]2[CH2:18][CH2:17]2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2Cl)[CH3:3].[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C@H:2]([C:4]1[N:5]([CH:16]2[CH2:18][CH2:17]2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:23]1[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=1)[CH3:3]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: C[C@H](N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1C1CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-3-(1-aminoethyl)-8-chloro-2-cyclopropylisoquinolin-1(2H)-one II-6 (878 mg, 3.35 mmol, 1.0 eq) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (815 mg, 3.92 mmol, 1.2 eq) in anhydrous DMA (10 mL) in a sealed tube, PdCl2(dppf) (219 mg, 0.27 mmol, 0.08 eq) and aqueous Na2CO3 solution (1 M, 10.0 mL, 10.0 mmol, 3.0 eq) were added and the resulting mixture was stirred at 120° C. for 3 h. The reaction mixture was allowed to cool to RT, quenched with water, and then extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-8% MeOH-DCM) to afford the product, (S)-3-(1-aminoethyl)-2-cyclopropyl-8-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1(2H)-one II-12 as a pink/magenta solid. ESI-MS m/z: 309.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[CH3:25][C:26]1([CH3:33])[O:31][CH2:30][C:29](=O)[CH2:28][O:27]1.[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:29]3[CH2:30][O:31][C:26]([CH3:33])([CH3:25])[O:27][CH2:28]3)[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Reactant: CC1(C)OCC(=O)CO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(NC4COC(C)(C)OC4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (200 mg, 0.63 mmol) and 2,2-dimethyl-1,3-dioxane-5-one (98 mg, 0.76 mmol) in MeOH (10 mL) was stirred at room temperature for 15 min., and then NaCNBH3 (79 mg, 1.26 mmol) was added. After stirring the reaction mixture overnight the volatiles were removed under vacuo and the residue was purified by preparatory TLC (1% MeOH/CH2Cl2) to give 3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyl-1,3-dioxan-5-ylamino)phenyl]-1H-pyrrole-2,5-dione (185 mg, 68%). MS(EI): M+ 431, MP: 201-203° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:33][C:32]5[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN2CCn3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)cc1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-methoxybenzyl chloride, to give the desired product as a white solid (50%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:15]1([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: C1CCNC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: CCCCCC
Product: c1ccc(N2CCCC2)cc1
Yield: 90.3 %

Procedure:
The general procedure under argon or air was followed using copper(I) iodide (10 mg, 0.05 mmol or 2.0 mg, 0.01 mmol), K3PO4 (425 mg, 2.00 mmol), pyrrolidine (100 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rƒ=0:4) afforded N-(phenyl)pyrrolidine (133 mg, 90% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Ishikawa, T.; Uedo, E.; Tani, R.; Saito, S. J. Org. Chem. 2001, 66, 186-191.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.FC1C=CC=CC=1[C:33]1C2C=C(NC(NCCO)=O)C=CC=2N2C=NN=C2[CH2:35][N:34]=1.NC1C=CC2N3C(C)=NN=C3CN=C(C3C=CC=CC=3Cl)C=2C=1.C(=O)([O-])[O-].[Na+].[Na+].CNC>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20](=[O:21])[N:34]([CH3:35])[CH3:33])[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(N=C=O)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(NCCO)Nc1ccc2c(c1)C(c1ccccc1F)=NCc1nncn1-2
Agent: CNC
Agent: Cc1nnc2n1-c1ccc(N)cc1C(c1ccccc1Cl)=NC2
