Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[CH:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.C([O-])([O-])=O.[K+].[K+].[NH:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]1.O>C1COCC1.C(OCC)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([CH:7]([N:27]2[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:28]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: O=S(=O)(OC(c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(Cl)nc2)C(F)(F)F)C1
Yield: 74.1 %

Procedure:
A solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.55 g, 1.60 mmol), K2CO3 (0.33 g, 2.40 mmol), and (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.42 g, 2.24 mmol) in THF (8 mL) was stirred at 50° C. for 20 hours. Water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate) to give tert-butyl (3S)-1-(1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (0.45 g, 74.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].B.C1COCC1>O1CCCC1>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Step A To a solution of 3-methyl-3-phenylbutanoic acid (ChemBridge) (4.46 g, 25 mmol) in anhydrous tetrahydrofuran (150 mL) at 0° C. was added a tetrahydrofuran solution (1 M) of BH3.THF (Aldrich, 50 mL, 50 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated to give 3-methyl-3-phenyl-butan-1-ol as a colorless oil (4.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5].CO.[H][H]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5]
Reactant: [H][H]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 11 h

Procedure:
8.00 g (0.023 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide in 75 g of toluene and 8 g of methanol were admixed with 0.24 g (0.05 mol %) of 2.4% Pt/2.4% Pd/C and hydrogenated with 5 bar of hydrogen with stirring at 70° C. After 11 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 6.48 g (90%) of the title compound in the form of a solid (m.p.: 147-149° C.).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](CCO)=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1>N1C=CC=CC=1.CCOC(C)=O>[C:5]([O:4][CH2:1][CH2:2][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([NH2:8])=[CH:10][C:11]=1[N+:22]([O-:24])=[O:23])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])c(CCO)c2ccccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCc1c([N+](=O)[O-])cc(N)c2ccccc12
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Acetic anhydride (4.0 mL, 42.39 mmol) was added to a solution of 2-[4-amino-2-nitronaphthalen-1-yl]ethanol (3.3 g, 14.21 mmol) in dry pyridine (33 mL) at room temperature and stirred for 2 hr. The mixture was diluted with AcOEt (100 mL). The organic layer was washed with H2O (30 mL), saturated aqueous NaHCO3 (30 mL), saturated aqueous NaCl (30 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (33% AcOEt-Petroleum ether) afforded 2-[4-amino-2-nitronaphthalen-1-yl]ethyl acetate (1.0 g, 26%) as an orange solid.; mp 108-110 ° C.; 1H NMR (CDCl3, 500 MHz) δ 8.33 (d, 8.5, 1H), 7.84 (dd, 8.0, 0.5, 1H), 7.70 (dt, 7.5, 0.5, 1H), 7.64 (dt, 8.5, 1.5, 1H), 7.11 (s, 1H), 4.44 (t, 8.0, 2H), 4.38 (brs, 2H), 3.49 (t, 8.0, 2H), 2.06 (d, 0.5, 3H); FABMS (NBA) m/z 274 (M+), IR (neat) 3381, 1728, 1636, 1589, 1516, 1469, 1437, 1342, 1241, 1041, 754 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:16])[CH2:13][CH2:14]Cl)[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[C:8](=[O:21])[NH:7][C:6]=2[CH:22]=1.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:16])[CH2:13][CH2:14][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]3[CH3:23])[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[C:8](=[O:21])[NH:7][C:6]=2[CH:22]=1
Reactant: CC1CCCCN1
Reactant: O=C1Nc2cc(Cl)ccc2N(C(=O)CCCl)c2ccccc21
Solvent: CC(C)O
Product: CC1CCCCN1CCC(=O)N1c2ccc(Cl)cc2NC(=O)c2ccccc21

Procedure:
11.5 gm (0.034 mol) of 8-chloro-5-(3-chloro-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (m.p. 235°-237° C.) and 16.2 gm (0.16 mol) of 2-methyl-piperidine were refluxed in 100 ml of isopropanol for 1 hour. The reaction mixture was then evaporated in vacuo, the residue was dissolved in chloroform, the solution was washed with sodium hydroxide, and the organic solvent was distilled off in vacuo. The residue was recrystallized from xylene.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=O)=O)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][S:27][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)C(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N)[C@H](CSC(C)(C)C)C1
Reaction time: 3 h
Yield: 104.4 %

