Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10](=[N:24][O:25][CH3:26])[CH:11]2[CH:16]3[CH:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH:6]=[CH:7][C:8]=1[Cl:9].CCCCCC>C(Cl)Cl>[ClH:2].[CH3:26][O:25][N:24]=[C:10]([CH:11]1[CH:16]2[CH:12]1[CH2:13][NH:14][CH2:15]2)[C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=1
Reactant: CON=C(c1ccc(Cl)c(Cl)c1)C1C2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CON=C(c1ccc(Cl)c(Cl)c1)C1C2CNCC21
Yield: 198.2 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 6-((3,4-dichlorophenyl)(methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (90 mg, 0.23 mmol) obtained in step-1 of example 3 in dry DCM (5 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 3-azabicyclo[3.1.0]hexan-6-yl(3,4-dichlorophenyl)methanone O-methyl oxime (65 mg, 86%) as a white solid as a mixture of isomers.
Reaction SMILES: [Si]([C:8]1[S:9][C:10]([C:13]2([OH:31])[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH:21]([NH:23]C(=O)OC(C)(C)C)[CH2:20]3)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)(C(C)(C)C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:23][CH:21]1[CH2:22][CH:19]([N:16]2[CH2:15][CH2:14][C:13]([C:10]3[S:9][CH:8]=[N:12][CH:11]=3)([OH:31])[CH2:18][CH2:17]2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CC(N2CCC(O)(c3cnc([Si](C)(C)C(C)(C)C)s3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CC(N2CCC(O)(c3cncs3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl 3-(4-(2-(tert-butyldimethylsilyl) thiazol-5-yl)-4-hydroxypiperidin-1-yl)cyclobutylcarbamate (as prepared in the previous step) (950 mg, 2.03 mmol, 1.00 equiv) in dichloromethane (10 mL) and CF3COOH (2 mL). The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: ClCCOc1cccc2ccoc12
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4ccoc34)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A solution of 2-(benzofuran-7-yloxy)ethylchloride (0.58 g, 2.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (1.4 g, 7.4 mmol) and triethylaniine (0.74 g, 7.4 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (7% methanol-methylene chloride) afforded 0.31 g (30%) of product as a light-brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:18][CH:17]=[CH:16][CH2:15][N:14]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]1[C:30](O)=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([NH:40][OH:41])(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:18][CH:17]=[CH:16][CH2:15][N:14]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]1[C:30](=[O:31])[NH:40][OH:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid (21 mg, 0.043 mmol) is dissolved in dry Dimethylformamide (DMF) and cooled to -20° C. tert-Butyldimethylsilylhydroxyl amine (7 mg, 0.05 mmol), Hunigs Base (9.8 μl, 0.05 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (18 mg, 0.05 mmol) are added. The reaction solution is stirred for 1 h and then allowed to warm to room temp. The solvent is evaporated. The residue is purified by flash-chromatography, Dichloromethane/Methanol (9:1), to afford the desired hydroxamide: Cal. 476.5, Found (MH)+ 476.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)C=CC=CC=1.C([Li])CCC.[CH3:37][O:38][CH2:39][CH2:40][O:41][CH2:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=O>C1COCC1>[CH3:37][O:38][CH2:39][CH2:40][O:41][CH2:42][O:43][C:44]1[CH:51]=[CH:50][CH:49]=[C:46]([CH:47]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:45]=1
Reactant: COCCOCOc1cccc(C=O)c1
Reactant: c1ccc([P+](Cc2ccc3ccccc3n2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCOc1cccc(C=Cc2ccc3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) suspension of triphenyl-(quinolin-2-yl-methyl)-phosphonium chloride (1.76 g, 4 mmol, example 17) in THF (24 mL) is added, dropwise, n-butyl lithium solution (1.7 mL, 2.5 M in hexanes). The resulting mixture is stirred for 30 min. then a solution of 3-[(2-methoxyethoxy)-methoxy]-benzaldehyde (756 mg, 3.6 mmol, example 8a) in THF (3 mL) is added. This mixture is stirred for 30 min then the cold bath removed and stirring continued for 2 h. The reaction mixture is then diluted with ethyl acetate, washed with sat. ammonium acetate solution and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 40% ethyl acetate in hexanes) to give the title compound as an oil. MS (ESI) 