Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[N:10]([CH2:40][CH:41]=[CH2:42])[C:11]1[C:16](=O)[N:15]2[C@H:18]([C:24](N(C(OC(C)(C)C)=O)C3C=CC=CC=3)=[O:25])[CH2:19][C@@H:20]([CH2:21][CH:22]=[CH2:23])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.[Li+].[OH-:47].[O-:48]S([O-])=O.[Na+].[Na+]>C1COCC1.O.O>[CH2:21]([C@H:20]1[C:14]2=[N:13][CH:12]=[C:11]([N:10]([CH2:40][CH:41]=[CH2:42])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:43])[C:16](=[O:47])[N:15]2[C@H:18]([C:24]([OH:48])=[O:25])[CH2:19]1)[CH:22]=[CH2:23]
Reactant: [OH-]
Reactant: O=S([O-])[O-]
Reactant: C=CC[C@@H]1C[C@@H](C(=O)N(C(=O)OC(C)(C)C)c2ccccc2)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H]1C[C@@H](C(=O)O)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 28c (311 mg, 0.532 mmol) in 5 mL THF/H2O (4:1) at 0° C., were added 30% H2O2 (0.241 mL, 2.13 mmol) and IM LiOH (0.851 mL, 0.851 mmol). The mixture was stirred at 0° C. for 2 h, then Na2SO3 and 10 mL H2O were added. The organic solvent was evaporated under a stream of nitrogen. The precipitate was filtered and rinsed with H2O and 0.1 N NaOH. The combined aqueous filtrate was acidified with conc. HCl, then extracted with EtOAc (3×). The combined organic extract was washed with brine, dried (Na2SO4), and concentrated to afford 208 mg (96%) of 28d. MS (ESI) 410.3 (M+H+), 432.3 (M+Na+), 408.2 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:25]1[CH:30]=[CH:29][C:28](SC)=[CH:27][CH:26]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1.[CH3:34][N+]1([O-])CCOCC1.[S:42](S([O-])=O)([O-:45])(=O)=[O:43].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:25]1[CH:30]=[CH:29][C:28]([S:42]([CH3:34])(=[O:45])=[O:43])=[CH:27][CH:26]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: COC(=O)C(Cc1cccc(-c2cc(C(C)C)cc3cccnc23)c1)c1ccc(SC)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cccc(-c2cc(C(C)C)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of 3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-(4-methylsulfanyl-phenyl)-propionic acid methyl ester from Step 1 (1.05 g, 2.3 mmol), NMO (655 mg, 4.85 mmol) and OsO4 (4%, H2O, 1 mL, 0.16 mmol) in THF (20 mL) was stirred 18 h at 21° C. The resulting reaction mixture was diluted with a sodium metabisulfite solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 80:20) provided the 3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=2)[NH:6][CH:5]=1.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(Cl)Cl>CN(C=O)C.O>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=2)[N:6]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCc1cnc2[nH]cc(Br)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3nc(CNC(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.8 %

Procedure:
A flask was charged with NaH (60 wt % in mineral oil, 0.025 g, 0.64 mmol) in DMF (2.0 mL). The suspension was cooled to about 0° C., followed by the addition of a solution of tert-butyl (7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (0.16 g, 0.49 mmol) in DMF (2.0 mL). The mixture was stirred at about 0° C. for about 10 min and then at rt for about 20 min. The mixture was cooled to about 0° C. followed by the addition of a solution of TsCl (0.112 g, 0.587 mmol) in DMF (1.0 mL). The mixture was stirred at 0° C. for about 20 min and warmed to rt and stirred for about 1 h. To the mixture were added DCM (10 mL) and water (10 mL). The organic layer was isolated and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. EtOAc (10 mL) and heptane (10 mL) were added and then the mixture was concentrated under reduced pressure to give tert-butyl (7-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (0.24 g, 91%): LC/MS (Table 2, Method c) Rf=1.59 min; MS m/z 481 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:15])[CH3:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)[C@@H](N)C(C)(C)C
Reaction time: 16 h
Yield: 303.5 %

