Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc(-c2cc(C(Cl)CC(C)C)c(C)o2)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (400 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.7 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (153 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](N(OC)C)=[O:12])=[CH:5]2.[CH2:17]([Li])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5]2
Reactant: [Li]CCCCCC
Reactant: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: C1CCOC1
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a cooled (−78° C.) solution of the title compound of Example 1 Step A (ca. 42.6 mmol) in THF (100 mL) was added n-hexyllithium (74 mL, 2.3 M in hexanes, 170.4 mmol) dropwise. The mixture was stirred at −78° C. for 2 h, then was quenched by addition of 2 N aqueous hydrochloric acid. The resulting suspension was allowed to warm to room temperature, then was extracted with ethyl acetate. The organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc in hexanes) provided the title compound: LCMS B, tr=2.70 min, m/z 264.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.37 (br s, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.29 (dd, J=9.0, 2.0 Hz, 1H), 7.13 (s, 1H), 2.94 (t, J=7.5 Hz, 2H), 1.78 (quint., J=7.5 Hz, 2H), 1.43-1.29 (m, 6H), 0.89 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:2]1.[C:16]1([C:22]2[O:26][C:25]([C:27](OCC)=[O:28])=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][N:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:3]2[CH2:2][N:1]([C:27]([C:25]3[O:26][C:22]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:23][N:24]=3)=[O:28])[CH2:4]2)=[CH:11][CH:10]=1)[CH3:15]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: CN(C)Cc1ccc(OC2CNC2)cc1
Product: CN(C)Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Yield: 38 %

Procedure:
Using a similar protocol as described in Example 16 employing 33B (0.10 g, 0.48 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.12 g, 0.53 mmol) as starting materials afforded 69 mg (38%) of 33 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.24 (s, 6H), 3.37 (s, 2H), 4.34 (dd, 1H), 4.65 (dd, 1H), 4.77 (dd, 1H), 5.10 (m, 2H), 6.74 (d, 2H), 7.24 (m, 2H), 7.55 (m, 3H), 8.15 (d, 2H), MS (APCI+) m/z 379 [M+H]+, LC purity: 95%.
Reaction SMILES: C(O[C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@:11]2([CH2:26][OH:27])[C@H:9]1[CH2:10]2)=[O:7])(C)(C)C.[C:28]([C:31]1[N:32]=[C:33]([CH2:40]C(O)=O)[N:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=12)(=[O:30])[CH3:29]>C(Cl)Cl.CO>[Cl:23][C:19]1[C:18]([F:24])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C@@H:13]1[CH2:12][C@:11]2([CH2:26][OH:27])[C@@H:9]([CH2:10]2)[N:8]1[C:6](=[O:7])[CH2:40][C:33]1[N:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]2=[C:31]([C:28](=[O:30])[CH3:29])[N:32]=1)=[O:25]
Reactant: CC(=O)c1nc(CC(=O)O)n2ccccc12
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(CO)C[C@@H]12
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1nc(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)n2ccccc12

Procedure:
was prepared using the protocols described for the preparation of Example 758 from (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]-hexane-2-carboxylic acid tert-butyl ester (prepared as described in Scheme B28) and (1-acetyl-imidazo[1,5-a]pyridin-3-yl)-acetic acid (prepared as described in Scheme A19). Rf, TLC (CH2Cl2/MeOH 9:1)=0.40; MS (UPLC/MS): 499.4/501.4 [M+H]+, 521.4/523.4 [M+Na]+, 543.5/545.5 [M+HCOO]−; tR (HPLC conditions f): 1.66 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:4][CH:3]1[C:5]([O:7][CH3:8])=[O:6].[CH2:10]([OH:12])[CH3:11]>Cl(O)(=O)(=O)=O>[CH2:10]([O:12][C:2]([CH3:9])([CH3:1])[CH:3]([OH:4])[C:5]([O:7][CH3:8])=[O:6])[CH3:11]
Reactant: CCO
Reactant: COC(=O)C1OC1(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(C)(C)C(O)C(=O)OC
Temperature: 50 °C
Yield: 91.6 %

