Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N:22](CC)C(C)C)(C)[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(CN)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Br:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:13])[N:22]3[CH2:19][CH2:20][O:8][C:1]32[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: NCCO
Solvent: O
Product: O=C1c2ccc(Br)cc2C2(c3ccccc3)OCCN12

Procedure:
To a solution of 2-Benzoyl-4-bromo-benzoic acid (100 mg; 0.33 mmol) in N,N-dimethylformamide (1 ml) with N,N-Diisopropylethylamine (127 μl; 0.98 mmol) is added HATU (137 mg; 0.36 mmol). It is stirred at ambient temperature for 5 minutes before ethanolamine (21 μl; 0.33 mmol) is added. After 4 hours the reaction mixture is purified via reversed phase chromatography under basic conditions. The received 5-Bromo-3-hydroxy-2-(2-hydroxy-ethyl)-3-phenyl-2,3-dihydro-isoindol-1-one is taken up in 1 ml toluene and treated with p-Toluenesulfonic acid monohydrate (3 mg; 0.02 mmol) at 120° C. for 2 days. It is purified via reversed phase chromatography under basic conditions.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18]C(=O)C)[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@H:6]1[S:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:112])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([S:68][C@@H:69]3[O:106][C@H:105]([CH2:107][O:108]C(=O)C)[C@@H:80]([O:81][C@H:82]4[O:99][C@H:98]([CH2:100][O:101]C(=O)C)[C@@H:93]([O:94]C(=O)C)[C@H:88]([O:89]C(=O)C)[C@H:83]4[O:84]C(=O)C)[C@H:75]([O:76]C(=O)C)[C@H:70]3[O:71]C(=O)C)=[CH:64][CH:63]=2)=[O:60])=[CH:47][CH:46]=1)(=O)C>CO.N>[C@H:82]1([O:81][C@@H:80]2[C@@H:105]([CH2:107][OH:108])[O:106][C@@H:69]([S:68][C:65]3[CH:66]=[CH:67][C:62]([NH:61][C:59](=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C:52]([NH:51][C:48]4[CH:47]=[CH:46][C:45]([S:44][C@@H:6]5[O:7][C@H:8]([CH2:39][OH:40])[C@@H:9]([O:15][C@H:16]6[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]([OH:23])[C@H:17]6[OH:18])[C@H:10]([OH:11])[C@H:5]5[OH:4])=[CH:50][CH:49]=4)=[O:112])=[CH:63][CH:64]=3)[C@H:70]([OH:71])[C@H:75]2[OH:76])[O:99][C@H:98]([CH2:100][OH:101])[C@@H:93]([OH:94])[C@H:88]([OH:89])[C@H:83]1[OH:84]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(NC(=O)CCCCCCC(=O)Nc3ccc(S[C@@H]4O[C@H](COC(C)=O)[C@@H](O[C@H]5O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=C(CCCCCCC(=O)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 28.4 g portion of N,N'-bis[4-[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-glucopyranosylthio]phenyl]octanediamide was dissolved in a 0° C. solution of 500 ml of methanol saturated with ammonia. The solution was allowed to stand at 0° C., under an inert atmosphere, for 18 hours, then was warmed to ambient temperature and evaporated. The residue was triturated with 200 ml of absolute ethanol, filtered, washed in sequence with absolute ethanol, acetonitrile, then ether and dried in vacuo at 40° C., giving 12.1 g of the desired intermediate as an amorphous solid.
Reaction SMILES: CS(C)=O.F[C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:7]=1[CH:8]=O.C(N(CC)CC)C.[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>ClCCl.CCCCCC>[Cl:14][C:10]1[C:7]2[CH:8]=[C:23]([C:22]([O:26][CH3:27])=[O:25])[S:24][C:6]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
A 100 ml 3-necked round-bottomed flask, reflux condenser, thermometer adapter, gas inlet, and Teflon stirrer were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, fitted with a thermometer, flushed with dry nitrogen gas, sealed with rubber septa, and allowed to cool to room temperature. The cooled reaction flask was charged with anhydrous dimethyl sulfoxide (40 ml), 2-fluoro-6-chlorobenzaldehyde (5 g, 31.53 mmole), anhydrous triethylamine (2.5 equivalents, 78.83 mmole, 7.976 g, 11 ml) and methyl thioglycolate (1.1 equivalents, 3.681 g, 3.10 ml, 34.68 mmole). The reaction mixture was heated to 75° C. with rapid stirring. The progress of the reaction was monitored by thin-layer chromatography (TLC, silica, 10% dichloromethane-hexane developing solution and UV visualization). After 3 hours the reaction mixture was allowed to cool to room temperature and poured into an ice/water mixture (250 ml). The resulting slurry was stirred for 20 minutes, filtered, washed with cold water (2×100 ml) and dried in vacuo to give 6.07 g (85%) of methyl 4-chlorobenzo[b]thiophene-2-carboxylate. See, A. J. Bridges, A. Lee, E. C. Madukor, and C. E. Schwartz, Tetrahedron Letters, 33:7499 (1992).
Reaction SMILES: [P:1]([O:19][C:20]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49])([CH:27]([C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].Br[Si](C)(C)C.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[P:1]([OH:11])([OH:3])([O:19][C:20]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49])([CH:27]([C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[O:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(Cn1cncn1)(OP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(F)cc1F
Agent: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(Cn1cncn1)(OP(=O)(O)O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
A solution of the compound of step (a) (310 mg, 0.44 mmol) in methylene chloride (5 ml) was cooled to 0° C. and then treated with bromotrimethylsilane (303 mg, 1.98 mmol) and pyridine (215 mg, 3.70 mmol). The resulting mixture was stirred at 0° C. for 3 hours and then quenched with water (1 ml) containing sodium hydroxide (115 mg, 2.87 mmol). A yellow precipitate was formed, which was isolated by filtration and then partitioned between dilute sulphuric acid and methylene chloride. The organic phase was washed with brine, dried (MgSO4) and the solvent evaporated to give the title compound as a pale yellow solid (80 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1Cl.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Reactant: C1COCCN1
Solvent: O
Product: COc1ccc(Cn2ncc(N3CCOCC3)c(Cl)c2=O)cc1