336 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CCOCC>C1COCC1>[CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:35][CH:34]=2)=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 16 m moles (3.3 g) of the above 4-hydroxybenzoic acid 2-methylbutyl ester in 20 ml of THF and 40 ml of pyridien was cooled, and a THF solution of 10 m moles (2.9 g) of the above 4-carbobenzoxyoxybenzoyl chloride was added dropwise. The mixture was returned slowly to room temperature, then stirred for 8 hours. After the reaction, the reaction mixture was ether extracted and concentrated, and then purified by column chromatography to obtain 2.9 g of 4-(4'-carbobenzoxyoxybenzoyloxy)benzoic acid 2-methylbutyl ester [m.p. 64.4°-65.4° C⟧ (yield: 63%)
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C@H:20]([O:22][CH3:23])[CH3:21])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7].Br[CH2:25][C:26]#[N:27].C(N(C(C)C)C(C)C)C>C(#N)C>[C:26]([CH2:25][NH:3][C@@H:4]([C@H:20]([O:22][CH3:23])[CH3:21])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:7])=[O:8])#[N:27]
Reactant: N#CCBr
Reactant: CO[C@H](C)[C@H](N)CS(=O)(=O)Cc1cnc2ccccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NCC#N

Procedure:
A mixture of (2S,3R)-2-amino-3-methoxy-1-(3-quinolylmethanesulfonyl)butane dihydrochloride (0.93 g), bromoacetonitrile (0.41 ml) and N-ethyldiisopropylamine (1.7 ml) in acetonitrile (15 ml) was refluxed for 16 h, cooled and evaporated. The residue was partitioned between MDC (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic phase was collected and the aqueous re-extracted with MDC (15 ml). The combined MDC phases were dried (MgSO4) and evaporated. The residue was flash chromatographed (silica gel, step gradient: 70–100% EtOAc/hexane) to give the subtitle compound (0.59 g). MS (APCI+ve ion) 348(MH+); 1H NMR δ(CDCl3): 8.91 (1H, m), 8.3 (1H, d, J=2 Hz), 8.14 (1H, d, J=8 Hz), 7.78 (1H, d, J=8 Hz), 7.78 (1H, t, J=8 Hz), 7.60 (1H, t, J=8 Hz), 4.55 (2H, s), 3.4–3.88 (4H, m), 3.33 (3H, s), 2.93–3.28 (2H, m), 2.18 (1H, m), 0.93 (3H, d, J=6.3 Hz).
Reaction SMILES: C(OC(N1CCC[C@H]1/C=C(/[C:15]1[CH2:21][C@H:20]2N([C:18](=O)[C@@H:19]2[C@H:22]([OH:24])C)[C:16]=1[C:26](OCC=C)=O)\C)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=[O:58])CC(=O)C1>O1CCCC1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:19]([C:22]([OH:58])=[O:24])=[CH:20][CH2:21][CH2:15][CH2:16][CH3:26]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCC=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.2 %

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.82 g) in a mixture of tetrahydrofuran (28 ml) and ethanol (14 ml) were added successively triphenylphosphine (0.51 g), 5,5-dimethyl-1,3cyclohexanedione (dimedone) (1.79 g), and tetrakis-(triphenylphosphine) palladium (0) (220 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration, washed with tetrahydrofuran (40 ml) and dissolved in water (150 ml). The solution was washed with ethyl acetate (50 ml×2), concentrated in vacuo and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[b 3.2.0]hept-2-ene-2-carboxylic acid (1.52 g).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29]C)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.CN.N[C:48]1C=CC=C[CH:49]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH3:29])=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:48][CH2:49]1)[CH2:5][O:12][CH2:9]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccccc1
Agent: CN
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)NC)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing methylamine (2M in THF) as the aniline component. (51%, MS=408.4 (M+H))
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Cl[CH2:26][C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[C:27]([CH2:26][N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[C:9]([F:19])=[CH:8][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)#[N:28]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg), chloroacetonitrile (31 μL) and anhydrous potassium carbonate (124 mg) in dry acetonitrile (4 mL) under N2 was stirred at ambient temperature for 20 hours, diluted with methylene chloride (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 165-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9](S(C)(=O)=O)[S:10]([CH3:13])(=[O:12])=[O:11])=[C:4]([F:18])[CH:3]=1.[OH-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:4]([F:18])[CH:3]=1