Procedure:
To a solution of (1(S)-acetyl-2,2-dimethylpropyl)carbamic acid-tert-butyl ester (700 mg, 2.55 mmol) in dichloromethane (10 mL) at 0° C. was added trifluoroacetic acid (5 mL). The reaction was left at <5° C. for 16 hours before the solvents were removed in vacuo to give a bright yellow oil. The residue was dissolved in methanol (30 mL) and was treated portionwise with Dowex 1X8-400 basic resin until pH 9. Filtration and removal of the solvents in vacuo gave the title compound as a pale yellow oil (˜1.0 g, >100%, residual water). The material was used without further purification.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:36])[CH2:7][C:8]1[C:9](=[O:35])[N:10]=[C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=3)=[CH:19][CH:18]=2)[NH:12][CH:13]=1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:6]4[O:36][C:1]([CH3:2])=[N:4][N:5]=4)[C:9](=[O:35])[N:10]=3)=[CH:22][CH:21]=2)=[CH:25][C:26]=1[C:31]([F:34])([F:32])[F:33]
Reactant: CC(=O)NNC(=O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1nnc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)o1
Temperature: 130 °C
Yield: 39.5 %

Procedure:
To a solution of N′-acetyl-2-(2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-4-oxo-1,4-dihydro-5-pyrimidinyl)acetohydrazide (26 mg, 0.050 mmol) in THF (5 mL) was added Burgess reagent (17.71 mg, 0.074 mmol). The mixture was heated with a microwave reactor at 130° C. for 0.5 h. Purification via MDAP then afforded the title compound (10 mg, 9.8% yield). LCMS: rt=3.38 min, [M+H+]=507
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH3:14])[C:8]2=[O:15])=[C:4]([Cl:18])[CH:3]=1.[CH:19]1([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27](B4OC(C)(C)C(C)(C)O4)[CH:28]=3)[C:23]2=[O:40])[CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Cl:18][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:40])[N:22]([CH:19]2[CH2:21][CH2:20]2)[CH2:30]3)[CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH3:14])[C:8]1=[O:15]
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: CCN1C(=O)CN(Cc2ccc(Br)cc2Cl)C1=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2Cl)C1=O
Yield: 33.6 %

Procedure:
1-(4-Bromo-2-chlorobenzyl)-3-ethylimidazolidine-2,4-dione (2C5) (0.106 mmol, 35 mg), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (106 mmol, 31.6 mg), tris(dibenzylidineacetone)dipalladium (0.005 mmol, 4.8 mg), tricyclohexylphosphine (0.013 mmol, 3.6 mg) and potassium phosphate (0.317 mmol, 67 mg) were dissolved in dioxane (2 ml) and water (1 ml) and the mixture was heated at 120° C. in the microwave for 30 min. The sample was concentrated and partitioned between DCM and water and the organic layer collected and dried using a hydrophobic fritted tube before concentration. Purification using basic semi-prep HPLC afforded 1-(2-chloro-4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-3-ethylimidazolidine-2,4-dione (Example 2a) 15.1 mg (33%); 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 1H) 7.62 (m, 2H) 7.56 (s, 1H) 7.51 (d, 1H) 7.43 (d, 1H) 4.76 (s, 2H) 4.39 (s, 2H) 3.85 (s, 2H) 3.61 (q, 2H) 2.98 (m, 1H) 1.25 (t, 3H) 0.96-89 (m, 4H); LCMS m/z (M+H) 424.0.
Reaction SMILES: OC1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:3]1[NH:12]C(C)=O.[OH:16][CH:17]1O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]1O.C(OC)#N>>[CH2:3]([NH2:12])[CH:4]([OH:5])[CH:6]([OH:7])[CH:8]([OH:9])[CH:10]([OH:11])[CH2:17][OH:16]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: COC#N
Product: NCC(O)C(O)C(O)C(O)CO