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccc(NC(=O)N(C)C)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of [6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]isocyanate, prepared as described in paragraph (a) of Example 1 from 7.0 g (21.6 mmol) of 8-amino-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, but using methylene chloride in place of 1,2-dichloroethane, is treated while stirring and cooling with ice with a suspension of 8.7 g (81.9 mmol) of sodium carbonate in 50 ml of ice-cold methylene chloride and 5 g (111.1 mmol) of dimethylamine, the suspension being added in one portion. After the addition of 60 ml of dry acetonitrile, the mixture is stirred at room temperature for 20 hours and concentrated at 50° C. in vacuo. The residue is suspended in 100 ml of methylene chloride and 100 ml of water and filtered off. The material remaining is dissolved in 80 ml of hot ethanol and left to stand at -10° C. overnight. After filtering off the resulting crystals, there is obtained 3-[6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin-8-yl]-1,1-dimethylurea of melting point 186° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=[O:27])=[O:26].[C:40](Cl)(=[O:42])[CH3:41].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[C:40]([N:31]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[CH2:30][CH2:29][NH:28][S:25]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])[C:6]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:26])=[O:27])(=[O:42])[CH3:41]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCNc2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCN(C(C)=O)c2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The material from Example 96, Step C was combined with acetyl chloride (1.1 equivalents) and triethylamine (3 equivalents) in dichloromethane and stirred for for two hours at room temperature. The reaction was diluted with EtOAc, washed with sat NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to obtain the titled compound. ESI+ MS: 678 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([O:27][CH3:28])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=3)[CH2:23][CH2:22][CH2:21][CH2:20][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ncc(Cl)cc3Cl)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a stirred solution of methyl 4-chloro-2-[(3,5-dichloropyridin-2-yl)amino]-1-(4-hydroxybutyl)-1H-benzimidazole-7-carboxylate (Reference example 165, 2.45 g, 5.52 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (30 mL) was added methanesulfonyl chloride (513 μL, 6.62 mol) at 0° C. After 15 min, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (55 mL) and potassium carbonate (2.29 g, 16.6 mmol) was added. After being stirred for 1 h at 80° C., the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (2.24 g, 5.26 mmol, 95%).
Reaction SMILES: C([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[NH2:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:5]([OH:4])[CH2:6]2
Reactant: CC(=O)OC1Cc2cccc(N)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Product: Nc1cccc2c1CC(O)C2
Yield: 98.6 %

Procedure:
A slurry of 4-amino-2,3-dihydro-1H-inden-2-yl acetate (12.6 g, 65.9 mmol; prepared according to US2003109700), MeOH (63 mL), and potassium carbonate (13.7 g, 99.0 mmol) was stirred at ambient temperature for 15 minutes. The reaction mixture was diluted with IPA (630 mL), passed through a plug of silica gel, washed with IPA (100 mL), and concentrated to give the title compound (9.70 g, 65.0 mmol, 99%). MS (DCI) m/z 267 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[O:8])=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
The product from step (b) (0.7 g) and 1,1′-carbonyldiimidazole (0.62 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature for 1 hour. tert-Butyl 4-(2-aminoethyl)-1-piperazinecarboxylate (2.73 g) was added, the solution stirred for 16 hours and then evaporated to leave a gum. Dichloromethane and sodium bicarbonate solution were added, the organic phase was separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate:triethylamine, 10:1) to give the product as a solid (0.62 g), m.p. 139-140° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[PH+](C)C.[C:12]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([O:27][CH3:28])=[C:21]2[C:24](=O)[CH3:25])=[CH:16][CH:15]=1)#[N:13]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[C:21]([C:24]([CH3:1])=[CH2:25])[C:20]([O:27][CH3:28])=[CH:19][CH:18]=2)[CH:23]=1)#[N:13]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2ccc(C#N)cc2c1C(C)=O