Reactant: CS(=O)(=O)N(c1c(F)cc(Br)cc1F)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1c(F)cc(Br)cc1F
Yield: 89.7 %

Procedure:
A mixture of N-(4-bromo-2,6-difluorophenyl)-N-(methylsulfonyl)methanesulfonamide (2.20 g, 6.04 mmol) and sodium hydroxide (pellet) (1.20 g, 30.0 mmol) in tetrahydrofuran. (30 ml) and water (10 ml) was stirred for 2 hours at ambient temperature. After the solvent was evaporated in vacuo and the residue was acidified to pH 2 with 2M hydrochloride aqueous solution. The aqueous solution was extracted with ethyl acetate and the combined solution was washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was recrystallized from ethyl acetate and hexane to furnish 1.55 g (90% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C@H:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:6]([NH:21][C:22](=[O:37])[C@H:23]([CH3:36])[NH:24][C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[C:5]1=[O:38])[CH:2]=C.I([O-])(=O)(=O)=[O:40].[Na+]>C1COCC1.O.S(=O)(O)[O-].[Na+].O=[Os](=O)(=O)=O>[F:34][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([NH:24][C@H:23]([C:22]([NH:21][C@@H:6]2[C:5](=[O:38])[N:4]([CH2:1][CH:2]=[O:40])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C@@H:7]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:37])[CH3:36])=[O:35])[CH:32]=[C:31]([F:33])[CH:30]=1
Reactant: C=CCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(CC=O)c2ccccc2O[C@@H]1c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 63c (582 mg) in THF (10 mL) was treated with a solution sodium periodate (530 mg) in water (10 mL) followed by a 4% solution of OsO4(1 mL). The reaction mixture was stirred for 16 h, diluted with sodium bisulfite solution (20 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were washed with NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. The product thus obtained was dissolved in THF (50 mL) and treated with a solution sodium periodate (530 mg) in water (50 mL). After stirring for 16 h the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (2×100 mL). The organic layers were concentrated under reduced pressure and the product was purified by chromatography to obtain the title compound in 1:1 mixture with the (2S,3R) diastereomer (417 mg). 1H NMR (300 MHz, CDCl3) δ 1.05 (m, 3H), 3.47 (two peaks, 2H), 6.74 (m, 2H), 7.25-7.60 (m, 12H).
Reaction SMILES: CON(C)C([C:6]1[CH:14]=[C:13]2C(C(C)=C[N:12]2[CH2:15][C:16]2[CH:21]=CC(OC)=[CH:18][CH:17]=2)=CC=1)=O.C([Li])CCC.CN(C)C=[O:34].[Cl-].[NH4+]>C(OCC)C>[CH3:21][C:16]1[CH:15]=[N:12][CH:13]=[C:14]([CH3:6])[C:17]=1[CH:18]=[O:34]
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=O)N(C)OC)cc32)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cncc(C)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of 4-bromo-3,5-dimethylpyridine (3.72 g, Reference Example 25) in diethyl ether (50 ml), at −78° C. and under nitrogen, was treated dropwise with n-butyl lithium (0.025 ml, 1.6M). After stirring at −78° C. for 1 hour the resulting homogeneous solution was treated with dry dimethylformamide (6 ml) whilst maintaining the temperature below −65° C. The reaction mixture was allowed to warm to room temperature over 1 hour, then treated with a saturated aqueous solution of ammonium chloride (10 ml), and then extracted twice with ethyl acetate (100 ml). The combined extracts were evaporated to yield an orange oil which was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and pentane (1:4, v/v) to afford the title compound (2.3 g) as a semi-solid.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[CH:5][C:4]=1[C:8](Cl)=[O:9])[CH3:2].[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8]([C:4]2[CH:5]=[N:6][O:7][C:3]=2[CH2:1][CH3:2])=[O:9])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCc1oncc1C(=O)Cl
Product: CCc1oncc1C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