Procedure:
1H NMR of IV, Na-salt (500 MHz, D2O, 2 mM NaHCO3, 30° C.): δ=5.473 (m, 2 —CH═CH— of DOPE), 5.328 (m, OCH2CHCH2O of DOPE), 4.574 and 4.473 (m, HA: H-1 of GlcNAc, H-1 of GlcA; CO—OCHCHCH2 of DOPE), 4.246 (dd, J=12.3 Hz, J=6.8 Hz, CO—OCHCHCH2 of DOPE), 4.027 (t, J=5.7 Hz, POCH2CH2N of DOPE), 3.95-3.34 (HA: H-2+H-6 of GlcNAc, H-2+H-5 of GlcA; POCH2CHCH2 of DOPE), 2.413 (m, 2 CH2COO of DOPE), 2.302 (m, 2 CH2CON), 2.049 (m, 2 CH2CH═CHCH2 of DOPE), 2.039 (m, NCOCH3 of GlcNAc), 1.630 (m, 2 CH2CH2CON and 2 CH2CH2COO of DOPE), 1.306 (m, —CH2— of DOPE), 0.892 (˜t, 2 CH3 of DOPE) ppm.
Reaction SMILES: F[C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1C=CC=C(C#N)C=1O>>[C:15]([C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:14]
Reactant: NCC1CNc2cccc(F)c2O1
Reactant: N#Cc1cccc(N)c1O
Product: N#Cc1cccc2c1OC(CN)CN2

Procedure:
This compound is obtained using the same reaction sequence and the same experimental conditions as those used for the synthesis of intermediate 2b but replacing 2-amino-6-fluorophenol with 2-amino-6-cyanophenol. The title compound of formula (2f) is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[NH:13][N:12]=[C:11]([C:14]2[N:15]([CH2:25][CH3:26])[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.COC(N1C=CN=C1)=O>C(Cl)Cl.C(OCC)(=O)C.OS([O-])(=O)=O.[Na+]>[CH3:1][O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[NH:13][N:12]=[C:11]([C:14]2[N:15]([CH2:25][CH3:26])[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH:10]=1
Reactant: CCn1nc(-c2ccccc2)cc1-c1cc(CNC(=O)OC(C)(C)C)[nH]n1
Agent: COC(=O)n1ccnc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(-c2ccccc2)cc1-c1cc(CNC(=O)OC)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature solution of the above-prepared (2′-ethyl-5′-phenyl-1H,2′H-[3,3′]bipyrazolyl-5-ylmethyl)-carbamic acid tert-butyl ester (25 mg, 68 μmoles) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL, excess). The resulting solution was stirred at room temperature for one hour, then concentrated and azeotroped with acetonitrile (3×) in vacuo. To the resulting crude deprotection product in acetonitrile was added triethylamine, then 1-methoxycarbonyl imidazole (26 mg, 204 μmoles) and the mixture was heated to 90° C. for two hours. The reaction was then cooled to room temperature, diluted with ethyl acetate and 1 M NaHSO4, and stirred vigorously for 20 minutes. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): 7.87 (d, 2H); 7.41 (dd, 2H); 7.37 (dd, 1H); 6.75 (s, 1H); 6.42 (s, 1H); 5.30 (dd, 1H); 4.68 (q, 2H); 4.40 (d, 2H); 3.73 (s, 3H); 1.51 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:17]=[C:12]([CH3:11])[CH:13]=[CH:14][CH:15]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: COc1cc(Br)ccc1O
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxyphenol (1.0 g, 0.0049 mol), 3-methylbenzeneboronic acid (1.7 g, 0.012 mol), TEA (4.1 mL, 0.030 mol), cupric acetate (1.4 g, 0.0079 mol) and DCM (50 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.31 (s, 3H), 3.83 (s, 3H), 6.68-6.77 (m, 2H), 6.82 (d, J=8.34 Hz, 1H), 6.87 (d, J=7.58 Hz, 1H), 7.03 (dd, J=8.46, 2.15 Hz, 1H), 7.11 (d, J=2.27 Hz, 1H), 7.17 (t, J=7.83 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8](C(C)(C)C)[CH:7](O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)=O>[Br:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N1C(O)c2cccc(Br)c2S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Product: O=S1(=O)NCc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
7-bromo-2-(1,1-dimethylethyl)-2,3-dihydro-1,2-benzisothiazol-3-ol 1,1-dioxide (1.4 g, 4.4 mmol) was treated with formic acid (10 mL). The reaction was stirred at ambient temperature over 18 h, concentrated in vacuo and dissolved in methanol (10 mL). The mixture was cooled to 0° C. and treated with sodium borohydride (0.17 g, 4.4 mmol) in small portions over 20 min. The cooling bath was removed and the resulting reaction mixture stirred at ambient temperature over 18 h. The work-up consisted of slowly quenching the reaction mixture with ice, dilution with water and extraction with ethyl acetate. Drying over sodium sulfate and concentrating under reduced pressure provided the crude product that was purified by a plug of silica gel (ethyl acetate/hexane, 1:4) to afford the desired 7-bromo-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (0.6 g, 60% over 2 steps). 1H NMR (CD3OD): δ 4.40 (s, 2H), 7.53 (m, 2H), 7.70 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH2:11])(=[O:10])[CH:8]=[CH2:9].[CH2:12]=[O:13]>O>[OH:13][CH2:12][NH:11][C:7](=[O:10])[CH2:8][CH2:9][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=CC(N)=O
Reactant: C1COCCN1
Reactant: C=O
Solvent: O
Product: O=C(CCN1CCOCC1)NCO
Temperature: 50 °C