Procedure:
A mixture of 4,5-dichloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one [P. Matyus, Gy. Rabloczky, L. Jaszlits, J. Kosary, M. Kurthy, A. Papp Behr, D. Zara, E. Karpati, A. Kovacs, WO1992/9212137] (10.15 g, 35.61 mmol) and morpholine (7.66 g, 87.92 mmol) in water (200 ml) was refluxed for 18 h. After cooling, the mixture was extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by recrystallization from ethanol (95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1([CH3:23])[CH2:11][C:10]2[C:12]([CH3:22])=[C:13]([NH:18]C(=O)C)[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1)C.[ClH:25]>CO>[ClH:25].[NH2:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]2[O:8][C:7]([CH:6]=[CH:5][C:4]([O:3][CH3:1])=[O:24])([CH3:23])[CH2:11][C:10]=2[C:12]=1[CH3:22]
Reactant: CCOC(=O)C=CC1(C)Cc2c(C)c(NC(C)=O)c(C)c(C)c2O1
Agent: Cl
Solvent: CO
Product: COC(=O)C=CC1(C)Cc2c(C)c(N)c(C)c(C)c2O1
Yield: 74.7 %

Procedure:
3-[5-Acetylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl]acrylic acid ethyl ester (0.5 g, 1.58 mmol) was dissolved in methanol (5 ml). Conc. hydrochloric acid (5 ml) was added to the solution and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled and the crystals precipitated were filtered. The crude crystals obtained were recrystallized from ethanol-isopropyl ether to obtain the desired compound (0.35 g, yield: 74.7% yield), m.p. 225°-234° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[C:9]([CH2:15]OC(=O)C)[CH:8]=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.CC(O)=O>CO.[Pd]>[CH3:15][C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]3[C:14]=2[C:10]=1[CH:11]=[CH:12]3
Reactant: CC(=O)OCc1ccc2c3c1ccn3C(=O)CNC2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c3c1ccn3C(=O)CNC2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75 %

Procedure:
Acetic acid-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-ylmethyl ester (0.508 g, 1.97 mmol) was dissolved in MeOH (70 mL) and glacial AcOH (30 mL). To the solution was added 10% Pd/C (0.076 g) and the suspension was stirred under an atmosphere of H2 for 4.5 h at rt. The black suspension was filtered and the filtrate was concentrated to give a white solid, which was purified by flash silica gel chromatography eluting with a gradient of 0-1% MeOH in CHCl3 to give 0.296 g (75%) of the title compound: 1H NMR (DMSO-d6) δ 2.52 (s, 3H), 3.51-3.54 (m, 2H), 4.27-4.28 (m, 2H), 7.11 (t, 1H, J=7.5 Hz), 7.15 (s, 1H), 7.69 (d, 1H, J=7.5 Hz), 7.81 (d, 1H, J=7.5 Hz), 8.22-8.24 (m, 1H). HRMS calcd. for C12H12N2O (M+) 200.0950, found 200.0955. Anal. (C12H12N2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:63]=[CH:62][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([N:15]2[CH2:19][CH2:18][C@H:17]([S:20][C:21]([CH2:23][C@H:24]3[N:27]([C:28]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=4)=O)=C(C)C)[C:26](=[O:45])[C@@H:25]3[C@H:46]([O:48][C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])[CH3:47])=[O:22])[CH2:16]2)[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(Cl)Cl>[N+:1]([C:4]1[CH:63]=[CH:62][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([N:15]2[CH2:19][CH2:18][C@H:17]([S:20][C:21]([CH2:23][C@H:24]3[N:27]([CH2:28][CH2:32][O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=4)[C:26](=[O:45])[C@@H:25]3[C@H:46]([O:48][C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])[CH3:47])=[O:22])[CH2:16]2)[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Solvent: ClCCl
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2CCOCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 103.8 %

