Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9](C1C=CC=CC=1)[CH2:10][CH:11]=C)=O)(C)(C)C.[ClH:19].[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[ClH:19].[NH2:8][C@H:9]([CH:10]=[CH2:11])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CCC(NC(=O)OC(C)(C)C)c1ccccc1
Reactant: Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H](N)Cc1ccccc1

Procedure:
A solution of 5.00 g (20.21 mmol) of (S)-2-(tert-butoxycarbonylamino-1-phenylbut-3-ene [J. R. Luly et al., J. Org. Chem. 52, 1487 (1987)] in 100 ml of a 4N solution of gaseous hydrogen chloride in anhydrous dioxane was stirred at room temperature for 30 min. 15 ml of toluene were then added and the mixture was concentrated in vacuo. This process was repeated twice more, then the residue was triturated with a little ether, filtered off with suction and dried in a high vacuum over KOH. 3.69 g (99% of theory) of the title compound were obtained as colourless crystals.
Reaction SMILES: C(F)(F)=C(Cl)F.[Br:7][C:8]1[C:18]2[O:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH:14]=[C:13]([C:23](O)=[O:24])[C:12]=2[CH:11]=[CH:10][CH:9]=1>CCCCCC.C(OCC)(=O)C>[Br:7][C:8]1[C:18]2[O:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH:14]=[C:13]([CH2:23][OH:24])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2c(Br)cccc21
Agent: FC(F)=C(F)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCC1=Cc2ccccc2Oc2c(Br)cccc21
Yield: 99 %

Procedure:
Preparation analogous to Example 12 f) from 6-bromo-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 99% crude, brown oil; TLC (silica gel; hexane/ethyl acetate=7.3; UV): Rf =0.07; 1H-NMR (CDCl3, 200 MHz): 3.54 (s, 2H), 6.70-7.49 (m, 8H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59](=[O:70])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:55][CH2:54]1)=[O:52].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[C:10]1([S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:49][CH2:50][C:51](=[O:52])[N:53]3[CH2:54][CH2:55][N:56]([C:59](=[O:70])[C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[C:66]([F:67])([F:69])[F:68])[CH2:57][CH2:58]3)=[O:25])=[CH:26][CH:27]=2)(=[O:17])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
DIPEA (0.084 mL, 0.49 mmol) was added drop wise to 4-benzenesulfonyl-benzoic acid (51 mg, 0.20 mmol) in DMF (5 mL). EDCI (78 mg, 0.41 mmol) and HOBT (26 mg, 0.20 mmol) were added consecutively and, after 10 mins, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its TFA salt form (70 mg, 0.16 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added and the resulting solid was filtered to afford 60 mg (65% yield) of 4-benzenesulfonyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LC-MS purity: 95.5%. 1H NMR (DMSO-D6): δ 8.8 (t, 1H), 8.1 (m, 5H), 7.8 (m, 6H), 7.6 (m, 1H), 4.2 (d, 2H), 3.6 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[S:17][C:16]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[N:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)Cl.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>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[S:17][C:16]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:25])([CH3:26])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[N:15][N:14]=1
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(c1nnc(-c2ccc(F)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a stirred suspension of (2-chloro-4-fluorophenyl)boronic acid (251 mg, 1.44 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (400 mg, 1.2 mmol) in dioxane (10 mL) under nitrogen was added Pd(PPh3)4 (69 mg, 0.06 mmol) followed by a solution of Na2CO3 (382 mg, 3.6 mmol) in water (2.5 mL). The reaction mixture was sealed and heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM (100 mL) and washed with saturated NaHCO3(aq) (40 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was diluted with MeOH (10 mL) and SiliaMetS-DMT (0.61 mmol/g, 0.984 mg, 0.6 mmol) was added. The resulting suspension was stirred at room temperature for ˜18 hours then filtered. The filtrate was concentrated in vacuo to afford the crude product as a yellow/orange oil. The crude material was purified by flash chromatography using a 24 g silica cartridge running a gradient from 2-10% [2M NH3 in MeOH]/DCM to afford the title compound as a pale yellow solid (312 mg, 68% yield). LC-MS: Rt 0.97 min; MS m/z 383.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (dd, J=8.84, 6.32 Hz, 1H), 7.65 (dd, J=9.09, 2.53 Hz, 1H), 7.36-7.43 (m, 1H), 4.34 (tt, J=12.38, 3.28 Hz, 1H), 3.00 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H), 1.43 (t, J=12.38 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.08 (s, 6H).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[C:17]1[CH:21]=[CH:20][N:19]([CH:22]([O:36][CH2:37][CH3:38])[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[NH:35])[NH2:34])=[CH:29][CH:28]=2)=[O:24])[N:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:16].[C:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23](=[O:24])[CH:22]([N:19]2[CH:20]=[CH:21][C:17]([C:11]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=3[OH:9])=[N:18]2)[O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1)(=[NH:34])[NH2:35]
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)n1ccc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)n1ccc(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.6 %