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(tert-butylsulfonylmethyl)cyclohexylcarbamate (7.3 g) in MeOH (80 mL) was charged with 10% Pd/C, Degussa (5.0 g). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 3 h and then filtered and concentrated to provide tert-butyl (1R,3R,4S)-4-amino-3-(tert-butylthiomethyl)cyclohexylcarbamate (5.0 g). MS (ES+)=349.3 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[CH2:20][CH3:21])C.[BH4-].[Li+]>O1CCCC1>[Br:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH2:20][CH3:21])[CH:15]=1)[NH:12][C:11]1[C:6]([CH2:5][CH2:4][OH:3])([CH2:22][CH3:23])[O:7][CH2:8][CH2:9][C:10]2=1
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(CC)cc(Br)cc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc2c3c([nH]c12)C(CC)(CCO)OCC3
Temperature: 90 °C
Yield: 81.7 %

Procedure:
To a solution of (6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (5.2 g, 13.2 mmol) in tetrhydrofuran at room temperature under nitrogen was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was heated at 90° C. (oil bath) for 5 hours. After cooling to room temperature, it was quenched with 5% hydrochloric acid solution until the excess lithium borohydride was destroyed. Water was added and the mixture extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50% ethyl acetate/hexane) to give the title compound (3.80 g, 82% yield). 1H NMR (CDCl3) δ8.07 (s, 1H), 7.64 (d, 1H), 7.26 (d, 1H), 4.17 (m, 2H), 3.86 (m, 2H), 2.94 (m, 3H), 2.87 (dt, 1H), 2.76 (t, br, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.49 (t, 3H), 1.08 (t, 3H). ES-MS (m/z) 352 [M+1]+, 350 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:35]([N:37]1[CH:41]=[C:40]([S:42]([NH2:45])(=[O:44])=[O:43])[C:39]([CH3:46])=[N:38]1)[CH3:36]>CN(C)C1C=CN=CC=1.C(OCC)C.CCCCCC.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:45][S:42]([C:40]3[C:39]([CH3:46])=[N:38][N:37]([CH2:35][CH3:36])[CH:41]=3)(=[O:43])=[O:44])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCn1cc(S(N)(=O)=O)c(C)n1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CCn1cc(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c(C)n1
Reaction time: 0.25 h

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-c]pyridine-2-carboxylic acid (63 mg, 0.24 mmol, prepared as described in Example 1 Step C) in a 1:1 mixture of t-butanol (5 mL) and dichloromethane (5 mL) was added 4-(dimethylamino)pyridine (88 mg, 0.71 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 0.60 mmol). The reaction mixture was stirred for 15 min, after which time 1-ethyl-3-methyl-1H-pyrazole-4-sulfonamide (41 mg, 0.22 mmol, the product of Step A) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (100 mL) was added and the mixture was washed with 1 N hydrochloric acid (3×50 mL). The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford a solid. The solid was suspended in a mixture of diethyl ether and hexane, filtered, and dried to afford 25 mg of the title compound, a compound of the present invention, as a solid, m.p. 189-190° C. 1H NMR (CDCl3) δ 9.85 (br s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.53 (s, 1H), 4.14 (q, 2H), 2.51 (s, 3H), 1.51 (t, 3H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C@H:21]([CH2:22][CH2:23][OH:24])[O:20][CH2:19][CH2:18][C:17]=2[CH:25]=1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>CN(C)C=O>[Si:1]([O:24][CH2:23][CH2:22][C@H:21]1[C:16]2[CH:15]=[CH:14][C:13]([Br:12])=[CH:25][C:17]=2[CH2:18][CH2:19][O:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1M solution of tert-butyldimethylsilyl chloride in dichloromethane (30 mL, 30 mmol) was added dropwise under nitrogen to an ice/water-cooled solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (6.7 g, 24.4 mmol), diisopropylethylamine (6.7 g. 51.8 mmol) and dimethylaminopyridine (0.32 g, 2.5 mmol) in dry dimethylformamide (70 mL). After stirring overnight at room temperature, the mixture was quenched with ice/water and extracted with ether (2×). The combined organic extracts were washed with water (5×), dried (MgSO4) and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (0:100 to 10:90), to give the title compound as oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]3[O:40][CH:39]=[CH:38][C:37]=3[CH:41]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:40]1[C:36]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[CH:4][CH:3]=3)=[CH:41][C:37]=2[CH:38]=[CH:39]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
In a microwave vial, a mixture of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (322 mg, 0.77 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (208 mg, 0.85 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (32 mg, 0.04 mmol) in 2M aq potassium carbonate solution (1.5 mL, 3 mmol) and 1,4-dioxane (3 mL) was stirred at 100° C. for 3 h. The reaction was cooled to room temperature. The layers were separated and an aliquot of the basic potassium carbonate aqueous layer was analyzed by LCMS and showed that desired product was present. The aqueous layer was acidified using 1N aq HCl solution to pH˜6 by pH paper and was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, 0-10% MeOH/CH2Cl2, SF15-12 g, 20 min) followed by another purification (100% EtOAc for 10 min and then 0-8% MeOH/CH2Cl2 for 15 min) and finally subsequent purification by silica gel chromatography (Analogix IF280, SF15-4 g, Solvent A=EtOAc; Solvent B=10% MeOH/CH2Cl2; Gradient: 100% A for 10 min then ramped to 100% B over 20 min (i.e. 0-100% of B/A) provided the title product as a pale yellow solid (232 mg, 0.53 mmol, 69%). MS(ES)+ m/e 428.9 [M+H]+.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][CH2:15][CH:16]([OH:19])[CH:17]=[CH2:18].O>CN(C=O)C>[Br:14][CH2:15][CH:16]([O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:17]=[CH2:18]
Reactant: C=CC(O)CBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(CBr)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h