Procedure:
34 mg (0.038 mmole) of (3S, 4R)-4-([(S)-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl)-1-[2-methyl-1-(p-nitrobenzyloxycarbonyl)-prop-1-enyl]-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-azetidinone were dissolved in 10 ml of methylene chloride. Ozone was bubbled through the solution at -78° C. For 3 minutes. The mixture was then left to stand at that temperature for 10 minutes, after which nitrogen gas was bubbled through to drive out the excess ozone. 50 mg of dimethyl sulphide were then added to the mixture, which was then warmed to room temperature over about 10 minutes and poured into a mixture of ice and water. The chloroform layer was separated, washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off, to afford 33 mg (yield 100%) of the title product as an oily substance.
Reaction SMILES: C1([C:6]([OH:24])([C:17]#[C:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:7][C:8]2[O:13]C(C)(C)O[C:10](=[O:16])[CH:9]=2)CCCC1.[CH:25]1(C(O)(C#CC2C=CC(OC)=CC=2)CC2OC(C)(C)OC(=O)C=2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O>[CH:25]1([CH:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:17]#[C:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[O:24][C:10]2=[O:16])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2nccs2)C2CCCC2)O1
Solvent: O
Product: O=C1CC(C#Cc2nccs2)OC(=O)C1C1CCCC1

Procedure:
The title compound was prepared analogously to example 1, except 6-(2-cyclopentyl-2-hydroxy-4-thiazol-2-yl-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (from Step 1) was used rather than 6-[2-cyclopentyl-2-hydroxy-4-(4-methoxy-phenyl)-but-3-ynyl]-2,2-dimethyl-[1,3]dioxin-4-one. 1H NMR (CDCl3): δ 1.63-2.05 (bm, 4H), 2.23 (pentet, 1H, J=8.1 Hz), 2.78 (d, 1H, J=17.7 Hz), 3.04 (d, 1H, J=17.7 Hz), 3.51 (d, 1H, J=20.0 Hz), 3.97 (d, 1H, J=20.0 Hz), 7.46 (d, 1H, J=3.2 Hz), 7.89 (d, 2H, J=3.4 Hz). Anal. Calcd. for C15H15N1O3S1.0.25 H2O: C, 57.75; H, 4.93; N, 4.35. Found: C, 58.2; H, 5.34; N, 4.36; ESIMS (M+Na+): 312.0.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[F:21].[CH3:22][Si:23](Cl)([CH3:25])[CH3:24].[NH4+].[Cl-]>C1COCC1.CCCCCC.O>[F:13][C:14]1[C:15]([F:21])=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=1[Si:23]([CH3:25])([CH3:24])[CH3:22]
Reactant: Cc1ccc(F)c(F)c1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: Cc1cc(F)c(F)c([Si](C)(C)C)c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 129.8 %

Procedure:
To a solution of diisopropylamine (20.2 g, 0.2 mol) in THF (500 mL) cooled with an ice-water bath was added a solution of n-BuLi in hexane (2.5 M, 80 mL) dropwise for over 30 min. The mixture was stirred in the ice bath for 30 min then cooled to −78° C. A solution of 1,2-difluoro-4-methylbenzene (12.8 g, 0.1 mol) in THF (80 mL) was added dropwise, after 20-30 min, a solution of TMSCl (21.6 g, 0.2 mol) in THF (20 mL) was added dropwise. The mixture was stirred at −78° C. for 2-3 h. Sat. NH4Cl (300 mL) was added to the mixture, diluted with water (200 mL) and extracted with ether. The ether layer was washed with brine and dried over Na2SO4, the solvent was removed to give (2,3-difluoro-5-methylphenyl)trimethylsilane (26 g, 100%), which was used for the next step without purification. 1H NMR (CDCl3) δ 6.90 (m, 2H), 2.40 (s, 3H), 0.33 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]2[S:8][C:9]3[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=3[CH:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])[CH2:15][CH2:14]3)[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:32]=[CH:31][C:7]2[S:8][C:9]3[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=3[CH:11]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])[CH2:17][CH2:18]3)[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1OCCN1CCN1CCN(C2Cc3cc([N+](=O)[O-])ccc3Sc3ccccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2

