Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH2:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([SH:4])[CH2:6][C@H:7]1[CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCNC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCNC(N)=O
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (8.20 g) in methanol (82 ml) was added sodium methoxide (28% solution in methanol) (5.7 ml) at -10°-0° C. in a nitrogen stream and the mixture was stirred at the same condition for 1 hour. To the mixture was added glacial acetic acid (1.9 ml) at -10°-0° C. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 ml). The solution was washed with water (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (75 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-mercapto-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (6.89 g)
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:16]=[N:17][C:18]=1[Cl:22])[CH:24]=[CH2:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 72.8 %

Procedure:
3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (1.0 g, 2.57 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (15 mg) and allyltributyltin (1.6 mL, 5.1 mmol). The mixture was stirred and refluxed for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (660 mg, 73%): 1H NMR (CDCl3, 300 MHz) δ 1.24-1.40 (m, 2H), 1.46 (s, 9H), 1.62 (m, 1H), 1.88 (m, 1H), 2.02 (m, 1H), 3.38 (m, 1H), 3.45 (d, 2H, J=7.0 Hz), 3.90 (m, 1H), 4.16 (m, 2H), 5.10-5.20 (m, 2H), 5.94 (m, 1H), 7.14 (m, 1H), 7.96 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26](OC)[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC1C2C(=CC=CC=2)N(CCC(C)C)C1=O)(=O)[C:37]1C=CC=C[CH:38]=1.BrCC1C=CC(OC)=C(OC)C=1>>[C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][CH2:21][CH:37]([CH3:38])[CH3:36])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: COc1ccc(CBr)cc1OC
Product: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCC(C)C)c3ccccc32)cc1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 1-isopentyl-2-oxoindolin-3-yl benzoate and 4-(bromomethyl)-1,2-dimethoxybenzene. 1H-NMR δ 8.06 (d, 2H), 7.55 (t, 1H), 7.43 (t, 2H), 7.29 (t, 1H), 7.13 (d, 1H), 7.01 (t, 1H), 6.69 (t, 2H), 6.61 (d, 1H) 6.34 (s, 1H), 3.82 (s, 3H) 3.63 (m, 4H), 3.49 (m, 2H), 3.28 (d, 1H), 1.51 (m, 1H), 1.51 (q, 2H), 0.92 (dd, 6H). Calculated mass for C29H31NO5, 473.22. Observed 496.2 (M+Na).
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:12]([C:22]1[NH:23][CH:24]=[C:25]([CH3:28])[C:26]=1[CH3:27])=[CH:13][C:14]=2[S:15][CH2:16][CH2:17][NH:18]C(=O)O.C(OC(=O)NCCSC1C=C(C2NC=C(C)C=2C)C2C(=O)NC3C=2C=1C(F)=CC=3)(C)(C)C.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62].[OH-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[NH2:18][CH2:17][CH2:16][S:15][C:14]1[CH:13]=[C:12]([C:22]2[NH:23][CH:24]=[C:25]([CH3:28])[C:26]=2[CH3:27])[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3
Reactant: Cc1c[nH]c(-c2cc(SCCNC(=O)O)c3c(F)ccc4c3c2C(=O)N4)c1C
Agent: Cc1c[nH]c(-c2cc(SCCNC(=O)OC(C)(C)C)c3c(F)ccc4c3c2C(=O)N4)c1C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1c[nH]c(-c2cc(SCCN)c3c(F)ccc4c3c2C(=O)N4)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [2-[6-fluoro-2-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tent-butyl ester (from Example 49 above) (66 mg, 0.145 mmol) in CH2Cl2 (5 mL) was added TFA (Aldrich, 2.5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Aqueous ammonium hydroxide (4 mL) and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by RP-HPLC (C-18, eluted with 1% acetonitrile/0.05% TFA in H2O) to give 5-(2-amino-ethylsulfanyl)-6-fluoro-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one trifluoroacetic acid salt as a yellow-green solid. (Yield 20 mg, 29.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][C@@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25].C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][C@@H:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][OH:25])[CH:6]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H](CO)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.166 g, 0.49 mmol), (S)-(−)-2-amino-3-phenyl-1-propanol (0.091 g, 0.6 mmol), sodium cyanoborohydride (0.062 g, 1.0 mmol), and acetic acid (1 drop) were combined in CH2Cl2 (10 mL) and stirred overnight at room temperature. After aqueous work-up, the crude material was used directly in the next step.