Procedure:
Imidazole (2.25 g) and tert-butyldimethylsilylchloride (4.75 g) were added to a solution of 1-bromo-3-buten-2-ol (4.5 g) in DMF (30 ml) at room temperature. The mixture was stirred at the same temperature for 16 hours, and water was added thereto, followed by extraction with hexane. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, oily substance (7.0 g).
Reaction SMILES: [CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6]C)[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].C[C@H]1[C@H](C)O[C@@H](OC)C[C@@H]1NC(=O)C(F)(F)F.C(Cl)(Cl)Cl>CO.[Pd].C(O)(=O)C.O>[CH3:1][C@H:2]1[C@H:9]([CH3:10])[O:8][C@@H:5]([OH:6])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C=C1[C@@H](NC(=O)C(F)(F)F)C[C@H](OC)O[C@H]1C
Agent: [Pd]
Agent: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@@H](C)[C@H](C)O1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@@H]1[C@@H](NC(=O)C(F)(F)F)C[C@H](O)O[C@H]1C

Procedure:
Stereoselective reduction of 0.5 g of the intermediate VIII (prepared as described in Example 1) in 40 ml of methanol in the presence of 0.5 g of 20% palladium on charcoal under a pressure of 20 atmospheres gave, in quantitative yield, methyl 2,3,4,6-tetradeoxy-4-C-methyl-3-trifluoroacetamido-L-arabino-hexopyranoside (XI) as a white solid: m.p. 132°-134° C., [α]D23° -82° (c=0.5, CHCl3). The PMR spectrum (CDCl3) showed absorptions at: 0.90 (d, CH3 --C--4), 1.23 (d, CH3 --C--5), 1.26 (m, H--C--4), 3.42 (s, OCH3), 3.70 (dq, H--C--5), 4.20 (m, H--C--3) and 4.87 δ (dd, H--C--1). A solution of 0.385 g, 1.5 mmol of XI in 7 ml of acetic acid and 28 ml of water was heated at 100° C. for two hours and then evaporated to dryness to give, in quantitative yield, 2,3,4,6-tetradeoxy-4-C-methyl-3-trifluoroacetamido-α-L-arabino-hexopyranose (XII) as a white solid: m.p. 158°-159° C., [α]D23° -62° (c=0.5, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][N:3]=1.[CH3:24][C:25]1[N:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:32][CH2:31][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[N:30]=3)=[O:14])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][N:3]=1
Reactant: Cc1cccc(CN)n1
Reactant: Nc1ncc(C2CCOCC2)cc1-c1ccc(C(=O)O)c(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(CNC(=O)c2ccc(-c3cc(C4CCOCC4)cnc3N)cc2F)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a vial were charged with 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acid (20 mg, 0.063 mmol), (6-methylpyridin-2-yl)methanamine (11.6 mg, 0.095 mmol), DIEA (28 μL, 0.158 mmol), PyBOP (65.8, 0.126 mmol) and DMF (0.5 mL). The mixture was stirred at room temperature for 10 min. The reaction mixture was then purified by preparative HPLC, and product fractions were combined, frozen and lyophilized to afford 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-((6-methylpyridin-2-yl)methyl)benzamide as a white powder. LCMS (m/z) 421.3 (MH+) 0.41 min. 1H NMR (DMSO-d6) δ ppm 8.99 (d, J=3.1 Hz, 1H), 7.95-7.83 (m, 3H), 7.79 (t, J=7.6 Hz, 1H), 7.53 (d, J=11.7 Hz, 2H), 7.44 (dd, J=8.0, 1.4 Hz, 1H), 7.24 (d, J=7.4 Hz, 2H), 4.60 (d, J=5.5 Hz, 2H), 4.02-3.88 (m, 2H), 3.40 (td, J=11.2, 2.7 Hz, 3H), 2.88-2.71 (m, 1H), 2.51 (br. s., 3H), 1.82-1.58 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCOC(C)=O>CN(C=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1cc(-c2ncc[nH]2)ccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnc2-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
1-Fluoro-4-nitro-benzene (80.2 g, 0.57 mmol) is dissolved in DMF (550 mL) and to that solution is added K2CO3 (157.0 g, 1.14 mmol). To that solution is added 4-(1H-imidazol-2-yl)-pyridine (55.0 g, 0.38 mmol) and the reaction is heated at 100° C. for 18 h. The solution is then cooled to RT and EtOAc (1.5 L) and water (2.0 L) are then added and the suspension is vacuum filtered. The resulting solid was then purified by column chromatography (EtOAc) to afford 4-[1-(4-nitro-phenyl)-1H-imidazol-2-yl]-pyridine as a brown solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([Cl:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CC(C)([O-])C.[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>CS(C)=O>[CH2:1]([C:4]1[N:8]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([Cl:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1nc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.27 g (10.0 mMol) of 2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazole are dissolved in 50 ml of dimethylsulphoxide, 1.23 g (11.0 mMol) of potassium tert.butoxide are added in batches thereto and the resulting mixture is stirred for 30 minutes at ambient temperature. Then 3.38 g (11.0 mMol) of methyl 4'-bromomethyl-biphenyl-2-carboxylate are added in batches thereto. The reaction mixture is then stirred for 3 hours at ambient temperature, stirred into ice water and extracted 3 times with ethyl acetate. The combined organic phases are washed with saline solution and dried over magnesium sulphate. Then the solvent is removed in vacuo and the residue is chromatographed on silica gel (particle size 0.032-0.063 mm), using as eluant first petroleum ether and then mixtures of petroleum ether and ethyl acetate of increasing polarity (9:1, 4:1 and 7:3). The uniform fractions are combined and evaporated down.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1([CH3:28])[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[C:14]([CH3:21])[CH:13]=2)[C@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:5][C:6]1([CH3:28])[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:3])=[O:17])=[C:14]([CH3:21])[CH:13]=2)[C@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)ccc1C(=O)Cl
Temperature: 40 °C