Procedure:
24.1 g of 3-[2-[4-(10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone in 2000 ml of ethyl acetate are hydrogenated in the presence of 5.7 g of palladium/carbon (5%) at 70° C and 10 atmospheres of hydrogen. After filtration, the filtrate is concentrated under reduced pressure. There is obtained 3-[2-[4-(2-amino-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 193°-196° C. After chromatographic purification over aluminium oxide using acetone/hexane as the elution agent, there is obtained a pure product which melts at 195.5°-196.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:10])=[O:9].[F:27][C:28]([F:42])([F:41])[C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([N:38]2[CH2:39][CH2:40][N:35]([C:30]3[C:29]([C:28]([F:42])([F:27])[F:41])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]2)=[O:18])[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:9])=[O:10]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(O)[C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl
Product: O=C([C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 1, step 5, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 70, step 4) was coupled with 1-[3-(trifluoromethyl)pyrid-2-yl]-piperazine to give the title compound as a colorless solid. MS: 628.3 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1>C1COCC1>[Br:15][C:16]1[C:17]([O:12][CH:10]2[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2nc(Cl)ncc2Br)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.5 g, 14.43 mmol) in anhydrous THF (65 mL) was added NaH (55 w/w % in mineral oil, 381 mg, 15.9 mmol) under N2 atmosphere at 0 to 5° C. The mixture was allowed to warm to room temperature and stirred for 2 hr. Then, this reaction mixture was cooled to −5 to 0° C., and was added slowly to a solution of 5-bromo-2,4-dichloropyrimidine (3.28 g, 14.43 mmol) in anhydrous THF (28 mL) at −5 to 0° C. The mixture was stirred at −5 to 0° C. for 2 hr, then allowed to warm to room temperature and stirred for additional 6 h. After this time, the mixture was quenched with water (75 mL) at 0° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; eluting with 10% ethyl acetate in hexane) to give the title compound (1) (3.35 g, 64%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 5.38-5.46 (m, 1H), 4.38 (dd, J=10.3, 6.5 Hz, 2H), 4.06 (dd, J=10.4, 4.1 Hz, 2H), 1.46 (s, 9H); MS (APCI, M+H+) C12H16BrClN3O3, calcd. 364.0. found 307.9 (M+1-t-butyl), 309.9 (M+3-t-butyl)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]1=2>>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[C:13](=[CH:12][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: Oc1ccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)cc1

Procedure:
Following procedures essentially as described in Example 219, below, and using (4-hydroxyphenyl)boronic acid (55 mg, 0.40 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (103 mg, 0.32 mmol) provides the title compound. Mass Spec (EI+) 332.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]([CH3:4])[CH3:3].[CH3:7][CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl>C1COCC1>[OH:14][C:12]1([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH:8]([CH3:7])[CH2:13]1
Reactant: CC(C)C[Mg]Cl
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CC1(O)CCN(C(=O)OC(C)(C)C)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, in a 50-mL pear-shaped evaporating flask was weighed a solution of lanthanum chloride lithium chloride complex in THF (15.6 mL) and cooled to 0° C. To the solution was added dropwise a solution of isobutylmagnesium chloride in THF (3.5 mL) and stirred at 0° C. for 3 hours. A solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1 g) in THF (2.0 mL) was further added dropwise. The reaction solution was stirred at 0° C. for 1 hour, heated to 25° C., poured to hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→3:1) to give the titled compound (450 mg) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:20])[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
6-Amino-9-benzyl-2-methoxypurine (118 mg, 0.46 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (90 mg, yield 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[N:17]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH:27]1[CH:32]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:28]=1.BrCCCO.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[H-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:32][CH2:27][CH2:28][N:12]([C:13]3[S:14][CH:15]=[C:16]([C:18]4[C:26]5[C:21](=[N:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[N:17]=3)[C:10]2=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)Nc2nc(-c3c[nH]c4ncccc34)cs2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OCCCBr
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C2CCCN(c3nc(-c4c[nH]c5ncccc45)cs3)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To 2-(3-methoxy-phenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (1 mmol) in THF was added 1.2 mmol of PPh3, 1.2 mmol of 3-bromopropanol and 1.2 mmol of DIAD and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0° C. and 1.2 mmol of NaH was added and reaction mixture was stirred at 0° C. for 30 minutes. MeOH was added to quench reaction and the solvent evaporated. The residue was redissolved in EtOAc and the organic layer was washed with H2O and dried over Na2SO4. After removal of solvent, the final product was purified by preparative HPLC to afford 3-(3-methoxy-phenyl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-piperidin-2-one in 30% yield.