(of melting point 139° to 141° C.) from 5-ethylisoxazole-4-carbonyl chloride and 4-nitroaniline.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:18](COCC[Si](C)(C)C)[C:17]([CH3:27])=[N:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:6][CH:5]1[CH3:36])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:18]=[C:17]([CH3:27])[NH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:6][CH:5]1[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnc(C)n3COCC[Si](C)(C)C)cc2C(Nc2ccc(Cl)cc2)CC1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3c[nH]c(C)n3)cc2C(Nc2ccc(Cl)cc2)CC1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[Step 2] 12 mg (cis:trans=3:1) of 1-acetyl-6-{2-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1 H-imidazol-5-yl}-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 1 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added to the solution. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, trifluoroacetic acid and dichloromethane were distilled off under reduced pressure. The resulting residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and then was extracted three times with chloroform. The extraction product was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (methanol:chloroform=1:10), and thus 9 mg (cis:trans=3:1, 100%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:21])=[C:9]([CH3:20])[C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4].C(O)(=O)C>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:10]3[C:9]([CH3:20])=[C:8]([CH3:21])[S:7][C:6]=3[NH:5][C:3](=[O:4])[C:2]([CH3:23])([CH3:22])[N:1]=2)=[CH:13][CH:14]=1
Reactant: Cc1sc(NC(=O)C(C)(C)N)c(C(=O)c2ccc(Cl)cc2)c1C
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)C(=O)N2

Procedure:
A round bottomed flask was charged with 2-amino-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide (1 g, 2.85 mmol) and a stir bar. Ethanol (25 mL, 0.1 M) was added, followed by acetic acid (4.08 ml, 71.3 mmol, 25 equiv), and the solution was stirred at reflux 4 h before being concentrated and purified by column chromatography (eluting with hexanes/ethyl acetate) to yield 5-(4-chlorophenyl)-3,3,6,7-tetramethyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one as a yellow amorphous solid (m/z=333) that was used in the subsequent reaction.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:14]([O:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(CO)N1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CCC(=O)N1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To an ice cold solution of 5-Hydroxymethylpyrrolidin-2-one (5 grams, 43.4 mmol) in dichloromethane (174 mL) was added imidazole (6.5 grams, 95.5 mmol), 4-dimethylaminopyridine (530 mg, 4.3 mmol) followed by tert-butyldiphenylsilyl chloride (12.53 grams, 45.57 mmol). The reaction mixture was gradually warmed to room temperature and upon completion of 2 hours, diluted with dichloromethane, washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain title compound of 15.37 grams, as gummy liquid, which was taken up for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:10])[CH3:9].[Br:11]Br.C(OC)(C)(C)C.[OH-].[Na+]>C(O)(=O)C>[Br:11][C:5]1[S:4][C:3]([CH2:7][CH:8]([NH2:10])[CH3:9])=[C:2]([Cl:1])[CH:6]=1
Reactant: BrBr
Reactant: CC(N)Cc1sccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(N)Cc1sc(Br)cc1Cl
Temperature: 15 °C

Procedure:
In a sulfonation flask 5 g (0.028 mol) 2-(3-chlorothiphen-2-yl)-1-methylethylamine is dissolved in 70 ml of acetic acid. The mixture is then cooled to 15° C. and 4.8 g (0.30 m) of bromine is added under stirring (internal temperature 15-17° C.). After warming up to rt, the mixture is stirred for 16 hours. Then the mixture is poured to a mixture of tert. butylmethylether (ca. 250 ml) and 2N sodiumhydroxide. The final pH is 11. After washing with brine, drying with sodium sulphate and evaporation of the solvent the crude material is obtained. Purification is achieved by column chromatography over silicagel (eluent: tert. butylmethylether/EtOH 10:1). Yield: 5.4 g (75% of theory) of a colourless oil (1H-NMR: 1.18/d/3H, 2.68-2.87/m (diasterotopic protons)/2H, 3.2/m/1H, 6.87/s/1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FCCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (3 ml, 17.5 mmol) was added to a solution of 4-(2-fluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.5 mmol) in methylene chloride (12 ml). The reaction mixture was stirred at ambient temperature for 40 minutes, before the solvent was evaporated under high vacuum. The residue was azeotroped with toluene to give 1-(2-fluoroethyl)-piperazine diTFA salt (377 mg, 96%).