Agent: C[PH+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)c1c(OC)ccc2ccc(C#N)cc12
Temperature: 100 °C
Yield: 93.7 %

Procedure:
Under nitrogen atmosphere, 0.62 g of potassium t-butoxide was suspended in 10 ml of toluene, and 2.26 g of trimethylphosphonium iodide was added to the resulting suspension at room temperature. The resulting mixture was stirred under heating at 100° C. for one hour to give a yellow suspension. Then, 0.84 g of 7′-cyano-2′-methoxy-1′-acetonaphthone was added to the yellow suspension, and the resulting mixture was further stirred at 10° C. for 30 minutes, cooled to room temperature by allowing to stand, diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to give 0.78 g of the title compound as an oil.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:26]Br>C(Cl)Cl>[C:1]([NH:8][C:9]1[S:10][C:11]([Br:26])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: BrBr
Reactant: CCOP(=O)(COC(=O)c1csc(NC(=O)OC(C)(C)C)n1)OCC
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1Br)OCC

Procedure:
A solution of 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) in CH2Cl2 (5 mL) was treated with bromine (2 mmole) at room temperature for 4 h. Evaporation and extraction gave 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole as an orange oil which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-bromo-4-phosphonomethoxycarbonylthiazole (18.2) as a solid. Mp>230° C. (decomp). Anal. Calcd. for C5H6N2O5PSBr: C, 18.94; H, 1.91; N, 8.84. Found: C, 19.08; H, 1.76; N, 8.67.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O-:16].[Na+]>>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Reaction of 4-chloro-3-nitrobenzotrifluoride with sodium methoxide to give 4-methoxy-3-nitro-benzotrifluoride
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:20]#N)[C:6]2[N:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH:19]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:35].[K+].[Na+].[BH4-].[Li+]>ClCCl.O1CCCC1.CC(C)=O>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH2:20][OH:35])[C:6]2[N:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH:19]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(C#N)cc(C(F)(F)F)cc21
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2c(CO)cc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A 0.05 M solution of 6-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-benzo[d]imidazole-4-carbonitrile (124 mg, 0.363 mmol) in dichloromethane (7 mL) at −78° C. was treated with diisobutylaluminum hydride (1 M in tetrahydrofuran, 0.8 mL, 2.2 equiv). After 2 h, acetone (3 mL) was added followed by the addition of a 20% aqueous sodium potassium tartrate solution (5 mL). The mixture was warmed to ambient temperature and then extracted with dichloromethane (3×20 mL). The combined organic layer washed with water, brine and dried (sodium sulfate). The organic layer was evaporated in vacuo and the residue obtained was dissolved in tetrahydrofuran (3 mL) and treated with lithium borohydride (27 mg, 3.4 equiv). After 18 h, acetone (3 mL) was added. After 1 h, the reaction was concentrated. Extractive work up with ethyl acetate (3×20 mL) and water (15 mL) followed by evaporation of the dried (sodium sulfate) organic layer gave the crude product which was purified by preparative HPLC (HPLC method 13). Pooled fractions containing the required product were evaporated in vacuo to give 25 mg (20% yield). 1H-NMR (CD3OD, 500 MHz) δ 9.14 (s, 1H), 8.12 (s, 1H), 7.83 (s, 1H), 5.87 (s, 2H), 5.13 (s, 2H), 3.67 (t, J=7.94 Hz, 2H), 0.95 (t, J=7.94 Hz, 2H), −0.03 (s, 9H); 19F NMR (471 MHz, CD3OD) −63.1, −77.8; LC/MS (HPLC method 7): tR=2.4 min, 347(MH)+.