Procedure:
To a stirred suspension of 10% Pd/C (10 mg) at r.t. in ethanol (2 ml) was added (RS)-2-[3-(2-benzyloxy-5-chloro-phenyl)-pyrazol-1-yl]-N-(4-carbamimidoyl-benzyl)-2-ethoxy-acetamide hydrochloride (100 mg). Stirring at r.t. under a hydrogen atmosphere was continued for 3 hrs. The catalyst was filtered off over a celite pad and washed with ethanol. The filtrate was concentrated to give (RS)-N-(4-carbamimidoyl-benzyl)-2-[3-(5-chloro-2-hydroxy-phenyl)-pyrazol-1-yl]-2-ethoxy-acetamide hydrochloride (48 mg) as off-white solid. MS 428.2 ([M+H]+)
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[C:6]([NH:17][C:18](=O)[CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=1.Cl>O1CCOCC1>[CH3:16][CH:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:26])=[CH:5][C:6]=2[N:17]=[C:18]1[CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(NC2CCCC2C)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCCC1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Yield: 121.8 %

Procedure:
0.88 g 4-(2-Methyl-cyclopentylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were reacted with 10 ml of 4M hydrochloric acid in dioxane at 110° C. in a microwave reactor for 30 min. The reaction was concentrated and 0.98 g (99%) of 1-(2-Methyl-cyclopentyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][C:39](=[O:40])[N:38]([CH3:42])[CH3:37])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OC(=O)N(C)C)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 65 °C