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:17]1([P:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>C1COCC1>[C:34]1([P:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[NH:32][CH:31]([C:2]2[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=2)[CH:30]=[CH:29]3)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Brc1cccc2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=CC(c2cccc3ccccc23)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 1-bromonaphthalene (8.57 mL, 60 mmol) in dry THF (100 mL) under nitrogen was added n-BuLi (37.5 mL, 1.6 M in hexanes, 60 mmol) at −78° C. and the solution was stirred for 30 minutes at −78° C. before adding 8-diphenylphoshinoquinoline (1) (9.4 g, 30 mmol). After stirring at 0° C. for 10 minutes the solution was again cooled down to −78° C., saturated aqueous NH4Cl solution (10 mL) was added and the mixture was warmed to room temperature. Products were then extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give the 11 as a tan solid (13.0 g, 98%). 1H NMR (400.13 MHz, CDCl3) δ 8.0-7.9 (m, 1H, C5′—H), 7.8-7.7 (m, 1H, C8′—H), 7.66 (d, 1H, J=8.0 Hz, C2′—H), 7.5-7.3 (m, 2H, C6′/7′—H), 7.36 (d, 1H, J=6.4 Hz, C4′—H), 7.3-7.1 (m, 11H, C3′—H/Ph-H), 6.86 (dd, 1H, J=7.2, 1.2 Hz, C5—H), 6.64 (ddd, 1H, J=8.0, 6.4, 1.6 Hz, C7—H), 6.48 (t, 1H, J=7.6 Hz, C6—H), 6.35 (dd, 1H, J=9.6, 1.6 Hz, C4—H), 6.16 (t, 1H, J=1.6 Hz, C2—H), 5.70 (ddd, 1H, J=10.0, 3.6, 1.6 Hz, C3—H), 5.02 (bd, 1H, J=7.6 Hz, N—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 146.6, 146.5, 139.8, 129.5, 128.7, 128.6, 128.5, 128.4, 128.3 (m), 127.7, 135.1 (d, J=8.1 Hz), 134.9 (d, J=7.1 Hz), 134.5 (d, J=5.1 Hz), 133.9, 133.5 (d, J=13.1 Hz), 133.3 (d, J=12.1 Hz), 126.2, 125.6, 125.3, 125.2, 124.8, 124.4, 122.5, 118.8, 117.1, 116.3, 54.0 ppm; 31P NMR (161.97 MHz, CDCl3) δ −23.1 ppm.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1>C(#N)C>[C:1]1(=[O:4])[CH2:2][CH2:7][CH2:6][CH:5]=[CH:10]1.[C:1]([O:4][CH:10]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:3])[CH3:2]
Reactant: C1=CCCCC1
Reactant: CC(=O)O
Solvent: CC#N
Product: CC(=O)OC1C=CCCC1
Product: O=C1C=CCCC1
Yield: 43 %
Yield: 41 %

Procedure:
The reaction was conducted in the same manner as Example C1 except that acetic acid was employed for acetonitrile and the reaction temperature was set at 90° C. As a result, cyclohexene was transformed into 2-cyclohexen-1-one (cyclohexene-based selectivity 43%, yield 41%) and 1-acetyloxy-2-cyclohexene (cyclohexene-based selectivity 45%, yield 43%) with a transformation rate of 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[Na+].[OH-].[Na+].Cl>O.C(O)(=O)C>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:14][C:13](=[O:12])[NH:1]2
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2c(Br)cccc2[nH]1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
2-Amino-6-bromobenzoic acid (2.97 g, 13.7 mmol) was suspended in a mixture of water (100 mL) and acetic acid (1.5 mL) at 35° C. then a suspension of sodium cyanate (2.23 g, 34.4 mmol) in 10 mL of water was added slowly to the mixture. Upon completion of addition, the resulting mixture was stirred at 35° C. for 30 minutes and then sodium hydroxide (24.7 g, 619 mmol) pellets were slowly added to the mixture to yield a thick precipitate. The mixture was cooled to 5° C. in an ice bath and the pH of the suspension was adjusted to 4 using concentrated HCl. Once at the prescribed pH, the suspension was filtered and the solid was washed with water and dried under vacuum while heating at 100° C. to give 5-bromo-1H-quinazoline-2,4-dione (1.91 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.30 (1 H, br. s.), 11.26 (1H, br. s.), 7.43-7.48 (1H, m), 7.40 (1H, dd, J=7.78, 1.25 Hz), 7.16 (1H, dd, J=7.91, 1.13 Hz).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([NH:11][CH2:2][C:3]([O:5][CH3:6])=[O:4])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)N
Solvent: CCOCC
Product: COC(=O)CNC(C)(C)C
Temperature: 25 °C
Yield: 96.6 %

Procedure:
Methyl bromoacetate (7.1 mL, 75 mmol) is added dropwise to tert-butylamine (31.5 mL, 300 mmol) at 0° C. The reaction mixture is diluted with ether, warmed to room temperature and filtered. The filtrate is concentrated in vacuo to obtain the title product as a clear liquid (10.52 g) which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C1C=CC=CC=1.NCCC(O)=O>O.C(O)(=O)C>[C:17]([C:19](=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCOC(=O)CC#N
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: NCCC(=O)O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 336 h