Procedure:
Morpholine (348 g) was added over a period of 5 minutes to an aqueous solution of acrylamide (54%; 522 g). External cooling was applied to maintain the temperature of the mixture below 80° C. After 2h, water (394 g) and paraformaldehyde (120 g) was added to the cooled solution. After warming to 50° C., an exothermic reaction caused the temperature to rise to 60° C. and after holding at this temperature for a further 2h, the solution of N-hydroxymethyl-morpholine propanamide thus formed was transferred to a stainless steel reaction vessel and quaternised with methyl chloride gas at 50 p.s.i. for 3h at 80° C. This product was assayed by chloride titration and found to be 55% w/w quaternised intermediate (I).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 28 g of 4-nitrophenol, 36 g of ethyl 2-bromopropionate, 27.6 g of potassium carbonate and 500 ml of butanone was stirred and refluxed for 17 hours. The resulting mixture was diluted with 500 ml of water and extracted with ether. The extract was concentrated in a rotary evaporator and the residue was recrystallized from ether-hexane to give ethyl 2-(4-nitrophenoxy)propionate (1D), as a yellow solid, m.p.: 55-56° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Al]>O.CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 190 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
An oven-dried 20 mL microwave tube was charged with 4-fluoronitrobenzene (0.752 mL, 7.02 mmol), 4-phenylpiperidine (1.166 g, 7.02 mmol), and potassium carbonate (0.970 g, 7.02 mmol) under nitrogen, anhydrous DMSO (7 mL) was added, the tube was sealed with an aluminum crimp cap, and heated in a microwave reactor (Personal Chemistry, 300 W, 2.4 bar) at 190° C. for 10 minutes. TLC (SiO2, 5% EtOAc/hexanes) showed complete reaction. The reaction was poured into water (50 mL), stirred for 5 minutes, and vacuum filtered in a Büchner funnel. The collected yellow solids were washed with water (2×10 mL) and Et2O (5 mL), and the bright yellow solid was dried in vacuo to provide the title compound (1.712 g, 6.06 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 1.73-1.90 (m, 2H), 2.00 (d, J=13.34 Hz, 2H), 2.73-2.86 (m, 1H), 3.02-3.17 (m, 2H), 4.10 (d, J=13.23 Hz, 2H), 6.87 (d, J=9.43 Hz, 2H), 7.23 (t, J=7.75 Hz, 3H), 7.33 (t, J=7.43 Hz, 2H), 8.14 (d, J=9.33 Hz, 2H); MS (ESI+) m/z 283 (M+H)+.
Reaction SMILES: [ClH:1].CN([CH2:5][CH:6]1[CH2:18][CH2:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:7]1=[O:19])C.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.Cl>O>[ClH:1].[CH3:20][C:21]1[N:22]([CH2:5][CH:6]2[CH2:18][CH2:17][C:9]3[O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[C:7]2=[O:19])[CH:23]=[CH:24][N:25]=1
Reactant: Cc1ncc[nH]1
Reactant: CN(C)CC1CCc2oc3ccccc3c2C1=O
Agent: Cl
Solvent: O
Product: Cc1nccn1CC1CCc2oc3ccccc3c2C1=O
Yield: 15.5 %

