Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[C:71]([CH:73]=[CH2:74])[CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[C:71]([CH:73]=[CH2:74])[CH:70]=[CH:69][N:68]=4)[C:56]=3[CH3:75])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: C=Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: C=Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.019 g, 0.040 mmol), 2,5-dimorpholinopyridin-3-amine (0.080 g, 0.30 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-vinylpyridin-2-yl)quinoline (0.08 g, 0.25 mmol), Pd2dba3 (0.009 g, 0.010 mmol) and sodium tert-butoxide (0.061 g, 0.63 mmol) in toluene (2.5 mL) at 100° C. for 4.5 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-vinylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (1H, br. s), 8.28 (1H, d, J=5.9 Hz), 7.83 (1H, d, J=2.7 Hz), 7.50-7.58 (2H, m), 7.28 (1H, d, J=2.7 Hz), 7.24 (1H, m), 7.08 (1H, d, J=2.2 Hz), 6.87 (1H, dd, J=5.7, 2.3 Hz), 5.76 (1H, m), 5.41 (1H, dd, 17.8, 1.6 Hz), 3.71-3.76 (4H, m), 3.55-3.60 (4H, m), 3.08 (4H, m), 3.02 (4H, m), 2.40 (3H, s). Mass Spectrum (ESI) m/e=545.2 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20](=[CH2:23])[CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:1]([O:18][CH2:19][C:20](=[CH2:23])[CH:21]=[O:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C=C(C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 2-t-butyldiphenylsilyloxymethyl-2-propene-1-ol (25.5 g, 86.7 mmol), molecular sieves in powder (26 g), N-methylmorpholine-N-oxide (15.3 g, 130 mmol) and tetrapropylammoniumperruthenate (1.5 g, 4 mmol) in anhydrous dichloromethane (400 ml) is stirred overnight at 20° C. Then the reaction mixture is concentrated in vacuo and purified by flash chromatography on silica gel to give the title product (21 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and methyl 3-bromopropionate (0.12 ml, 1.1 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (146 mg, yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][C@H:7]([CH3:12])[C:6]=2[C:13]=1[Cl:14].[C:15](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClC(Cl)C.[OH-].[Na+]>[CH3:15][N:9]1[CH2:8][C@H:7]([CH3:12])[C:6]2[C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: C[C@H]1CNCCc2ccc(Cl)c(Cl)c21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: C[C@H]1CN(C)CCc2ccc(Cl)c(Cl)c21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of (R)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.05 g, 0.20 mmol) in dichloroethane (3 mL) was treated with sodium triacetoxyborohydride (0.073 g, 0.35 mmol) and formaldehyde (0.017 mL, 37% solution in water). This was stirred at 20° C. for 2 h. The reaction was diluted with 15% NaOH and extracted with ethyl acetate (2×10 mL). The organics were dried with MgSO4, filtered and concentrated to give 0.042 g as an oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 3.91-3.88 (m, 1H), 3.28 (ddd, J=15, 12, 2 Hz, 1H), 2.99-2.88 (m, 2H), 2.68 (ddd, J=15, 5, 1 Hz, 1H), 2.36-2.32 (m, 4H), 2.13 (t, J=11 Hz, 1H), 1.27 (d, J=7 Hz, 3H). MS calculated for C12H15Cl2N+H: 243, observed: 243.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([CH:12]=[CH:13][C:14]([OH:16])=O)=[O:11])([OH:3])=[O:2].CC([O-])=O.[Na+]>O(C(C)=O)C(C)=O>[O:16]=[C:14]1[CH:13]=[CH:12][C:10](=[O:11])[N:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: O=C(O)C=CC(=O)NCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O

Procedure:
The acid 14 (4.5 g, 21 mmol) was refluxed in 60 mL of (Ac)2O with NaOAc (1.72 g, 21 mmol) for 3 h. After cooling, the reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to give a deep red oil that was purified by silica gel column chromatography (CHCl3:MeOH/99:1). The maleimide product 15 was isolated as a white solid (1.4 g, 32%). 1H NMR (DMSO-d6): δ 1.18-1.24 (2H, m), 1.45-1.52 (4H, m), 2.18 (2H, t, J=7.5), 3.38 (2H, t, J=7.0), 7.01 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][C:18]1[S:22][C:21](/[CH:23]=[CH:24]/[C:25](Cl)=O)=[CH:20][CH:19]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:25](/[CH:24]=[CH:23]/[C:21]3[S:22][C:18]([CH3:17])=[CH:19][CH:20]=3)=[N:16][C:5]=2[CH:4]=1
