Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[CH:27]1([C:30]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31](O)=[O:32])[CH2:29][CH2:28]1.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:27]1([C:30]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:32])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C(O)(c1ccccn1)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccn1)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (120 mg, 0.316 mmol), the sodium salt of 2-cyclopropyl-2-(2-pyridyl)hydroxyacetic acid from the previous step (63 mg, 0.326 mmol), and NMM (36 μL, 0.326 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (173 mg, 0.391 mmol). The mixture was stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of 95:5 to 0:100 (water:CH3CN containing 0.1% TFA) over 60 min with a flow rate of 60 mL/min. After concentration of desired fractions in vacuo, the two diastereomers of 1-(2-cyclopropyl-2-(2-pyridyl)hydroxyacetyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide were obtained as amorphous solids (isomer 1 (less polar) 50 mg; HPLC RT=3.06 min, method A; LC-MS m/z=543.2; 1H NMR, 400 MHz, CDCl3, 7.81 ppm (d, 1H), 7.74 ppm (t, 2H), 7.28 ppm (d, 2H), 7.22 ppm (d, 1H), 7.14 ppm (t, 1H), 5.45 ppm (br s, 1H), 5.0 ppm (br s, 1H), 4.8 ppm (d, 1H), 4.6 ppm (dd, 1H), 4.42 ppm (d, 1H), 4.35 ppm (m, 1H), 4.2 ppm (m, 1H), 3.43 ppm (m, 1H), 3.1 ppm (br t, 1H), 2.25 ppm (m, 1H), 2.1 ppm (m, 1H), 1.8 ppm (m, 2H), 1.48 ppm (m, 1H), 1.45 ppm (s, 9H), 1.0 ppm (m, 1H), 0.85 ppm (m, 1H), 0.65 ppm (m, 1H), 0.5 ppm (m, 1H); isomer 2 (more polar)38 mg; HPLC RT=2.99 min, method A; LC-MS m/z=543.2).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][O:18][CH3:19])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:20])[C:3]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:24]=2[S:23](=[O:40])(=[O:39])[N:22]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[C:41]([N:17]([O:18][CH3:19])[C:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:30][C:24]=3[S:23](=[O:39])(=[O:40])[N:22]=2)[C:4]1=[O:20])(=[O:43])[CH3:42]
Reactant: CONC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CON(C(C)=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of the product from Example 18B (23 mg, 0.04 mmol) in pyridine (0.5 mL) was added acetic anhydride (38 μL, 0.4 mmol). The reaction solution was stirred at room temperature for 18 h. After which, the solution was concentrated in vacuo. The resulting residue was taken up ethyl acetate (2 mL) and washed with aqueous 1 N HCl (2×1 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (1%→3%→5% methanol/dichloromethane) afforded the title compound as a yellow solid (17 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.34-0.52 (m, 1H), 0.58-0.76 (m, 6H), 0.88-1.04 (m, 1H), 1.20-1.37 (m, 2H), 1.50 (s, 9H), 2.04 (s, 3H), 7.53 (t, J=7.54 Hz, 2H), 7.62-7.77 (m, 3H), 8.07-8.17 (m, 2H), 9.89 (s, 1H), 13.49 (s, 1H); MS m/z 613.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C1N=CN([C:13](N2C=NC=C2)=[O:14])C=1.C[O:21][C:22](=[O:73])[C@@H:23]([NH:40][C:41]([C@@H:43]1[CH2:52][C:51]2[CH:50]=[C:49]3[O:53][CH2:54][C@H:55]([C:57]4[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=5)=[CH:59][CH:58]=4)[O:56][C:48]3=[CH:47][C:46]=2[CH2:45][NH:44]1)=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:27][CH:26]=1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:72][C:67]1[CH:66]=[C:65]([CH:70]=[CH:69][C:68]=1[Cl:71])[CH2:64][O:63][C:60]1[CH:61]=[CH:62][C:57]([C@H:55]2[CH2:54][O:53][C:49]3=[CH:50][C:51]4[CH2:52][C@@H:43]([C:41]([NH:40][C@@H:23]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([O:31][C:32]6[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=6[CH3:39])=[CH:29][CH:30]=5)[C:22]([OH:21])=[O:73])=[O:42])[N:44]([C:13](=[O:14])[NH:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH2:45][C:46]=4[CH:47]=[C:48]3[O:56]2)=[CH:58][CH:59]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Nc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)Nc3cccnc3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Pyridine-3-ylamine was stirred at 60° C. with 1 eq CDI and a catalytic amount of DMAP in DCE for 1 h, then cooled. A solution of (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (1 eq) in DCE was added and stirred at 60° C. for 1 hour. The reaction mixture was cooled, then directly purified by flash chromatography. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (3 mg). LCMS (m/z) 875.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].C(N(CC)CC)C.[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].CN([CH:38]=[O:39])C>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([NH:17][C:38]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:26]=2[Cl:25])=[O:39])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(NC(=O)NCc2ccc(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