Procedure:
Thionyl chloride (0.287 mL, 3.93 mmol) was added to a solution of (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoic acid (0.128 g, 0.393 mmol) in DCM (2.5 mL) and the mixture was heated at 40° C. for 1 hour. The reaction mixture was concentrated to afford (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoyl chloride as a yellow-orange solid. The yellow-orange solid was dissolved in DCM (2.5 mL) and the solution was cooled to 0° C. 1,5-Naphthyridin-4-amine (commercially available from Astatech Inc., Bristol, Pa.) (0.063 g, 0.433 mmol) and N,N-diisopropylethylamine (0.144 mL, 0.826 mmol) were added and the ice bath was removed. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated and the residue was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 50-100% EtOAc-hexane) to afford (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methyl-N-(1,5-naphthyridin-4-yl)benzamide (0.070 g, 0.155 mmol, 39% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 3H), 1.65 (s, 3H), 2.44 (s, 3H), 5.54 (s, 1H), 7.17-7.51 (m, 6H), 7.61 (d, J=2.15 Hz, 1H), 7.67 (d, J=8.51 Hz, 1H), 7.86 (dd, J=8.56, 4.16 Hz, 1H), 8.44 (dd, J=8.56, 1.61 Hz, 1H), 8.54 (d, J=5.09 Hz, 1H), 8.81-9.09 (m, 2H), 10.31 (s, 1H). m/z (ESI) 453 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH:24]([CH3:25])[CH2:23][C:22]2[C:17](=[N:18][C:19]([N:31]3[CH2:36][CH2:35][CH:34]([O:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=4[F:45])[CH2:33][CH2:32]3)=[C:20]([NH:26][CH2:27][CH:28]([F:30])[F:29])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:30][CH:28]([F:29])[CH2:27][NH:26][C:20]1[N:21]=[C:22]2[CH2:23][CH:24]([CH3:25])[NH:15][CH2:16][C:17]2=[N:18][C:19]=1[N:31]1[CH2:32][CH2:33][CH:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[F:45])[CH2:35][CH2:36]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Reaction time: 3 h

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (135 mg, 0.210 mmol) and Pd(OH)2 on carbon (14.7 mg, 0.021 mmol) in THF (1.05 mL) was purged and stirred under hydrogen atmosphere for 3 h. The reaction mixture was filtered through Celite™ and the solvent was removed to give the title compound as a TFA salt (107 mg, 92%).