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:6])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO.O>[CH2:24]([O:15][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([NH:7][C:5]([O:4][C:2]([CH3:17])([CH3:1])[CH3:3])=[O:6])[CH2:9][CH2:10]1)=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NN1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acid (6 g, 26.16 mmol, 1 eq.), from step 1, was dissolved in methanol (150 ml) and cesium carbonate (4.26 g, 13.08 mmol, 0.5 eq.) was added. The mixture was stirred at room temperature for 2 h, the solvent was removed under reduced pressure. The crude was dissolved in DMF (100 ml) and benzylbromide (5.37 g, 31.39 mmol, 1.2 eq.) was added dropwise. The mixture was stirred overnight at room temperature and poured in water (300 ml), extracted with Ethyl Acetate (900 ml) The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Si](OCCC[C@H:33]1[O:37][C:36](=[O:38])[C@H:35]([S:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:34]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[O:38]=[C:36]1[CH:35]([S:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:9])[CH:34]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:33][O:37]1
Reactant: CC(C)(C)[Si](OCCC[C@H]1OC(=O)[C@H](Sc2ccccc2)[C@H]1c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1OCC(c2ccccc2)C1S(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (242 mg) was added to a solution of (3R*,4S*,5R*)-5-[3-(t-butyldiphenylsilyloxy)propyl] -2-oxo-4-phenyl-3-phenylthiotetrahydrofuran in dichloromethane (10 ml) at 0° C. and the resulting mixture was stirred at 0° C. for 30 minutes. The resulting mixture was poured into a mixture of diethyl ether, aqueous sodium bisulfite and aqueous sodium bicarbonate. The organic layer was separated, washed with water and brine successively, dried over ( magnesium sulfate, and evaporated in vacuo to give (3R*,4S*,5R*)-5-[3-(t-butyldiphenylsilyloxy)propyl]-2(oxo-4-phenyl-3-phenylsulfinyltetrahydrofuran (537 mg) as an oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:14]([N:17](S(CC3C=CC=CC=3)(=O)=O)[S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[CH2:38]([C:13]1[C:14]([NH:17][S:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:19])=[N:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)[N:12]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(=O)Oc1ccc(-c2cnc(N(S(=O)(=O)Cc3ccccc3)S(=O)(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(Cc1ccccc1)Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
5-(4-Acetoxyphenyl)-3-benzyl-2-bis(benzylsulfonyl)aminopyrazine (c-20) (435 mg, 694 μmol) was dissolved in methanol (8 mL) and to this was added 10% (w/v) aqueous solution of sodium hydroxide (1.9 mL) while stirring at room temperature, and stirred at 65° C. for 9.5 h. After cooling to room temperature, to this was added 2 M hydrochloric acid to stop the reaction and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (35 g, n-hexane/ethyl acetate=3/1→2/1) to give 3-benzyl-2-benzylsulfonylamino-5-(4-hydroxyphenyl)pyrazine (h-coelenterasulfonamide) (c-15) as a pale yellow solid (286 mg, 95.6%). Rf=0.27 (n-hexane/ethyl acetate=3/2). Mp. 144-147° C. (dec.). UV (MeOH) λmax (log ε) 336 (4.06), 290 (4.23), 277.5 (4.25). UV (pH 7.4 PB) λmax (log ε) 351.5 (4.09), 283 (4.34). 1H NMR (400 MHz, DMSO-d6) δ 4.22 (s, 2H), 4.91 (s, 2H), 6.83-6.88 (AA′BB′, 2H), 7.14-7.20 (m, 1H), 7.22-7.29 (m, 4H), 7.36 (s, 5H), 7.86-7.93 (AA′BB′, 2H), 8.83 (s, 1H), 9.81 (s, 1H), 10.40 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 38.0, 59.6, 115.8 (2C), 126.2, 126.5, 127.7, 128.28 (2C), 128.33 (2C), 128.5 (2C), 128.9 (2C), 129.9, 130.9 (2C), 136.0, 138.2, 144.2, 145.8, 146.5, 158.8. IR (KBr, cm−1) 527, 542, 604, 698, 835, 893, 912, 926, 935, 1117, 1130, 1188, 1213, 1244, 1267, 1321, 1402, 1452, 1495, 1516, 1595, 1609, 3055, 3221, 3522. HRMS (FAB+) m/z 432.1385 (M+H, C24H22N3O3S requires 432.1382).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=CN=C([Cl:27])C=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]([Cl:27])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccnc(Cl)c2)cc1
Reactant: Clc1ccc(-c2ccncc2)cc1
Product: Clc1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
4-(4-Chlorophenyl)-2-chloropyridine is prepared from 4-(4-chlorophenyl)-pyridine using the same reaction sequence as that described for the preparation of 4-(4-fluorophenyl)-2-chloropyridine (Example 21, steps b and c).