Reactant: Cc1ccc(/C=C/C(=O)Cl)s1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccc(C)s1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(5-methyl-2-thienyl)acryloyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from MeOH/n-hexane yielded the titled compound. MW: 437.48; mp: 190.0-191.0° C.; 1H-NMR (DMSO) δ: 8.67-8.63 (1H, m), 8.06 (1H, td, J=7.9, 1.9 Hz), 7.79 (1H, d, J=15.6 Hz), 7.59 (1H, d, J=7.9 Hz), 7.54-7.48 (1H, m), 7.22 (1H, d, J=8.7 Hz), 7.12-7.08 (2H, m), 6.77 (1H, dd, J=8.7, 2.5 Hz), 6.71-6.68 (1H, m), 6.66 (1H, d, J=15.6 Hz), 3.72 (3H, s), 2.33 (3H, s).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][O:5][CH2:1][CH2:2][C:3]#[CH:4])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C1(CO)COC1
Reactant: C#CCCOCC(=O)O
Product: C#CCCOCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(but-3-ynyloxymethyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 2-(but-3-ynyloxy)acetic acid and 3-t-butyl-3-hydroxymethyloxetane using methodology described in Example I
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C@@H:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:12][C@H:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCCCCC[C@@H](C)O
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(C)c([N+](=O)[O-])c1

Procedure:
4-Methyl-3-nitrophenol (Compound 33, Scheme VI) was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-4-(1-methylheptyloxy)-2-nitro- toluene (Compound 34, Scheme VI, Rl =(S)--OCH(CH3)C6H13) as a yellow liquid; Rf [Hexanes/ethyl acetate 99/1]: 0.26; 1H NMR (300 MHz, CDCl3): δ0.87(t, 3H, J=6.6 Hz), 1.16-1.65(m, 12H), 1.70(m, 1H), 2.50(s, 3H), 4.37(m, 1H), 7.02(dd, 1H ,J=2.7 Hz, J=8.5 Hz), 7.19(d, 1H, J=8.5 Hz), 7.47(d, 1H, J=2.7 Hz); 13C NMR (300 MHz, CDCl3): δ13.97, 19.41, 19.63, 22.51, 25.32, 29.14, 31.69, 36.20, 74.72, 111.05, 121.44, 125.12, 133.44, 149.5, 156.77; IR (CHCl3): 3020, 2940, 2850, 1620, 1550, 1525, 1490, 1375, 1300, 1240, 1220, 1110, 1050, 975, 860, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 265(M+ 11), 153(33), 136(100), 112(21), 71(40), 57(70), 51(11), 43(78), 41(66).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.CN(C=O)C.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCCCO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1

Procedure:
1.9 g (10 mmol) of 2,6-dichloro-purine are stirred in 60 ml of butanol and 3 ml of DMF with 8.05 g (50 mmol) of 3-amino-benzotrifluoride at 60° C. for 3 h. On cooling, 2-chloro-6-(3-trifluoromethyl-phenyl-amino)-purine is obtained as a crystalline mass. This is filtered off and dried in vacuo; m.p. 248° C.; FAB-MS: (M+H)+=314; Rf=0.45 (CH2Cl2:methanol=95:5).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[NH2:27])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:27][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)([CH3:28])[CH3:29])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(C)(C)N)cc1
Product: COC(=O)c1ccc(CC(C)(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared as in Example 1a from 3-trifluoromethylphenyl glyoxal (2.0 g) and 2-(4-carbomethoxyphenyl)-1,1-dimethyl ethanamine (2.0 g) and crystallised from hexane m.p. 88°-90°. τ(CDCl3) 8.93 (6H,s), 6.8-8.0 (4H,m+2H replaceable by D2O), 6.1 (3H,s), 5.33 (1H,m), 2.8 (2H,d,J=8 Hz), 2.2-2.6 (4H,m), 2.03 (2H,d,J=8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[C:11]=1[C:12]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2c(Oc3ccc(F)cc3)cc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
4-Fluorophenol (12.05 mg, 0.1075 mmol), methyl 4-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate (40 mg, 0.09774 mmol), and K2CO3 (40.52 mg, 0.29 mmol) were combined in DMF (0.5 mL) and heated at 90° C. for 10 min resulting in complete conversion to methyl 4-[[2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate. NaOH (97.73 μL of 3 M, 0.29 mmol) was added and the reaction heated at 90° C. for 2 hours, then at 50° C. for overnight. Additional NaOH was added [2×NaOH (97.73 μL of 3 M, 0.29 mmol), 6 eq] and the reaction heated at 90° C. for 5 hours. HPLC purification using a gradient of acetonitrile in water (10-99%) with 5 mM HCl as a modifier provided 4-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid (11) as a white solid. ESI-MS m/z calc. 487.06. found 488.3 (M+1)+; Retention time: 1.84 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 11.14 (s, 1H), 7.99 (s, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.48 (s, 1H), 7.36-7.22 (m, 4H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CNCCN(C)C.C([Li])CCC.[I:28]I>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[C:13]=1[I:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: Cc1cncc(NC(=O)OC(C)(C)C)c1
