Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[NH:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=1)[CH3:10].[OH-].[Na+]>C(Cl)Cl>[Br:1][C:12]1[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=1[CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(CC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(CC)[nH]1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-Bromosuccinimide (5.86 g, 0.033 mol) was added to a solution of ethyl 5-ethyl-1H-pyrrole-2-carboxylate (Intermediate 12, 5.0 g, 0.03 mol) in DCM (85 ml) at 0° C., and the reaction was stirred for 30 minutes then poured to a chilled beaker containing 2 N NaOH (50 ml). The layers were separated and the aqueous layer was extracted with DCM (×3). The combined organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The resultant dark brown solid was purified by flash chromatography (hexanes/EtOAc, 10:1) to give the title product as a white solid (5.0 g, 68%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:21])([F:20])[C@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCCP(=O)=O.[CH2:28]([S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[C:38]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)[C:37]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([N:62]3[CH2:66][CH2:65][CH2:64][CH2:63]3)[CH2:58][CH2:57]1)=[C:36]2[C:67](O)=[O:68])(=[O:32])=[O:31])[CH3:29]>C(OCC)(=O)C.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:28]([S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[C:38]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:53])([F:54])[F:52])[CH:46]=1)[C:37]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([N:62]3[CH2:66][CH2:65][CH2:64][CH2:63]3)[CH2:58][CH2:57]1)=[C:36]2[C:67]([NH:19][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([F:20])([F:21])[F:10])=[O:68])(=[O:31])=[O:32])[CH3:29]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: CCCP(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1cc2c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reaction time: 15 h
Yield: 54 %

Procedure:
N,N-Diisopropylethylamine (0.087 mL, 0.495 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.045 g, 0.215 mmol), and propylphosphonic anhydride (0.126 mL of a 50% solution in ethyl acetate, 0.215 mmol) were added to a suspension of 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.165 mmol) in dichloromethane (2.54 mL). The mixture was stirred for 15 h, diluted with 10% Na2CO3 (2 mL) and methylene chloride (5 mL), and poured into a hydrophobic frit to separate the phases. The organic phase was absorbed onto florisil and purified via column chromatography (ISCO, 1-10% methanol/methylene chloride). The material was dissolved in methylene chloride, and the organic phase was washed with 10% Na2CO3 (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide as a light orange solid (0.068 g, 51% yield). MS (m/z) 763.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1)[CH3:10].CS(O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: CCc1ccc(CO)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Product: CCc1ccc(Cc2cc(Cl)ccc2O)cc1
Temperature: 160 °C
Reaction time: 0.42 h
Yield: 46.2 %

Procedure:
A mixture of 4-chlorophenol (2.0 g, 15.6 mmol), 4-ethylbenzylalcohol (2.12 g, 15.6 mmol) and methanesulfonic acid (80 mg, 0.83 mmol) was heated and stirred at 160° C. for 25 minutes. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4-chloro-2-(4-ethylbenzyl)phenol (1.78 g, 46%) as a light-yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][C@H:25]2[CH2:29]OS(=O)(=O)[N:26]2C(OC(C)(C)C)=O)=[CH:22][CH:21]=1.O>CN(C=O)C>[NH2:26][C@@H:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[CH:40][CH:39]=1)[CH2:29][NH:18][C:16]1[CH:15]=[N:14][N:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:3]=[N:4][CH:5]=[CH:6]3)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Cl)cc2)COS1(=O)=O
Reactant: Nc1cnn(-c2ccc3cnccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H](CNc1cnn(-c2ccc3cnccc3c2)c1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (9.6 mg, 251 μmol) was added to a mixture of 1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (44 mg, 209 μmol) and (S)-tert-butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (109 mg, 314 μmol) in DMF (1 mL) at ambient temperature and the mixture was stirred at ambient temperature for 1.5 hours. H2O (15 mL) was added, and the mixture was extracted with DCM (4×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in DCM (3 mL), TFA (2 mL) was added, and the mixture was stirred at ambient temperature for 2 hours. Toluene (3 mL) was added, and the mixture was concentrated under reduced pressure. The resulting orange oil was dissolved in DCM, evaporated onto a silica gel plug, and purified by flash chromatography (Biotage Si 25+M, 5% to 10% 2 N NH3 in MeOH/DCM) to provide N-((S)-2-amino-3-(4-chlorophenyl)propyl)-1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (18 mg, 23% yield) as an off-white solid. LCMS (API-ES) m/z (%): 412.2 (100%, M++H); 1H NMR (300 MHz, CDCl3) δ ppm 1.54 (br s, 3H), 2.62 (dd, J=13.1, 8.1 Hz, 1H), 2.79-2.94 (m, 2H), 3.15 (dd, J=11.8, 2.6 Hz, 1H), 3.25 (d, J=4.