203 mg (1.236 mmol) of CDT in 4 mL DMF was added to a solution of 345 mg (1.236 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine-hydrochloride (intermediate product Z1b) and 0.56 mL (4.000 mmol) of triethylamine in 40 mL THF and the mixture was stirred for 2 hours at RT. 176 mg (1.236 mmol) of 2,4-dichloro-benzylamine was added, the reaction mixture was refluxed for 4 hours and then evaporated down i. vac. The residue was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 80:20:1) and the product was triturated with diisopropylether.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[C:12]([C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20])(=[O:14])[CH3:13].O>C(OCC)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]([C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])([OH:14])[CH3:13])=[CH:3]1
Reactant: Brc1ccoc1
Reactant: CC(=O)c1scnc1C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ncsc1C(C)(O)c1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromofuran (6.8 g) in diethylether (15 ml) was added dropwise to n-butyllithium (2.5M solution in hexane, 18.4 ml) in diethylether (20 ml) at -70° C. under a nitrogen atmosphere. After 1 hour, 5-acetyl-4-methylthiazole (5 g) in diethylether (15 ml) was added dropwise. After a further 3 hours at -70° C., the mixture was allowed to warm to room temperature and was then left overnight. The mixture was poured into water and extracted with diethylether. The product thus obtained was crystallised from diethylether, m.p. 102°-104° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N:23]1[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]1>C1COCC1>[O:4]1[CH2:5][CH2:6][C@@H:2]([O:1][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[N:23]2[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]2)[CH2:3]1
Reactant: O[C@@H]1CCOC1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2O[C@@H]2CCOC2)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
(R)-(−)-3-Hydroxytetrahydrofuran (440 mg, 5 mmol, 2 equiv) in THF (15 ml) under argon gas, was cooled to 0° C. Potassium tert-butoxide (617 mg, 5.5 mmol, 2.2 equiv) was added in one portion, and the reaction mixture was stirred for 20 minutes at 0° C. Then 1-(2-fluoro-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (Described in: WO 2011/068898. 598 mg, 2.5 mmol, 1 equiv) was added in one portion, and the reaction mixture was stirred for 10 minutes at 0° C. and allowed to warm up to ambient temperature over 2 hours. The reaction mixture was concentrated, and the residue was taken in DCM and water. The layers were separated, and the organic layer was washed with water (×2), dried over Na2SO4, filtered, and concentrated to provide 1-(2-((R)-tetrahydrofuran-3-yloxy)-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (723 mg, 94%) as a yellow solid that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19]([C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)=[O:20].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(=O)(O)[O-].[Na+].O>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.O1CCOCC1>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[CH:3]=2)[NH:8][C@@H:7]([CH3:18])[CH2:6]1)=[O:20]
Reactant: C[C@H]1CN(C(=O)c2ccco2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)c2ccco2)c2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2N1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.626 g, 1.5 mmol), 1,4-dioxane (15 mL), 4-(methylsulfonyl)phenylboronic acid (0.360 g, 1.8 mmol), and sodium bicarbonate as a 1M solution in water (4.5 mL, 4.5 mmol). The reaction mixture was purged with nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (0.01 M solution in DMF, 7.5 mL, 0.075 mmol) was added, and the reaction mixture was purged with nitrogen and heated to 80° C. overnight. The reaction was diluted with ethyl acetate (30 mL) and washed with brine (15 mL). The aqueous layer was separated and washed with ethyl acetate (30 mL) and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 1:1 hexanes-ethyl acetate) to afford (S)-furan-2-yl(3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (0.33 g, 55% yield) as a viscous yellow oil. MS (ESI, pos. ion) m/z 397 [M+1]+.
