Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1.[NH3:30].[I-].[Na+]>C(#N)C>[NH2:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1
Reactant: N
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: NCCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reaction time: 5 h

Procedure:
A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was left to stand with ammonia solution (1 ml) and sodium iodide (5 mg) and 24 hours. After repeated addition of the ammonia solution, the reaction was kept at 40° C. for 5 hours. The cooled reaction solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 387.44 (C24H21N3O3); MS (ESI): 388 ([M+H]+), was obtained as hydroformate in this way.
Reaction SMILES: CN1C(=O)N(C)[CH2:5][CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH3:18][C:19]1([CH3:25])[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].IC(C)C>C1COCC1>[CH:4]([CH:21]1[C:20](=[O:24])[C:19]([CH3:25])([CH3:18])[CH2:23][CH2:22]1)([CH3:5])[CH3:3]
Reactant: CC1(C)CCCC1=O
Reactant: CN1CCCN(C)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)I
Product: CC(C)C1CCC(C)(C)C1=O
Temperature: -20 °C
Yield: 78 %

Procedure:
A solution of DMPU (9.86 g, 77.0 mmol) in THF (100 ml) was added at −70° C. within 5 min to a stirred solution of lithium diisopropylamide (2 M in THF, 38.5 ml, 77.0 mmol). After 10 min stirring at −70° C. a solution of 2,2-dimethylcyclopentanone (7.80 g, 70.0 mmol) in THF (50 ml) was added over a period of 30 min. The reaction mixture was warmed up to −20° C. and treated dropwise with 2-iodopropane (18.7 g, 105 mmol). The reaction mixture was warmed up slowly to room temp., stirred over night at room temp., and quenched with satd. aq. NH4Cl solution (300 ml) and extracted with Et2O (3×300 ml). The combined organic extracts were dried (Na2SO4), and concentrated under the reduced pressure. The resulting residue was purified by silica gel FC (pentane/Et2O, 98:2, Rf 0.25) to furnish 5-isopropyl-2,2-dimethylcyclopentanone (8.42 g, 78%). IR (neat): v=1731 (s, vC═O), 1462 [m, δas(CH3)], 1367 [m, δs(CH3)] cm−1. 1H NMR (CDCl3): δ=0.80/0.99 (2d, J=7.0 Hz, 6 H, 1′-Me2), 0.94/1.06 (2s, 6 H, 2-Me2), 1.62-1.69 (m, 2 H, 3-Hax, 4-Hax), 1.76-1.81 (m, 1 H, 5-H), 1.89-1.94 (m, 1 H, 1′-H), 2.11-2.17 (m, 2 H, 3-Heq, 4-Heq) ppm. 13C NMR (CDCl3): δ=18.4/21.1 (2q, 1′-Me2), 20.6 (t, C-4), 23.1/24.7 (2q, 2-Me2), 27.4 (d, C-1′), 36.4 (t, C-3), 45.3 (s, C-2), 224.1 (s, C-1) ppm. MS (EI): m/z (%)=154 (15) [M]+, 139 (7) [M-CH3]+, 112 (36) [M-C3H6]+, 97 (18) [M-C4H9]+, 56 (100) [C3H4O]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[F:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[F:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (7 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzoic acid (520 mg) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (12 ml), and the solution was dropwise added to a solution of 4-aminopyridine (140 mg) and diisopropylethylamine (210 mg) in dichloromethane (5 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The mixture was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 560 mg of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzamide.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH2:3]1.[C:15]([SiH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.CO>CN(C)C=O>[Si:19]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH2:3]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1coc(N2CC(O)C2)n1
Reactant: CC(C)(C)[SiH](c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-hydroxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (2.64 g, 13.4 mmol) (obtained as described in Reference Example 70(7)) in dimethylformamide (80 ml) were added t-butyldiphenylsilane (6.97 ml, 26.8 mmol) and imidazole (1.82 g, 26.8 mmol) in an ice bath and the mixture was stirred in an ice bath overnight. After checking the completion of the reaction, methanol was added to the reaction mixture and the mixture was stirred for 30 minutes. The resulting mixture was partitioned between ethyl acetate and 1 0% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:3→3:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (4.95 g, yield 85%) as a pale yellow solid.