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H) 7.45 (s, 2H), 7.64 (d, J=5.5 Hz, 1H), 7.89 (s, 1H), 8.00 (s, 2H), 8.51 (d, J=5.5 Hz, 1H), 9.20 (s, 1H). (S)-tert-Butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was prepared in a similar manner as that described for (S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide in Scheme 1, using (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-011434)) instead of (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[F:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[C:29]1[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=1>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[O:4][CH2:5][C:6]([OH:8])=[O:7])=[CH:19][C:14]=2[F:13])=[CH:30][N:31]=1
Reactant: O=C(O)COc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3OCC(=O)O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)acetic acid and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H14FN3O3, 339.10; m/z found, 339.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=1.4, 2H), 7.71 (d, J=13.3, 1H), 7.51 (d, J=5.7, 2H), 7.29 (dd, J=7.5, 1.7, 1H), 7.25-7.17 (m, 1H), 6.92-6.89 (m, 1H), 6.88-6.80 (m, 3H), 4.14 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:38])([C:34]([F:37])([F:36])[F:35])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:38])([C:34]([F:35])([F:37])[F:36])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(N)=N2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ((2R,5R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (2.27 g, 4.13 mmol) in CH2Cl2 (25 ml) was added TFA (41.3 mmol, 3.18 ml) and the reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was added to 10% aqueous NaHCO3 solution (pH >8) and the free base was extracted with EtOAc. Combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was re-crystallized twice by dissolving the material in EtOH (15 ml) at 50-60° C. and after saturation with H2O (6-8 ml) the clear solution was allowed to cool to ambient temperature overnight to provide after filtration and drying the title compound in >99% purity as white crystals: UPLC RtH5=0.905 min; ESIMS: 450 [(M+H)+]; 1H NMR (600 MHz, DMSO-d6): 10.72 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 7.78 (d, 1H), 7.71 (m, 1H), 7.15 (t, 1H), 6.08 (br s, 2H), 3.91 (d, 1H), 3.78 (d, 1H), 2.52 (s, 3H), 1.46 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH2:16]=[C:17]([CH3:19])[CH3:18].[OH-].[Na+]>CCOCC.C(COC)OC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8]([O:10][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:9]
Reactant: O=C(O)CNc1cccs1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CNc1cccs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 12.6 g of 2-thienylaminoacetic acid, 300 ml of dimethoxyethane, 15 ml of sulphuric acid and 100 ml of isobutene is stirred at room temperature in an autoclave for 5 h and poured into a mixture composed of 800 ml of ether and 800 ml of 1N sodium hydroxide solution. The ethereal phase is separated off, and the aqueous phase is extracted twice more by shaking with 200 ml of ether each time. After drying of the ether phases over MgSO4 and evaporation of the solvent there remains a yellowish oily residue.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:30])=[O:29])(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:40][C:37]([F:38])([F:39])[C:34]1[CH:33]=[CH:32][C:31]([S:28]([NH2:27])(=[O:29])=[O:30])=[C:36]([C:2]2[CH:22]=[CH:21][C:5]3[NH:6][C:7]([CH2:9][O:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)=[N:8][C:4]=3[CH:3]=2)[CH:35]=1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: NS(=O)(=O)c1ccc(C(F)(F)F)cc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.100 g, 0.269 mmol, from Example 1.1), N-tert-butyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-benzenesulfonamide (0.165 g, 0.404 mmol), sodium carbonate (0.171 g, 1.61 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.035 g, 0.0538 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product as a off-white solid. The obtained material was dissolved in TFA (2 mL) and the resulting solution was heated to 60° C. for 3 hours. The reaction mixture was concentrated in vacuo to provide a residue which was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a brown solid (0.101 g, 73%). 1H NMR (400 MHz, CD3OD) δ (ppm): 0.33 (d, 1H, J=8.0 Hz), 7.89 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.82 (d, 1H, J=0.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.69-7.65 (m, 3H), 7.50 (dd, 1H, J=8.8 Hz, J=1.6 Hz), 7.28 (d, 2H, J=8.8 Hz), 5.62 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H16F6N3O3S: 516.4 (M+H), Found 516.3.