Procedure:
Methyl 3,3-dimethylglycidate (20.0 g, 0.154 mmol) and ethanol (30 mL) were introduced into an eggplant type flask (100 cc) and stirred at room temperature while 70% perchloric acid (5 drops) was added gradually. The resulting reaction solution was heated at 50° C. for 2 hours with stirring. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a small amount of anhydrous sodium carbonate was added. The reaction solution was left to stand at room temperature for a while, and then the solid was removed by filtration to obtain methyl 3-ethoxy-2-hydroxy-3-methylbutanoate (24.9 g, yield 91.6%) as a transparent liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>N1C=CC=CC=1>[S:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)([CH3:26])(=[O:25])=[O:24]
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a stirred solution of 5-amino-3-(quinol-4-ylmethylene)-2-oxindole (2.873 g, 10 mmol) in pyridine (10 ml) was added gradually mesylchloride (1.146 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 5 h at 0°-5° C. and then for 15 hours at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 70% yield.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[N:18]([C@H:21]1[C@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]([S:31]([O-:34])(=[O:33])=[O:32])[C:22]1=[O:35])=[N+]=[N-]>CO.[Pt]=O>[NH2:18][C@H:21]1[C@H:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:23]([S:31]([OH:34])(=[O:32])=[O:33])[C:22]1=[O:35]
Reactant: [N-]=[N+]=N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1c1ccccc1
Agent: O=[Pt]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: N[C@@H]1C(=O)N(S(=O)(=O)O)[C@H]1c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of (±)-(trans)-3-azido-2-oxo-4-phenyl-1-azetidinesulfonic acid, tetrabutylammonium salt (see example 181) in 4 ml of methanol is hydrogenated over 30 mg of platinum oxide at 1 atmosphere and room temperature. After 15 minutes, the system is evacuated and fresh hydrogen is introduced. After an additional 45 minutes the reaction is complete, and the system is flushed with nitrogen. After several days at room temperature in dichloromethanemethanol (4:1, 200 ml) catalyst aggregation is complete and filtration is accomplished. The filtrate is concentrated in vacuo to 18 ml and 0.2 ml of 97% formic acid is added. After cooling at 5° C. for several hours the resulting solid is filtered and washed with dichloromethane to afford, after drying, 150 mg of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:20][OH:21]>CCO>[NH2:2][C:1](=[N:20][OH:21])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)COCCc1cccc(C#N)c1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)COCCc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
tert-butyl [2-(3-cyanophenyl)ethoxy]acetate obtained in step 1 (1.42 g; 5.43 mmol) was dissolved in EtOH (28.40 mL) to which was added hydroxylamine (401.26 μL; 50%, 27.17 mmol). Reaction mixture was stirred at RT for 18 h after which solvents were removed under vacuum, solubilized in a water/ACN mixture (1:1) and lyophilized to give the desired compound as a sticky colorless oil (1.32 g; 82%). 1H NMR (DMSO-d6, 300 MHz) δ 9.56 (bs, 1H), 7.53-7.48 (m, 2H), 7.27-7.25 (m, 2H), 5.76 (bs, 2H), 3.96 (s, 2H), 3.67 (t, J=6.9 Hz, 2H), 2.83 (t, J=6.5 Hz, 2H). LC/MS (Method B): 295.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]2[CH:33]=[CH:34][N:35]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]=2[C:19]1=[O:46]>>[CH:14]1([CH2:13][O:12][C:3]2[C:2]([C:22]3[C:21]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:20]=4[C:19](=[O:46])[N:18]([CH3:17])[CH:23]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2[CH:5]=[N:6][N:7]3[CH3:11])[CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: Cn1ncc2c(OCC3CC3)c(Br)ccc21
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(cnn5C)c4OCC4CC4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-(cyclopropylmethoxy)-1-methyl-1H-indazole and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C27H27N4O4S (M+H)+: m/z=503.2. found: 503.1.
Reaction SMILES: C(OP(N)(=O)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[N:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[C:17]=23)=[CH:9][C:8]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(C)C.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:63]=2)C=CC=1OCC1C=CC(OC)=CC=1)C1C=CC=CC=1.O=P(Cl)(Cl)Cl>>[NH2:63][C:18]1[C:17]2[N:16]([C:15]([CH:23]3[CH2:24][CH2:25][CH2:26]3)=[N:14][C:13]=2[C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:9]=2)[CH:21]=[CH:20][N:19]=1
Reactant: COc1ccc(COc2ccc(C(NC(=O)C3CCC3)c3nccnc3Cl)cc2OCc2ccccc2)cc1
Reactant: CC(C)OP(N)(=O)Oc1ccc(-c2nc(C3CCC3)n3ccnc(Cl)c23)cc1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(O)c(OCc4ccccc4)c3)c12