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cncc(NC(=O)OC(C)(C)C)c1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
(5-Methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (255 mg, 1.2 mmol, Example 139: step a) and trimethylethylenediamine (905 μL, 6.0 mmol) were dissolved into THF (4 mL) and cooled to −78° C. To this was added n-Butyllithium (2.5M, 2.4 mL, 6.0 mmol). The reaction was stirred at −78° C. for 30 minutes and then warmed to RT for 30 minutes. Iodine (1.5 g, 6.0 mmol) was dissolved into THF (4 mL) and added to the reaction mixture at −78° C. slowly. The reaction was warmed to RT for 1 hour and the solvents were removed in vacuo. The residue was dissolved into EtOAc and washed with brine and water. The combined organic layers were dried (MgSO4) and solvents were removed in vacuo followed by purification by flash column chromatography (SiO2) (50% EtOAc in hexanes) that yielded the title compound as a yellow solid (55 mg, 14%). 1H-NMR (CDCl3): δ 8.91 (s, 1H), 8.07 (s, 1H), 6.81 (br s, 1H), 2.44 (s, 3H), 1.56 (s, 9H). ESI-MS (m/z): Calcd. for C11H15IN2O2: 335.0 (M+1); found: 334.9.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=O)[CH3:2].[Se](=O)=O.[CH2:25]([NH2:28])[CH2:26][NH2:27].[OH-].[K+]>O1CCOCC1.O.C(O)C>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][C:7]2[CH:20]=[CH:21][C:4]([C:1]3[CH:2]=[N:28][CH:25]=[CH:26][N:27]=3)=[CH:5][C:6]=2[CH2:12][CH2:11]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCN
Reactant: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Agent: O=[Se]=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3cnccn3)cc2CC1
Yield: 25.6 %

Procedure:
To a stirred solution of 7-acetyl-3-(tert-butyloxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (12 g, 42 mmol) in dioxan (60 ml) was added selenium dioxide (4.61 g, 42 mmol) in dioxan (60 ml) and water (15 ml). The mixture was heated under reflux for 18 h., cooled and the solid residue filtered. The filtrate was evaporated in vacuo and the residue azeotroped with toluene to give an orange gum which was dissolved in ethanol and added dropwise to a stirred solution of ethylenediamine (3 g, 50 mmol) in ethanol at 0° C. After the addition was complete, KOH (2.6 g, 46 mmol) was added and the reaction heated under reflux for 3 h. The reaction mixture was then allowed to cool and evaporated in vacuo. The residue was partitioned between water and dichloromethane and the combined organic extracts dried and evaporated in vacuo to give a brown gum. Purification by silica gel chromatography (eluant 20% EtOAc:hexane) gave the title compound as a yellow oil (3.5 g).
Reaction SMILES: [Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([OH:14])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Br:34][CH2:35][C:36](Br)=[O:37].O>C(Cl)Cl>[Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([O:14][C:36](=[O:37])[CH2:35][Br:34])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1O
Reactant: O=C(Br)CBr
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1OC(=O)CBr
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred solution of 1-t-butyl dimethylsilyloxy-3-trifluoroacetamido-2,3,6-trideoxy-L-lyxohexopyranose (81 mg, 0.18 mmol) in CH2Cl2 (2 ml) at 0° C. were added collidine (47 μl, 0.36 mmol), and bromoacetylbromide (24 μl, 0.27 mmol). After 1 hour, the reaction mixture was worked up with CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give the titled compound (76 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N+:16]([O-])=O)(O)[CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:20].[NH4+]>C1COCC1.CO.[Pd].CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:20])[CH:12]([NH2:16])[CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: CCC(O)(Cc1ccc(C(=O)OC)cc1)[N+](=O)[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(N)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 1-(4-methoxycarbonylphenyl)-2-nitro-butan-2-ol (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added 10% palladium on carbon (50 mg) followed by ammonium formate (0.4 g, 5 equivalents). The resulting mixture was stirred at room temperature for 3 hours ten diluted with Et2O, filtered and evaporated in vacuo. Flash column chromatography (SiO2, 15% MeOH in CHCl3) gave erythro 1-(4-methoxycarbonylphenyl)-2-amino-butan-1-ol (0.22 g, 73%).