Procedure:
A stirred mixture of 2-[(dimethylamino)methyl]-3,4-dihydro-1(2H)-dibenzofuranone hydrochloride (1.00 g), 2-methylimidazole (1.47 g) and water (25 ml) was heated under reflux for 20 h. The cooled mixture was acidified to pH 1 with aqueous 2M hydrochloric acid and extracted with ethyl acetate (2×50 ml; discarded). The aqueous layer was basified to pH 8 with aqueous saturated sodium bicarbonate, extracted with ethyl acetate (5×40 ml), and the combined organic extracts were washed with water (50 ml). The organic layer was dried and evaporated, and the residue was crystallised from ethyl acetate to give the free base of the title compound (176 mg). Evaporation of the mother liquors afforded a further quantity of the free base of the title compound (370 mg). A portion of this solid (166 mg) was treated with ethyl acetate (40 ml), filtered, and concentrated to ca. 10 ml. The solution was acidified to pH 1 by the addition of ethanolic hydrogen chloride, and the precipitate was collected to give the title compound (171 mg), m.p. 217°-222°.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=1)[CH2:3][CH3:4].[C:22]([O:26][C:27](=[O:33])[NH:28][CH2:29][CH2:30][CH:31]=O)([CH3:25])([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:22]([O:26][C:27](=[O:33])[NH:28][CH2:29][CH2:30][CH2:31][NH:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=1)[CH2:3][CH3:4])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
2-(1-Amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 300 mg, 0.94 mmol) and (3-oxo-propyl)-carbamic acid tert-butyl ester (J. Med. Chem. 1985, 28, 317–323, 982 mg, 5.64 mmol) were dissolved in CH3OH (20 mL) and stirred for 1 h at 25° C. The mixture was then treated with NaBH(OAc)3 (1.19 g, 5.64 mmol) and stirred for 18 h. The reaction mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 30×250 mm column affording the desired compound (300 mg, 73%) as a colorless film: 13C NMR (CD3OD, 100 MHz) δ 160.8, 160.49, 154.89, 144.86, 136.06, 129.09, 128.04, 126.52, 121.79, 117.72, 115.16, 111.60, 109.53, 79.20, 57.97, 44.32, 27.38, 26.55, 25.5, 7.58; LC/MS (ESI+) 440 (M++H).
Reaction SMILES: C(O/C=C\[C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:7]=1)C.I([O-])(=O)(=O)=O.[Na+].[O:36]1CCOC[CH2:37]1>O.[Os](=O)(=O)(=O)=O>[CH:37]([C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:7]=1)=[O:36]
Reactant: C1COCCO1
Reactant: CCO/C=C\c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C=O)nc(C(F)(F)F)n2)CC1
Reaction time: 24 h

Procedure:
tert-Butyl 4-{[6-[(Z)-2-ethoxyvinyl]-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidine-1-carboxylate (0.80 g, 1.9 mmol, from Step 2) was dissolved in 1,4-dioxane (56 mL) and water (14 mL), then sodium periodate (1.2 g, 5.8 mmol) was added followed by osmium tetraoxide (4 wt % in water, 0.424 mL, 0.0666 mmol). After stirring for 24 hours, the reaction mixture was partitioned between water and EtOAc, the phases were separated and the aqueous phase was extracted with additional EtOAc. The combined organic extracts were washed with water, then sat'd NaCl, dried over Na2SO4, filtered and solvent removed in vacuo. The crude product was used in the next reaction without purification. LCMS (M+H)+: 375.0; (M+H2O+H)+: 393.0.