Procedure:
Phosphoramidic acid 2-benzyloxy-4-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-phenyl ester isopropyl ester: Followed General Cyclization described in Example 92-(a) whereby Cyclobutanecarboxylic acid [[3-benzyloxy-4-(4-methoxybenzyloxy)-phenyl]-(3-chloropyrazin-2-yl)-methyl]-amide was treated with POCl3 and then quenched with 2N NH3 in iPrOH to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 1.31 (d, 3H, J=6.0 Hz), 1.35 (d, 3H, J=6.4 Hz), 2.01-2.26 (m, 2H), 2.47-2.69 (m, 4H), 3.02 (d, 2H, J=4.0 Hz), 3.84 (quintet, 1H, J=8.4 Hz), 4.78 (septet, 1H, J=6.1 Hz), 5.17 (s, 2H), 7.27-7.53 (m, 10H); MS (ES): 526.9/528.9 (M/M+2).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:16][CH2:15][CH2:14]1.[C:24](=O)([O:27]C)[O:25][CH3:26]>CCOCC>[O:23]=[C:18]1[CH:19]([C:24]([O:25][CH3:26])=[O:27])[CH2:20][CH2:21][CH2:22][C:17]21[CH2:13][CH2:14][CH2:15][CH2:16]2
Reactant: O=C1CCCCC12CCCC2
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C1CCCC2(CCCC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.97 mL, 41.9 mmol) in ether (30 mL) was cooled to −78° C. and then was treated slowly with n-butyllithium (16.75 mL, 41.9 mmol). The mixture was stirred at −78° C. for 30 minutes, then this solution was transferred via cannula into a −78° C. solution of Example 1A (4.25 g, 27.9 mmol) in ether (30 mL). The mixture was stirred at this temperature for 30 minutes and then was treated with dimethyl carbonate (23.50 mL, 279 mmol). The resulting mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was quenched with saturated NH4Cl and diluted with ether (100 mL), then the layers were separated. The aqueous layer was extracted with additional ether, then the organic layers were combined, dried with MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica gel (100% hexane to 85:15 EtOAc/hexanes, eluant) to provide the title product. 1H NMR (300 MHz, CDCl3) δ 12.40-12.42 (m, 1 H), 3.72-3.76 (m, 3 H), 2.18-2.26 (m, 2 H), 2.00-2.12 (m, 2 H), 1.74-1.86 (m, 2 H), 1.57-1.62 (m, 2 H), 1.54-1.57 (m, 2 H), 1.35-1.48 (m, 4 H). MS (DCI+) m/z 211 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:11])/[C:7](=[N:12]\[OH:13])/[C:8](=[O:9])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. To this solution is added dropwise at 5°-10° C. during 21/2 hours a solution of 290.6 g of sodium nitrite in 655 ml of water. The resulting yellow suspension is stirred for 30 minutes at 20° C., treated with 940 ml of water and stirred for a further 2 hours. The mixture is treated with 900 ml of water and 900 g of ice and extracted in the stirring vessel three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 l of water each time, then treated with 5 l of water and the pH-value is adjusted to 6.8 with sodium hydrogen carbonate. After separating the aqueous phase, the organic phase is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated in vacuo at 40° C. There is obtained (Z)-2-hydroxyimino-3-oxo-butyric acid tert-butyl ester as a yellow oil which is dried for a further 9 hours in a high vacuum at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][NH2:29])[CH3:24].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH3:31])[CH2:23][CH3:24])=[O:12])[CH2:7]1
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Reactant: CCN(CC)CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNC(=O)N1CCC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 78 h

Procedure:
A stirred solution, 13 g (0.05 mole) of 3-(3-chlorophenoxy)-1-pyrrolidinecarbonyl chloride in 100 ml of chloroform was treated with 25 mg of ice and 12.8 g of sodium carbonate after 5 min. This mixture was treated with 7.15 g (0.055 mole) of N,N-diethyl-1,3-propanediamine dropwise and allowed to stir for 78 hours. The reaction mixture was transferred to a separatory funnel and enough water was added to form two distinct phases. The organic phase (chloroform) was separated and washed with 50 ml of water; the organic portion was extracted with 50 ml of 3N hydrochloric acid, separated and washed with 2×25 ml of water. All the aqueous portions were combined and the pH adjusted to neutral with 3N sodium hydroxide and extracted with 4×30 ml of chloroform. The extract was combined, washed with water, dried over magnesium sulfate and concentrated on a rotary vacuum to a pale yellow oil (12 g). The oil was dissolved in chloroform, treated with 1.5 g of charcoal and filtered hot. This was then slurried with 25 g of silica gel and filtered. The chloroform was discarded and the silica gel washed with methanol to give, after concentrating, 4 g of pale yellow oil. This was dissolved in ethyl ether and filtered through celite.
Reaction SMILES: [N:1]([CH2:4][C@:5]1([F:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@:5]1([F:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN)C1
Yield: 101.3 %