Reaction SMILES: [C:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[C:4]=1[C:9](OC)=[O:10])#[N:2].CO.[BH4-].[Li+]>C(OCC)C>[C:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[C:4]=1[CH2:9][OH:10])#[N:2]
Reactant: COC(=O)c1c(C)nsc1C#N
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: Cc1nsc(C#N)c1CO
Temperature: 40 °C
Reaction time: 2 h
Yield: 123.5 %

Procedure:
5-Cyano-4-methoxycarbonyl-3-methyl-isothiazole (1.14 g, 6.3 mmol) was dissolved in diethyl ether (20 ml) and methanol (0.38 ml, 9.4 mmol). Lithium borohydride (204 mg, 9.4 mmol) was added and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched by addition of aqueous hydrochloric acid (1M) (20 ml). The two phases were separated and the aqueous phase was extracted with diethyl ether (2×20 ml). The combined organic phases were dried over magnesium sulfate and concentrated to give a crude product (1.2 g), which consisted of a 1:1 mixture of methyl ester and product. The mixture was used without further purification.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:13]([OH:15])=O)=O)C1C=CC=CC=1.[NH2:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26]>>[NH2:11][CH:12]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:13]([NH:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26])=[O:15]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(NC(Cc1ccco1)C(=O)O)OCc1ccccc1
Product: NC(Cc1ccco1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of (RS)-α-(1-benzyloxyformamido)-3-(furan-2-yl)propionic acid [J. Biol. Chem. 171, 383 (1947)]and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by catalytic hydrogenation there was obtained rac-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(furan-2-yl)propionamide, MS: 365 (M+H)+, as a colourless foam.
Reaction SMILES: [CH3:1][N:2](C=O)C.[F:6][C:7]1[CH:12]=[C:11]([CH2:13]OS(C)(=O)=O)[CH:10]=[CH:9][N:8]=1.[C-]#N.[Na+]>C(OCC)(=O)C>[F:6][C:7]1[CH:12]=[C:11]([CH2:13][C:1]#[N:2])[CH:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)OCc1ccnc(F)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CCc1ccnc(F)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To the DMF (28 ml) solution of methanesulfonic acid (2-fluoropyridin-4-yl)methyl ester (1.16 g), sodium cyanide (0.42 g) was added and the mixture was stirred at 80° C. for 1 hr. The mixture was diluted with ethyl acetate (100 ml), and washed with 15% brine and distilled water in order. The organic layer was concentrated and purified by silica gel column (n-hexane/ethyl acetate=5/1) to obtain the title compound (278 mg, 36%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:42]=[CH:43][C:44]=1[CH3:45])[C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[O:30].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[CH:22]1([C:20]([NH:19][C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:25][C:26]4[CH:27]=[C:28]([CH:42]=[CH:43][C:44]=4[CH3:45])[C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)=[O:30])=[CH:3][CH:4]=3)[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=2)=[O:21])[CH2:24][CH2:23]1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N
Reactant: C[Si](C)(C)CCOCn1nc(NC(=O)C2CC2)c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Nc1ccc2c(NC(=O)C3CC3)nn(COCC[Si](C)(C)C)c2c1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