Reaction SMILES: C([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:14]=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH4+:8].[CH2:21]([O:20][C:16]1[CH:15]=[CH:14][C:13]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:12]2[C:17]=1[C:18](=[O:19])[NH:8][S:9]2(=[O:11])=[O:10])[CH3:22]
Reactant: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(Cc1ccccc1)S2(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)NS2(=O)=O
Yield: 209.8 %

Procedure:
By the method of part D of Example 45 in two successive preparations 2-benzyl-4-ethoxy-7-(t-butoxycarbonylmethoxy) saccharin (0.5 g, 6.5 g) was debenzylated with ammonium formate (0.25 g, 3.66 g) and palladium on carbon (10%, 0.25 g, 2 g) in methanol affording 4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin ammonium salt (0.44 g, 5.63 g), phenylthiomethylation of which with chloromethyl phenyl sulfide (0.2 g, 2.38 g) in dimethylformamide and purification of the combined products (0.46 g, 6.42 g) by column chromatography on silica gel using dichloromethane and dichloromethane-acetone (98:2) as eluants afforded 2-phenylthiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 1.92 g, 40% yield.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:29][NH:30][CH3:31]>C1COCC1.C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[C:13]([N:30]([CH3:31])[CH3:29])=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)C1=CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCOCC2)cc1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (1.0 g, 2.65 mmol) and a saturated solution of dimethylamine in THF (13 ml) in toluene/DMF (2:1; 15 ml) according to method 8b described above.
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][N:5]=1)[CH3:3]>ClC(Cl)C.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][N:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1nccc(=O)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(Cl)Cl
Product: CC(=O)c1nccc(=O)[nH]1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)pyrimidin-4(3H)-one (Intermediate 50, 5 g, 35.71 mmol) in dichloroethane (200 mL), manganese dioxide (31 g, 357.1 mmol) was added. The reaction mixture was heated to 90° C. for 5 h. The reaction mixture was filtered through a celite bed and washed with dichloroethane (60 mL). The filtrate was concentrated to dryness to yield 1.6 g (32.6%) 2-acetylpyrimidin-4(3H)-one.
Reaction SMILES: [C:1]([C:3]1([C:16]2[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>[Ni]>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:2][CH2:1][C:3]1([C:16]2[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:30]
Reactant: COCOc1cccnc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Ni]
Product: COCOc1cccnc1C1(CNC(=O)c2ccc(Cl)cc2Cl)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 4-cyano-4-[3-(methoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate was reduced using Raney nickel and acylated using 2,4-dichlorobenzoyl chloride using the method exemplified in example 8-1 to afford the desired product: tert-butyl 4-{[(2,4-dichlorobenzoyl)amino]-methyl}-4-[3-(methoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate: 1H NMR δ (ppm) (CDCl3): 8.18 (1H, dd, J=1.3, 4.5 Hz), 7.50-7.46 (2H, m), 7.33 (1H, d, J=1.9 Hz), 7.25 (1H, dd, J=8.3, 2.0), 7.15 (1H, dd, J=4.6, 8.3 Hz), 6.70 (1H, m), 5.25 (2H, s), 4.01 (2H, br s), 3.68-3.62 (2H, m), 3.49 (3H, s), 3.44-3.38 (2H, m), 2.75-2.69 (2H, m), 1.66-1.60 (1H, m) 1.46 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cc1F
Yield: 94 %

Procedure:
A solution of 2-fluoro-4-hydroxybenzoic acid (50.0 g) and concentrated sulfuric acid (10 mL) in methanol (700 mL) was stirred at 90° C. for 16 hr with heating. The reaction solution was concentrated, and the resulting colorless crystals were washed with water, and dried to give the title compound (51 g, yield 94%) as colorless crystals.