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:20])[N:11]=[CH:10]1)(=O)C(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][N:41]([CH3:47])[C:42](=[O:46])[C@H:43]([CH3:45])O>C(Cl)Cl>[CH3:40][N:41]([CH3:47])[C:42](=[O:46])[C@H:43]([O:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:18](=[O:19])[NH:9][CH:10]=[N:11]2)[CH3:45]
Reactant: C[C@H](O)C(=O)N(C)C
Reactant: CC(C)(C)C(=O)OCn1cnc2cccc(O)c2c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
DTAD (13.34 g, 58 mmol) was added portion-wise to an ice-cooled solution of (5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (8 g, 29 mmol), triphenylphosphine (15.2 g, 58 mmol) and (S)—N,N-dimethyl lactamide (5.1 g, 43.5 mmol; obtained as described in Larcheveque M., Synthesis 1986, 1, 60) in DCM (300 ml). The mixture was stirred at room temperature for one hour. After evaporation of the solvents under vacuum, the residue was diluted with 6N methanolic ammonia (100 ml). The mixture was stirred at room temperature for 18 hours. After evaporation of the solvents, the residue was triturated in ether. The resulting solid was filtered and purified further by chromatography on silica gel (eluant: 3 to 5% methanol in DCM) to give (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide as a white solid (5.4 g, 71%); NMR Spectrum (CDCl3) 1.77 (d, 3H), 2.94 (s, 3H), 3.19 (s, 3H), 5.10 (q, 1H), 6.92 (d, 1H), 7.35 (d, 1H), 7.63 (t, 1H), 8.00 (s, 1H); Mass spectrum MH+ 262.
Reaction SMILES: O1CCOCC1.Cl.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:46]=[CH:47][C:48]=1[OH:49])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=[O:45])[CH2:25][NH:26][C:27](=[O:44])[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[NH:36]C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)(=[O:10])[CH3:9]>CO>[C:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:46]=[CH:47][C:48]=1[OH:49])[CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][NH:23][C:24](=[O:45])[CH2:25][NH:26][C:27](=[O:44])[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[NH2:36])[CH2:20][CH2:21]1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3NC(=O)OC(C)(C)C)CC2)ccc1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 M dioxane solution of HCl (0.50 mL) was added to a methanol (1 mL) solution of the 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine obtained above, and the resulting solution was stirred at room temperature overnight and concentrated. The resulting residue was then dissolved in methanol, loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH3 (5 mL), concentrated and then purified by preparative TLC (SiO2, ethyl acetate/methanol=3:2) to thereby afford 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 2148) (2.3 mg, 9.2%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 490.3 (M++H, C24H29F2N5O4).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[CH2:12]([N:19]1[CH2:25][CH2:24][C:23]([C:26]#[N:27])=[C:22](Cl)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1>[NH2:27][C:26]1[C:23]2[CH2:24][CH2:25][N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][C:22]=2[O:3][C:2]=1[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: N#CC1=C(Cl)CCN(Cc2ccccc2)CC1
Reactant: CCCCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1oc2c(c1N)CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 gm (0.008 mol) of butyl glycolate in 8 ml of absolute dioxane was added dropwise to a suspension of 0.4 gm (0.008 mol) of 50% sodium hydride in 5 ml of absolute dioxane, and the mixture was stirred for one hour at room temperature. Then, while the mixture was cooled with ice, a solution of 1.0 gm (0.004 mol) of 1-benzyl-4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-azepine in 15 ml of absolute dioxane was added, and the mixture was stirred for one hour. The reaction mixture was then poured into about 80 ml of ice-cold water, and the aqueous mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulfate and concentrated by evaporation. The residue was purified by column chromatography on silicagel, using toluene/ethyl acetate (7:3) as eluant.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH3:23][N:24]([CH3:43])[S:25]([N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:29]1)(=[O:27])=[O:26]>C1COCC1.CCCCCC.[Cl-].[NH4+]>[CH3:23][N:24]([CH3:43])[S:25]([N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([C:37]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:42])[C:38]([F:39])([F:41])[F:40])=[CH:29]1)(=[O:26])=[O:27]
Reactant: CN(C)S(=O)(=O)n1cc(C(=O)C(F)(F)F)c2cccnc21
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
To a chilled (−78° C.) solution of 80 mg (0.27 mmol) of 5-bromo-1-(4-fluorophenyl)-1H-indazole in 1 mL of anhydrous THF was added 110 μL (0.28 mmol) of a solution of 2.5 M n-BuLi in hexane in one portion. This solution was then added to a chilled (−78° C.) solution of 88 mg (0.27 mmol) of 3-(2,2,2-trifluoro-acetyl)pyrrolo[2,3-b]pyridine-1-sulfonic acid dimethylamide in 3 mL of THF. The reaction was monitored by TLC (ethyl acetate-hexanes 4:6). After 30 minutes, the mixture was diluted with 7 mL of saturated aqueous ammonium chloride and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with three 10 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel (prep. plate, 2×1 mm, ethyl acetate-hexanes 30:70). The material from the prep plate was washed from the silica gel with ethyl acetate and concentrated. The residue was triturated with ether-hexanes to afford 42 mg (28%) of the title compound. MS m/z 534.22 (MH+).