To a solution of N-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)cyclo-propanecarboxamide (41 mg, 0.1 mmol) in t-BuOH (1.5 mL) were added 3-amino-4-methyl-N-(3-(trifluoromethyl)-phenyl)benzamide (29 mg, 0.1 mmol) and K2CO3 (42 mg, 0.3 mmol). The reaction mixture was degassed for 10 minutes. To a mixture were added Pd2(dba)3 (6.0 mg) and t-Bu-X-phos (4 mg). The reaction mixture was heated at 100° C. until it was complete as monitored by LC-MS. Then the resulting mixture was filtered through a pad of celite and eluted with dichloromethane. The to solvent was removed by rotavapor and the crude residue was purified by flash chromatography with methylene chloride-methanol to afford the title product (25 mg, 40%), MS (ESI) m/z 624 (M+H)+.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1.C(O[C@@H:18]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:19]1[O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.ClCCCl>C1C=CC=CC=1>[C:21]([O:20][C@@H:19]1[C@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:40][C@H:18]1[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: C[Si](C)(C)n1cnc(CC(=O)O)n1
Solvent: c1ccccc1
Solvent: ClCCCl
Product: O=C(O)Cc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Yield: 85.5 %

Procedure:
55 mmoles of 1-trimethylsilyl-3-carboxymethyl-1,2,4-triazole and 55 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose were combined, in 100 ml. of 1,2-dichloroethane, with 5 mmoles of (CH3)3Si--O--SO2CF3 in 20 ml. of C6H6 and refluxed for 4 hours at a bath temperature of 100° C. After working up the mixture as usual, 24 g. (85.5%) of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-3-carboxymethyl-1,2,4-triazole was produced.
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH:29]1([NH:35][C:36]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C@:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(C(=O)NC3CCCCC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
(S)-2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (236 mg, 0.88 mmol) was dissoloved in a mixture of methylene chloride (15 ml) and triethylamine (2 ml, 14.35 mmol). To the solution, cyclohexyl isocyanate (120 mg, 0.96 mmol) was added followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid cyclohexylamide (164 mg, 47%) as a light yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:13][CH2:12]2
Reactant: Brc1cccnc1
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1c2ccc(Cl)cc2CCN1c1cccnc1
Temperature: 110 °C
Yield: 65.3 %

Procedure:
In a sealed tube, 3-bromopyridine (0.1 g, 0.633 mmol) was combined with 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (intermediate A-2) (0.115 g, 633 mmol), copper (I) iodide (0.012 g, 0.063 mmol), potassium carbonate (0.175 g, 1.27 mmol) and N,N′-dimethylethylenediamine (0.013 g, 0.127 mmol) in 1,4-dioxane (2 mL). The reaction mixture was heated at 110° C. overnight. The mixture was cooled to room temperature, filtered through dicalite and washed with DCM. The residue was purified by silica gel flash chromatography eluting with a 5 to 100% EtOAc-heptane gradient to give the title compound (0.107 g, 65%) as a white solid. MS: 259.1 (M+H+).
Reaction SMILES: [Cl-].[CH3:2][CH:3]1[NH2+:8][CH:7]([CH3:9])[CH2:6][O:5][CH2:4]1.Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>>[CH3:9][CH:7]1[N:8]([CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:18])[CH:3]([CH3:2])[CH2:4][O:5][CH2:6]1
Reactant: CC1COCC(C)[NH2+]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [Cl-]
Product: CC1COCC(C)N1CCN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared by a similar method to Preparation 6 from 3,5-dimethyl-1,4-oxazinan-4-ium chloride [see Preparation 10] and N(2-bromoethyl) phthalimide. The crude produce was purified by column chromatography on silica gel eluting with a solvent system of 8:1, by volume, hexane:ethyl acetate to afford 2-[2-(3,5-dimethylmorpholino)ethyl]-1H-isoindole-1,3(2H)-dione (455 mg) as an oil.