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH2:34])O1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O.COCCOC.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>[NH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]c(-c3ccccc3N)c(C3CCCCC3)c2s1
Temperature: 25 °C

Procedure:
A solution of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (7 g, 20 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (4.8 g, 22 mmol), sodium hydrogen carbonate (6.7 g, 80 mmol) and tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol) in water (20 ml) and ethylene glycol dimethyl ether (50 ml) was stirred with heating under reflux for 4 hr. The reaction mixture was cooled to room temperature and ethyl acetate (200 ml) was added. The mixture was washed successively with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml), and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave a crude product of methyl 5-(2-aminophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate. The obtained compound was used for Step 10 without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:28][C:29]1[N:34]=[C:33]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CCN(c1ccnc(Cl)n1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol), 2,4-dichloropyrimidine (0.298 g, 2.0 mmol), and sodium bicarbonate (0.2 g, 2.4 mmol) in ethanol (10 mL) was heated at 80 ° C. for 3 hours. It was quenched with water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 30-6-% ethyl acetate/hexane) to provide the title compound (0.749 g, 79% yield): 1H NMR (CDCl3) 7.95 (d, 1H), 7.32-7.41 (m, 4H), 6.94 (d, 2H), 6.83 (d, 2H), 6.69 (m, 3H), 6.37 (m, 1H), 5.9 (d, 1H), 5.03 (s, 2H), 4.97 (m, 1H), 3.80 (s, 3H), 3.25-3.62 (m, 2H), 3.13 (m, 1H), 2.86 (m, 3H); ES-MS (m/z) 472 [M+H]+.
Reaction SMILES: [N:1]([CH:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=1)[CH2:5][CH:6]1OCC[O:7]1)=[N+:2]=[N-:3].Cl.C(OCC)C>O1CCCC1>[N:1]([CH:4]([C:11]1[CH:16]=[N:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=1)[CH2:5][CH:6]=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(CC1OCCO1)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(CC=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-(1-azido-2-(1,3-dioxolan-2-yl)ethyl)-2-(trifluoromethyl)pyridine (7.44 g, 25.8 mmol) in tetrahydrofuran (60 mL) was treated with 20% aq. HCl (60 mL) at 0° C. The mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, ethyl ether was added and the organic layer was separated, dried over MgSO4, and concentrated to give a crude oil without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[H-].[Na+].[C:16]1([C@@H:22]([NH:24][C:25]2[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:16]1([C@@H:22]([NH:24][C:25]2[N:26]=[C:27]([N:9]3[C:8]4[CH:7]=[CH:6][C:5]([CH3:13])=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=4[N:11]=[CH:10]3)[CH:28]=[CH:29][N:30]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc2nc[nH]c2c1[N+](=O)[O-]
Reactant: C[C@H](Nc1nccc(Cl)n1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ncn2-c2ccnc(N[C@@H](C)c3ccccc3)n2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a stirred solution of 4-nitro-5-methyl-benzimidazole (50 mg, 0.28 mmol, 1.1 eq) in DMF was added NaH (60% dispersion in oil, 11.4 mg, 0.28 mmol, 1.1 eq). After gas evolution ceased, 2-[(S)-1-phenylethylamino]-4-chloro-pyrimidine (60 mg, 0.26 mmol, 1 eq) was added and the mixture was warmed to 80° C. and stirred overnight. The reaction was cooled and the DMF was removed under reduced pressure. The products were purified by preparative thin layer chromatography to afford 35.8 mg of the title compound. Mass spectrum (ESI) 375 (M+).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH2:13][NH:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:7]([CH3:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1([S:34](Cl)(=[O:36])=[O:35])[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1.[OH-:38].[Na+]>CC(C)=O.O>[C:1]([C:5]1[CH:10]=[C:9]([CH3:12])[C:8]([CH2:13][N:14]([CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])[S:34]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([N:14]([CH2:13][C:8]3[C:7]([CH3:23])=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[C:10]([OH:11])[C:9]=3[CH3:12])[CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:32])=[O:31])[CH:25]=2)(=[O:36])=[O:35])=[C:7]([CH3:23])[C:6]=1[OH:38])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: [OH-]
Reactant: CCCCC(CC)CNCc1c(C)cc(C(C)(C)C)c(O)c1C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC(CC)CN(Cc1c(C)cc(C(C)(C)C)c(O)c1C)S(=O)(=O)c1cccc(S(=O)(=O)N(Cc2c(C)cc(C(C)(C)C)c(O)c2C)CC(CC)CCCC)c1