Reaction SMILES: C([O:8][C@H:9]([C@H:11]([N:22]1[CH:26]=[N:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[Cl:21])[CH3:10])C1C=CC=CC=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[OH:8][C@H:9]([C@H:11]([N:22]1[CH:26]=[N:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[Cl:21])[CH3:10]
Reactant: CCOC(=O)c1ncn([C@H](CCc2cccc(Cl)c2Cl)[C@H](C)OCc2ccccc2)n1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1ncn([C@H](CCc2cccc(Cl)c2Cl)[C@H](C)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A mixture of ethyl 1-[(2S,3R)-2-(benzyloxy)-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxylate (103 mg) and iodotrimethylsilane (0.08 ml) in chloroform (4 ml) was stirred at room temperature for 2 hours. The mixture was poured into cold methanol and the whole was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with water, aqueous sodium bisulfite and sodium bicarbonate, successively, and dried. The residue left after evaporation of solvent was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (50:1) to give a gummy oil of ethyl 1-[(2S,3R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxylate (32 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27](O)[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:23][CH:22]=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl>[Br:46][CH:27]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(Br)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 46.2 %

Procedure:
Triphenylphosphine (1.61 g, 6.12 mmol) was added to a solution of tert-butyl 3-(4-chlorophenyl)-3-hydroxypropylcarbamate (1.40 g, 4.90 mmol) in DCM (30 mL) at about 0° C. NBS (1.05 g, 5.88 mmol) was added portionwise. After 2 h, the reaction mixture was loaded to a short silica gel pad and eluted with EtOAc:hexanes (1:5) to give tert-butyl 3-bromo-3-(4-chlorophenyl)propylcarbamate (0.79 g, 46%) as an oil, which solidified on standing. 1H NMR (CDCl3, 400 MHz) δ 7.35 (m, 4H), 4.96 (m, 1H), 4.63 (br s, 1H), 3.28 (m, 2H), 3.21 (m, 1H), 2.37 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]1[OH:41])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]4[OH:41])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@@H]1O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H]3CCCC[C@@H]3O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((1R,2S)-2-hydroxycyclohexyl)benzenesulfonamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 2H), 8.15-8.11 (m, 1H), 7.98 (m, 1H), 7.69-7.64 (m, 1H), 7.61-7.56 (m, 1H), 7.42-7.32 (m, 3H), 3.70-3.63 (m, 1H), 3.09-3.03 (m, 1H), 1.70-1.61 (m, 1H), 1.60-1.44 (m, 3H), 1.42-1.24 (m, 3H), 1.22-1.10 (m, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Br[CH2:23][CH2:24][CH3:25].Cl>>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[N:12]([CH2:23][CH2:24][CH3:25])[C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCBr
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Agent: Cl
Product: CCCN1C(=O)c2cc3c(cc2C1=O)CC(N(CCC)CCC)C3

Procedure:
Using procedure 48, 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.15 g, 0.52 mmol) was treated with 1-bromopropane (0.07 mL, 0.78 mmol). Purification via silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 96 as a white solid (m.p. 217-218° C.).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([CH3:13])[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:14])=[C:2]=[S:3].[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1(C)C=CC=CC=1>[NH2:17][CH2:16][CH2:15][NH:18][C:2](=[S:3])[NH:1][C:4]1[CH:12]=[C:11]([CH3:13])[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:14]
Reactant: Cc1cc(N=C=S)c(C)c2c1OCO2
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=S)NCCN)c(C)c2c1OCO2
Yield: 96.9 %

Procedure:
A solution of 1.6 g of 5-isothiocyanato-4,7-dimethyl-1,3-benzodioxole in 35 mL of toluene at 25° C. is added to a solution of 1.89 g of ethylenediamine in 65 mL of toluene. The reaction gradually turns cloudy as a solid precipitates from solution. This solid is collected and dried under vacuum to give 2.0 g of 5-[N'-(2-aminoethyl)thioureido]-4,7-dimethyl-1,3-benzodioxole as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@@:6]2([O:9][CH2:8][CH2:7]2)[C@H:5]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:4][C@@H:3]1[CH2:18][OH:19].CN1C=CN=C1.Cl[C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31]>C1COCC1>[O:17]=[C:11]1[NH:12][C:13](=[O:16])[CH:14]=[CH:15][N:10]1[C@@H:5]1[O:4][C@H:3]([CH2:18][O:19][C:40]2[CH:41]=[CH:42][CH:43]=[CH:27][C:28]=2[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C@@H:2]([OH:1])[C@:6]21[O:9][CH2:8][CH2:7]2
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@]23CCO3)c(=O)[nH]1
Reactant: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]2(CCO2)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 10 (1.0 eq., 0.28 mmol, 75 mg) in dry THF (3 mL) was added 1-methylimidazole (NMI; 12.0 eq., 3.33 mmol, 0.27 mL) at room temperature. A solution of intermediate 11 (1.4 eq., 0.39 mmol, 0.43 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed three times with 0.5 M HCl. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-10% methanol in CH2Cl2) to give compound 12e (24 mg, yield=15%, purity=95%) as a mixture of diastereomers. HPLC Condition A; Rt: 1.49 min, m/z=526 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 3H), 1.37 (s, 3H), 2.42-2.43 (m, 2H), 3.56 (s, 3H), 3.70-3.79 (m, 1H), 3.80-3.88 (m, 0.4; H), 3.88-3.96 (m, 0.6; H), 4.09-4.20 (m, 1H), 4.26-4.48 (m, 3H), 5.50-5.56 (m, 1H), 5.61-5.69 (m, 1H), 5.88-5.97 (m, 1H), 5.97-6.04 (m, 1H), 7.12-7.24 (m, 3H), 7.31-7.41 (m, 2H), 7.44 (d, J=8.22 Hz, 0.4H), 7.52 (d, J=8.02 Hz, 0.6H), 11.49 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:12][C:13](N)=[O:14]>O>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[C:9]([OH:11])=[N:12][C:13]([OH:14])=[N:1][C:2]=2[CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Br)cnc1C(=O)O
Solvent: O
Product: Oc1nc(O)c2ncc(Br)cc2n1
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 89.8 %

Procedure:
To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid (1 g, 0.0046 mol) and urea (2.768 g, 0.4629 mol) were added. The reaction mixture was stirred at 200° C. for 2.5 h. The reaction mixture was cooled, water was added and stirred to provide a precipitate. The precipitate was filtered and dried to provide the title compound [1 g, 91%]. This material was taken to the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:28](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.C(N1C=CC(N)=N1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH3:28])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: CCn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 175 mg, 0.53 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (193 mg, 0.58 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (142 μL, 1.22 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Ethyl-1H-pyrazol-3-ylamine (59 mg, 0.51 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-ethyl-1H-pyrazol-3-yl)-propionamide as a white powder (139 mg, 62%) ESI-LRMS m/e calcd for C20H26ClN3O3S [M+] 423.1, found 424.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.21 (m, 2H, CH2), 1.44 (t, J=7.3 Hz, 3H, CH3), 1.47-1.96 (m, 8H, 4×CH2), 2.16-2.29 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.5 Hz, 1H, CH), 4.03 (q, J=7.3 Hz, 2H, NCH2), 6.64 (d, J=2.3 Hz, 1H, Ar), 7.27 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.94 (s, 1H, NH), 8.08 (d, Jo=8.1 Hz, 1H, Ar).