Procedure:
To a suspension of the product of Example 57 in CHCl3 was added TEA (84 μL, 0.6 mmol) and dimethylcarbamoyl chloride (56 μL, 0.6 mmol). The resulting suspension was heated to 65° C. overnight with shaking. Solvent was removed under vacuum to give a crude, which was purified by chromatography on silica gel, eluting by MeOH-DCM (5:95) to afford the title compound (38.6 mg). 1H-NMR indicated one isomer. 1H-NMR (DMSO-d6): δ 97.73 (1H, d), 7.28–7.39 (7H, m), 7.14 (1H, d), 6.97 (1H, dd), 6.63 (1H, dd), 5.12 (2H, s), 4.98(1H, t), 3.78 (3H, s), 3.05 (6H, m), 2.91 (3H, s), 0.99 (3H, t); MS (ESI): 585 (MH+).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O.O>[C:17]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzoin 23 (2.0 g, 9.40 mmol) was dissolved in acetic anhydride (15 mL, 158.70 mmol) followed by the addition of two drops of sulfuric acid which resulted in a pale yellow color. The reaction mixture was then stirred under a nitrogen atmosphere at room temperature (72 h) while monitoring its progress by TLC. The reaction mixture was then dissolved in water and extracted with dichloromethane (3×40 mL). The dichloromethane layer was then dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and removal of the solvent by rotary evaporation, the product was found to be of acceptable purity as evidenced by 1H NMR and TLC, Rf: 0.2 (hexane/ethyl acetate, 2:1): mp 83-85° C. (Lit. 85-87° C.).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.Cl[CH2:11][C:12]([NH2:14])=[NH:13]>C1COCC1>[O:6]1[CH2:7][CH2:8][N:3]([CH2:11][CH:12]([NH2:14])[NH2:13])[CH2:4][CH2:5]1
Reactant: N=C(N)CCl
Reactant: C1COCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g, 60 mmol, 60%) was added to the solution of morpholine (5.2 g, 60 mmol) in THF (40 mL, anhydrous) and stirred for 30 min at room temperature under nitrogen. Chloroacetamidine hydrochloride (2.58 g, 20 mmol) was added to this solution in one portion and stirred at 50° C. overnight. Solvent was removed under reduced pressure and the dark brown oily residue was directly used in the next step.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[C:13]([S-:15])#[N:14].[K+].BrBr.[NH4+].[OH-]>CC(O)=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]2[N:8]=[C:13]([NH2:14])[S:15][C:6]=2[CH:5]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 4-trifluoromethoxyaniline (Aldrich, 4.83 g, 30 mmol) in 50 mL of AcOH, was added KSCN (Aldrich, 11.64 g, 120 mmol). After the mixture was stirred for 30 min, a solution of bromine (Aldrich, 1.55 mL, 30 mmol) in 20 mL of AcOH was added over 30 min period, and the resulting reaction mixture was stirred overnight. The mixture was diluted with ice/water, brought to pH 8 with conc. NH4OH. The mixture extracted 3× with EtOAc (300 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (40%-45% EtOAc/Hexanes) to give 6.0 g (85%) of product.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:18])[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[Cl-].[Zn+2:20].[Cl-]>CO.O>[Zn:20].[CH3:2][C:3]1([CH3:18])[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: [Zn+2]
Agent: CC1(C)C=C(OS(C)(=O)=O)c2ccccc2N1
Agent: [Cl-]
Agent: [Na]
Solvent: O
Solvent: CO
Product: [Zn]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of 13.2 g. of (2,2-dimethyl-1,2-dihydroquinoline-4-yl)-methylsulfonic acid sodium salt in 10 ml of methanol 2.7 g or zinc chloride are added. The solution is stirred at room temperature of 2 hours, whereupon it is diluted with 40 ml of water. The solution is then evaporated in vacuo on water bath. 9.9 g (87%) of (2,2-dimethyl-1,2-dihydroquinoline-4-yl)-methylsulfonic acid zinc salt are obtained, melting at 98° to 100° C.
Reaction SMILES: [H-].[Na+].CC([Si](C)(C)[O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)(C)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[I-].[Na+]>O1CCCC1.CO.C(Cl)Cl>[CH:27]([O:15][CH2:14][C@H:13]1[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10][C@@H:9]1[OH:8])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
350 mg (8 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 1.426 g (4 mmol) of 3'-O-[(1,1-dimethylethyl)dimethylsilyl]thymidine [Can. J. Chem., 56, 2768 (1978)] in 8 ml of tetrahydrofuran under an atmosphere of argon, and the resulting mixture was stirred at 60° C. for 2 hours and then allowed to cool to room temperature. A solution of 988 mg (4 mmol) of benzyl bromide in 2 ml of tetrahydrofuran was then added dropwise to the mixture, followed by 300 mg (2 mmol) of sodium iodide. The reaction mixture was then stirred at room temperature for 17 hours, after which it was freed from the solvent by distillation under reduced pressure. The concentrate was dissolved in 50 ml of ethyl acetate, and the resulting solution was washed twice each time with 50 ml of a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 4 ml of tetrahydrofuran, and 4 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride were added to the solution. The resulting mixture was then stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride. The mixture was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 60 g of silica gel (230-400 mesh) using a gradient elution method, with methylene chloride containing from 1 to 2.5% by volume methanol as the eluent, to give 377.7 mg (yield 23%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20](O)=[O:21].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([CH3:33])[CH:32]=1)[NH:29][N:28]=[CH:27]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([CH3:33])[CH:32]=1)[NH:29][N:28]=[CH:27]2)=[O:21]
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Reactant: Cc1cc(N)cc2cn[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2cc(C)c3[nH]ncc3c2)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.2 %

Procedure:
The product of Example 21, Step 2 (165 mg, 0.52 mmol, 1.00 equiv), 5-amino-7-methylindazole (77 mg, 0.52 mmol, 1.0 equiv), and EDC (119 mg, 0.624 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.087 mL, 0.624 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 77 mg (33%) of the title compound as an off white solid. MS (ES+) m/e 447 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-])=O.[NH2:21][C@H:22]([C:28]([OH:30])=O)[CH2:23][CH2:24][C:25](O)=[O:26]>>[O:11]([S:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][CH:22]1[C:28](=[O:30])[NH:18]2)(=[O:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Oc2ccccc2)ccc1Cl
Product: O=C1Nc2cc(S(=O)(=O)Oc3ccccc3)ccc2N2C(=O)CCC12