Yield: 56.2 %

Procedure:
A mixture of 20.0 g (92 mmoles) of 4,4'-difluorobenzophenone, 11.0 g (97 mmoles) of ethyl cyanoacetate in a mixed solvent of 100 mL of dry benzene and 20 mL of glacial acetic acid containing a catalytic amount of β-alanine (0.9 g) was refluxed with separation of water using a Dean-Stark water trap. Separation of water was rapid during the first 2 hours (0.4 mL aqueous layer collected) but slower afterward. Azeotropic distillation was continued for a period of 14 days. Analytical TLC eluted with 10% EtOAc in hexanes (v/v) (Merck plate, 0.25 mm Silica gel-F) showed two spots at Rf =0.2 (desired product) and at Rf =0.45 (4,4'-difluorobenzophenone starting material). Crude reaction mixture was washed with water (40 mL×2), and the combined aqueous washes were extracted with EtOAc (150 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to crystallize the produce as pale cubic crystals. The crude product was collected, washed with 1:1 EtOAc in hexanes (v/v) then recrystallized from 8:1 (hexanes:ethyl acetate v/v) to give 16.2 g (56.3%) of analytical pure title compound; m.p.=114°-116° C.
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[OH:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16])[CH3:7]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Imidazole (0.15 g) and 0.36 ml of triethylsilylchloride were added to a solution of 0.32 g of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonyl imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one in 3.2 ml of dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with 80 ml of ethyl acetate, and the diluted reaction mixture was washed three times with 20 ml of a 10% aqueous sodium chloride solution and was then washed with an a saturated aqueous sodium chloride solution and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resultant solid was suspended in 4 ml of a hexane:ethyl acetate=1:1 solution and was collected by filtration to give 0.33 g of (3S,4R)-3-[(1R)-1-(triethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH3:21])=[N:17][O:18][C:19]=1[CH3:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH3:21])=[N:17][O:18][C:19]=2[CH3:20])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: Cc1noc(C)c1N
Solvent: c1ccncc1
Product: Cc1noc(C)c1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 48.7 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.19 mmol) and 4-amino-3,5-dimethylisoxazole (0.346 g, 3.1 mmol) in pyridine (6 ml) according to the method of intermediate 1, to give the title compound as a tan solid (606 mg, 1.51 mmol, 49%). δH (CDCl3, 300K) 7.70 (2H, s), 6.66 (1H, s), 2.23 (3H, s), 2.05 (3H, s). m/z (ES+, 70V) 400.9 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.[NH3:17]>>[NH2:17][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Product: Nc1nc(N)c2ncn(COCCO)c2n1
Temperature: 120 °C
Yield: 12 %

Procedure:
A mixture of 2-chloro-9-(2-hydroxyethoxymethyl)adenine (4.4 g) and liquid ammonia (40 ml) was heated at 120° C. in a bomb for 19 hours. The reaction mixture was removed from the bomb and excess ammonia removed in vacuo. The residue was partitioned between ether and water and the aqueous layer washed twice more with ether and once with chloroform. The aqueous solution was then treated with an excess of a strongly basic ion exchange resin to convert the ammonium chloride to ammonia and evaporated to dryness in vacuo. The residue was dissolved in a minimal amount of ethanol, Florisil (Registered Trade Mark) (10g) added, and the mixture evaporated in dryess. The residue was transferred to a prepared column of Florisil in chloroform and eluted with 5% methanol/95% chloroform (v/v). Fractions (30 ml) were collected and examined by TLC (silica gel plates developed in 10% methanol/90% chloroform) for the presence of product. The first 40 fractions contained starting material but no product and were discarded. Succeeding fractions which were found to contain the desired product were combined and evaporated to dryness. The residue was recrystallized from ethanol (with activated charcoal treatment) and from n-propanol to give 2-amino-9-(2-hydroxyethoxymethyl)adenine (0.5 g, 12% of theoretical), m.p. 183°-184° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].[N+:12]([O-])([OH:14])=[O:13].C(OCC)(=O)C>C(O)(=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([OH:11])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2]