Reaction time: 15 h
Yield: 32.7 %

Procedure:
The procedure of Example 1 is followed using 6-t-butyl-3-(2-ethylhexylaminomethyl)-2,4-dimethylphenol (13.40 grams; 0.042 mole) and 1,3-benzenedisulfonyl chloride (5.5 grams; 0.02 mole) in a mixture of acetone (100 mls) and water (35 mls) while adding a solution of sodium hydroxide (1.76 grams; 0.044 mole) in water (15 mls) and maintaining the temperature at 30°-35° C. The mixture is allowed to stand at ambient temperature for 15 hours. After separating the oily layer, treating the same with ice water to effect crystallization, the solid is filtered to obtain the crude product (15.5 grams; 92% of theoretical). Recrystallization of the crude product from a mixture of benzene and cyclohexane (1 volume: 2 volumes, respectively) affords the desired product (5.5 grams; m.p. 135°-136° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=2[C:24](O)=[S:25])[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1.[NH2:38][C:39]1[C:40]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=2)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C=O)C.C(Cl)Cl>[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:16][CH2:17][C@H:18]([O:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=2[C:24]([NH:38][C:39]2[C:40]([C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=3)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=2)=[S:25])[CH2:19][CH2:20]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: Cc1ccc(C(O)=S)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.18 h

Procedure:
A solution of oxalyl chloride (1.6 mL, 18 mmol) and CH2Cl2 (12 mL) was added over 7 min to a solution of 2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-methylthiobenzoic acid (7.00 g, 18.3 mmol), DMF (71 μL, 0.92 mmol), pyridine (1.5 mL, 18.9 mmol) and CH2Cl2 (62 mL) cooled in an ice bath. The bath was removed after the addition was complete. After 1 h the resulting yellow solution was added dropwise over 35 min to a slurry of 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (4.48 g, 18.0 mmol), pyridine (2.2 mL, 28 mmol), and CH2Cl2 (52 mL) cooled in an ice bath. At the end of the addition the bath was removed, and the mixture became homogeneous over 10-12 min, but became opaque again within 2 h. After 4 h the mixture was poured into satd citric acid (100 mL) and water (50 mL). The organic layer was extracted with a 1:1.5 solution of satd citric acid/water (125 mL), and the combined aqueous layers were back-extracted with CH2Cl2 (50 mL). The combined organic layers were rinsed with 25% NaCl (50 mL), heated to reflux on a steam bath to dissolve residual solids, dried (Na2SO4) and concentrated to a bright yellow solid (12.30 g) which was purified by flash chromatography (5% EtOAc/CH2Cl2, followed by 10% EtOAc/CH2Cl2) to provide 8.98 g (80%) of white foam.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:6](=O)[CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10]>CCOCC.C(Cl)(Cl)Cl>[Br:1][C:9]1[NH:10][C:6]([C:5]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:3]([Cl:2])[CH:4]=2)=[CH:7][C:8]=1[C:11]#[N:12]
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: Br
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)[nH]c1Br
Temperature: 0 °C
Yield: 24 %

Procedure:
Hydrogen bromide gas is bubbled through a mixture of (3,4-dichlorophenacyl)malononitrile (10.0 g, 0.0395 mol) in ether (150 mL) and chloroform (100 mL) at a moderate rate, keeping the reaction mixture temperature below 35°-40° C. After ten minutes, TLC shows the reaction is complete by UV analysis. The reaction mixture is poured into an ice-water mixture, the layers are separated and the aqueous layer is extracted with ether. The combined organic layer and ether extracts are dried and concentrated in vacuo to give a brown solid. The brown solid is washed with methylene chloride and filtered to obtain the title compound as an off-white solid (3.0 g, 24%, mp >200° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: [Si]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH2:19])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1cc(CO)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 793.1 %

Procedure:
To a solution of approximately 7.26 g (2.6 mmol) of crude 4-tert-butyldimethylsilyloxy-3-(prop-2-enyl)benzyl alcohol (Step D of Example 42) dissolved in 50 mL of anhydrous THF was added 26 mL (2.6 mmol) of tetra-n-butylammonium fluoride and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 5% methanol/chloroform to afford 3.386 g (79%) of the title compound as a colorless oil.