Procedure:
The compound was obtained in analogous manner by reacting phenyl 4-chloro-3-nitrobenzenesulfonate with L-glutamic acid, melting point 140° C. (decomp.).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][C:22](=[S:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>N1C=CC=CC=1>[C:31]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]([NH:21][C:22](=[S:30])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:10][CH:11]=2)=[CH:15][CH:16]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-hydroxyphenyl)-2-(phenylthioacetyl amino)pyrazine (h-coelenterathioamide) (c-14) (183 mg, 444 μmol) was dissolved in pyridine (2 mL) and cooled to 0° C. To this was added acetic anhydride (55 μL, 0.58 mmol) and stirred for 2 h after warming to room temperature. To this was further added acetic anhydride (25 μL, 0.26 mmol) and stirred at room temperature for 2.5 h. To this was added saturated aqueous solution of sodium bicarbonate and ethyl acetate to stop the reaction, and after separating the aqueous layer and organic layer, the organic layer was washed 3 times with water and once with brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. After purifying the residue by silica gel column chromatography (22 g, n-hexane/ethyl acetate=2/1), the obtained solid was further purified by silica gel column chromatography (7 g, n-hexane/ethyl acetate=2/1) to give 5-(4-acetoxyphenyl)-3-benzyl-2-(phenylthioacetylamino)pyrazine (c-31) as a pale yellow solid (96.3 mg, 47.8%). Rf=0.36 (n-hexane/ethyl acetate=2/1). Mp. 143-145° C. UV (MeOH) λmax (log ε) 320 (4.30), 258 (4.41). UV (pH 7.4 PB) λmax (log ε) 346 (4.36), 274 (4.35). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.95 (s, 2H), 4.14 (s, 2H), 7.00 (d, J=6.6 Hz, 2H), 7.12-7.24 (m, 3H), 7.26-7.32 (AA′BB′, 3H), 7.36 (t, J=7.3 Hz, 2H), 7.51 (d, J=7.5 Hz, 2H), 8.12-8.18 (AA′BB′, 2H), 9.04 (s, 1H), 12.23 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 20.9, 39.4, 51.6, 122.6 (2C), 126.4, 127.0, 128.0 (2C), 128.3 (2C), 128.4 (2C), 128.9 (2C), 129.0 (2C), 132.8, 136.8, 137.9, 138.6, 145.9, 149.0, 151.9, 152.4, 169.1, 204.7. IR (KBr, cm−1) 700, 1128, 1165, 1179, 1200, 1238, 1368, 1389, 1416, 1441, 1493, 1508, 1730, 3265. HRMS (FAB+) m/z 454.1583 (M+H, C27H24N3O2S requires 454.1589).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[O:8]1[CH2:23][CH2:24][O:25][CH:7]1[C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[CH:2][CH:1]=1
Reactant: OCCO
Reactant: O=Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1ccc(C2OCCO2)cc1
Temperature: 110 °C
Yield: 48 %

Procedure:
A mixture of terephthaldehyde (5.4 g, 40 mmol), para-toluenesulfonic acid—monohydrate (0.4 g, 2 mmol), and ethylene glycol in toluene (80 mL) was heated at 110° C. for 4 hours. The reaction mixture was allowed to cool and was washed with saturated sodium hydrogen carbonate and dried with anhydrous magnesium sulphate. The filtrate was evaporated at reduced pressure to afford a oil. The oil was dissolved in ethanol (200 mL), and then the reaction mixture cooled to 0° C. Sodium borohydride (5.9 g, 160 mmol) was added portionwise, and the resultant reaction mixture allowed to warm to ambient temperature over 16 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate and subsequently extracted twice with ethyl acetate. The combined organic extracts were dried with anhydrous magnesium sulphate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford the title compound as a colourless oil (3.4 g, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18]1([O:23][CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:12][C:11]=1[C:18]1([O:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2(OC)CCCC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(COS(C)(=O)=O)cc2C2(OC)CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20.6 (30 mg, 91 mmol) in 1 mL of DCM at 0° C., was added TEA (11 mg, 109 μmol) followed by methanesulfonyl chloride (12 mg, 109 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction was then quenched with water and extracted with EtOAc. The organic layers were combined, washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give the product as a residue which was used without further purification. MS ESI m/e: 409.1 (M+H)+.