Reactant: N#Cc1cc(C=O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 5-formyl-2-hydroxybenzonitrile (200 mg, 1.36 mmol) in acetic acid (4 mL) was added slowly concentrated nitric acid (0.8 mL) at 0° C. The resulting mixture was stirred for 5 hours. Then the mixture was poured into ice-water (40 mL) and ethyl acetate (100 mL). Organic was washed with brine (80 mL), dried over sodium sulfate and evaporated in vacuo, followed by column chromatography (petroleum ether/ethyl acetate=3:1) to give Intermediate 61 (250 mg, yield 96%).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO.[CH3:34][N:35]([CH3:61])[CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)(=[O:50])=[O:49])=[CH:43][CH:42]=1>C1COCC1>[CH3:61][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([N:47]([CH3:1])[S:48]([C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:59])([F:60])[F:58])=[CH:55][CH:56]=2)(=[O:50])=[O:49])=[CH:45][CH:46]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCCCOc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 98 mg (0.375 mmol) triphenylphosphine in 0.5 ml THF was treated at 0° C. with 0.06 ml (0.375 mmol) DEAD, then with 0.012 ml (0.3 mmol) methanol in 0.33 ml THF and finally with 104 mg (0.25 mmol) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide in 0.3 ml THF. The reaction mixture was stirred over night at RT, evaporated and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were dried over Na2SO4 evaporated and purified by flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 95:5) to yield 80 mg (74%) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, mp: 151-153° C.; MS: 431 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#N.[CH2:10]([Mg]Br)[CH3:11].[Cl-].[NH4+].[O:16]1CCCC1>>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1](=[O:16])[CH2:10][CH3:11])[CH:8]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc(C#N)c1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(=O)c1cc(C)ccn1
Temperature: -55 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2-cyano-4-methylpyridine (1.0 g) in tetrahydrofuran (10 ml) was added a solution of ethylmagnesium bromide in tetrahydrofuran (0.96M, 9.7 ml) dropwise at −55° C. The reaction mixture was stirred at −55° C. for 30 minutes and warmed to 0° C. Then the mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-(4-methylpyridin-2-yl)-propan-1-one (1.21 g).
Reaction SMILES: [C:1]1([N:7]([C:12]([OH:14])=O)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([O-:18])=O.[Na+].[CH3:20]C(OC(C)=O)=O>CN(C=O)C>[C:12]([N:7]1[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]([O:11][C:16](=[O:18])[CH3:15])=[CH:8]1)(=[O:14])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CN(C(=O)O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Yield: 73.7 %

Procedure:
To a mixture of phenylglycine-o-carboxylic acid obtained in Example 30 (2.30 g, 11.8 mmol) and NaOAc (3.75 g, 47.1 mmol) in DMF (29 mL) was slowly added Ac2O (11.7 mL, 118 mmol) and the mixture was refluxed for 2 hours. After cooling, the mixture was concentrated to 10 mL, partitioned between H2O (60 mL) and CHCl3 (120 mL), and the aqueous layer was extracted with CHCl3 (3×). The combined organics were washed with Na2CO3 (1 M), H2O, brine and dried (MgSO4). Purification of the crude oil by LPLC, eluting with hexane-EtOAc (2:1), afforded 1.89 g (74%) of the title compound as a light yellow powder, Rf 0.34 (hexane-EtOAc 2:1), mp 79.6-80.5° C.; 1H NMR (CDCl3) δ 8.47 (d, J=8.0, 1H), 7.72 (s, 1H), 7.55 (d, J=8.0, 1H), 7.40 (t, J=8.0, 1H), 7.31 (t, J=8.0, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 13C NMR (CDCl3) δ 168.7, 167.8, 134.6, 132.8, 126.2, 123.7, 123.6, 117.4, 116.7, 113.3, 23.9, 21.0; MS (EI, m/z) 217 (M+)
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]SC1SCC(=O)N=1.[OH-].[Na+]>CN(C=O)C>[Cl:11][C:12]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCCCSc2nc3ccccc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Stir at room temperature for four days 2.5 gms. 2-mercapto-benzimidazole, 2 gms. of the iodide prepared in Examples 2 or 3, 25 ml. DMF and 0.71 gm. sodium hydroxide in a reaction flask. Remove the solvent and partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride then 50/50 ethylacetate/methylene chloride to obtain the title compound. MS: m/z 391 (M+) H1 -NMR-200 mHz-εH (CDCl3), 1.5-1.6 (4H,m), 1.7-1.9 (4H,m), 3.35 (2H,t,J 7Hz), 3.75 (3H,s) 3.95 (2H,t,J 6Hz), 6.7-7.0 (3H,m), 7.2-7.4 (4H,m), 7.65-7.75 (1H,m).