Procedure:
1,1-Dimethylethyl (3S)-3-(azidomethyl)-3-fluoro-1-piperidinecarboxylate (36 g, 139 mmol) was dissolved in ethanol (500 ml) and added under nitrogen to Pd/C (2.6 g, 1.222 mmol). The mixture was hydrogenated at atmospheric pressure overnight. The suspension was filtered and the filtrate evaporated in vacuo to give 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate as a pale yellow oil (32.7 g). 1H NMR (CDCl3) 3.75-3.52 ppm (2H, 2×m, 2×CH), 3.30 ppm (1H, dd, CH), 3.20 ppm (1H, m, CH), 2.90-2.73 ppm (2H, m, CH2), 1.96-1.72 ppm (2H, 2×m, CH2), 1.70-1.58 ppm (1H, m, CH), 1.57-1.43 ppm (10H, m+s, CH+3×CH3), 1.32 ppm (2H, br.s, NH2).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15](Cl)=[O:16])[CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8]>C1C=CC=CC=1>[C:15]([CH:12]1[CH2:13][CH2:14][CH:9]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]1)(=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCC1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCC1CCC(C(=O)c2ccccc2)CC1
Temperature: 40 °C

Procedure:
To a stirred mixture of 500 ml abs. benzene and 240 g (1.8 mol) AlCl3 at 20° C., within 60 minutes, are added, dropwise, 302 g (1.5 mol) of 4-n-butyl-cyclohexanecarboxylic acid chloride (cis-trans mixture). The clear orange-yellow solution is then heated to 40° C. for 1 to 2 hours, cooled and poured onto 500 ml ice/concentrated HCl. The organic phase is separated, washed with water, with 10% aqueous potassium hydroxide solution and washed with water again. The aqueous phase is extracted two to three times with benzene or ether. The combined organic extracts are dried over Na2So4 and the solvent is removed in vacuum.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20].BrC(C)C.Cl>CS(C)=O.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([O:7][CH:2]([CH3:3])[CH3:1])[C:12]=2[CH:13]=1
Reactant: COC(=O)c1oc2ccc(OC)cc2c1O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)Br
Solvent: CS(C)=O
Product: COC(=O)c1oc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of potassium tert-butoxide (12.0 g, 107 mmol) in 50 mL of methyl sulfoxide is cooled in a cold water bath while a solution of methyl 3-hydroxy-5-methoxy-2-benzofurancarboxylate (16.2 g, 73 mmol) [Connor D. T., et al., J. Med, Chem. 35, 958 (1992)] in 150 mL of methyl sulfoxide is added dropwise. The mixture is stirred for 45 minutes and 2-bromopropane (12.0 mL, 15.7 g, 128 mmol) is added in one portion. After stirring at room temperature for 48 hours, the mixture is added to 1.2 kg of ice and water and acidified with 6.0N HCl . The mixture is extracted with dichloromethane, and the combined organic layers are washed with water, 5% aqueous Na2CO3, and water again, then dried (anhydrous sodium sulfate) and evaporated to an oil residue. The oil is purified by bulb-to-bulb vacuum distillation to provide 14.2 g (74%) to methyl 5-methoxy-3 -(1-methylethoxy)-2-benzofurancarboxylate, suitable for further synthesis; mp=55°-63° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:2]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([N:31]2[CH2:30][CH:29]=[C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:34])[F:35])[CH:23]=3)[CH2:33][CH2:32]2)=[O:10])[CH:2]=1
Reactant: O=C(Cc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: CCO
Product: O=C(Cc1cccnc1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
A suspension of 11.3 g of p-nitrophenyl 3-pyridylacetate and 10 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine in 150 ml of ethanol is stirred 1 hour at room temperature, then concentrated under reduced pressure. The residue is dissolved in diethyl ether, the solution is washed with water, then with sodium hydroxide and again with water, dried on anhydrous sodium sulfate and concentrated. Thus, 1-(3-pyridylacetyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (8 g) is obtained as an oil which is used for the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: Cc1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of o-toluidine (1.07 ml, 10 mmol) and pyridine (0.86 ml, 10.6 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (0.81 ml, 10.5 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by 1 N HCl aqueous solution and extracted with EtOAc. The organic layer was concentrated in vacuo to afford the title compound (1.84 g, 10 mmol, quant.) as an orange solid.