Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=2[CH3:21])=[C:11]2[C:6]([C:7]([Cl:22])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:21])=[C:11]2[C:6]([C:7]([Cl:22])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1C
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc2c(Cl)cccc2c1-c1ccc(O)cc1C
Yield: 108.8 %

Procedure:
Prepared according to Method D step C from 2-allyl-7-chloro-3-(4-methoxy-2-methylphenyl)-2H-indazole (0.068 g, 0.2 mmol), boron tribromide (0.20 mL, 2.10 mmol) and 1.0 mL of cyclohexene to give the product (0.065 g) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[N:50]=[C:21]3[C:22]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=4)=[C:23]([CH3:39])[C:24]([C:26]4[N:27]([C:31]5[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=5)[N:28]=[CH:29][CH:30]=4)=[CH:25][N:20]3[N:19]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([N:27]2[C:26]([C:24]3[C:23]([CH3:39])=[C:22]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:47])[F:48])[CH:41]=4)[C:21]4[N:20]([N:19]=[C:18]([NH:17][C:15]([NH:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:16])[N:50]=4)[CH:25]=3)=[CH:30][CH:29]=[N:28]2)=[CH:36][CH:35]=1)#[N:38]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 4-{3-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (Int. 32, 95 mg, 0.14 mmol) in DCM (2 mL) was added TFA (1 mL) and the solution was stirred at RT for 1 hr, then toluene (10 mL) was added and the reaction mixture concentrated in vacuo. The reaction mixture was partitioned between DCM (15 ml) and aqueous 2 M Na2CO3, and the organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (61 mg).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH3:29])=[O:14].CO.[OH-].[Na+].Cl>O>[Cl:10][C:8]1[CH:7]=[CH:6][C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:17][CH:16]2[CH3:29])=[O:14])=[C:4]([CH:9]=1)[C:3]([OH:30])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)CC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)/C=C/c1ccc(Cl)cc1C(=O)O
Reaction time: 8 h
Yield: 88.9 %

Procedure:
1.56 g (3.6 mmol) 5-Chloro-2-{(E)-3-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-3-oxo-propenyl}-benzoic acid methyl ester (Example 78) was suspended in a 1:1 mixture of methanol and water (20 ml). 0.5 ml 10 N NaOH was added and the mixture was stirred overnight. After acidification using 6.5 ml 1N HCl the product precipitated. Filtration and drying yielded 1.32 g (3.2 mmol, 87%) of the desired acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(C)C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C(O)C.[Ni].CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: [Ni]
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: CCCCCCCc1ccc([C@H]2CC[C@H](O)CC2)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-(4'-heptylphenyl)phenol (200 g) is dissolved in ethanol (0.5 l) and a commercially available Raney nickel (20 g) is added, followed by hydrogenation in an autoclave at 80°to 120° C. under a hydrogen pressure of 30 to 40 Kg/cm2G. The reaction is traced by gas chromatography (column: SIDC-560-10%, 2 m, 280° C.) and is stopped when the raw material is extinct. The catalyst is filtered off from the hydrogenation product and ethanol is distilled off under reduced pressure, followed by dissolving the residue in toluene (200 ml). On the other hand, metallic sodium (18.4 g) is added to toluene (400 ml) and heated to 110° C., followed by quenching under a high speed agitation to prepare a sodium dispersion, which is then cooled down to room temperature, after which the above toluene solution of the hydrogenation product is added and the mixture is then agitated at room temperature for one hour. The resulting material is agitated at 100° C., for 4 hours, followed by cooling and then gradually adding methanol (200 ml). The whole is transferred into a separating funnel, followed by washings twice with 10% hydrochloric acid (200 ml) and once with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and repeated washings with water untill the water layer becomes neutral. The toluene layer is dried over anhydrous sodium sulfate, followed by distilling off toluene under reduced pressure, adding n-hexane (200 ml) and standing overnight to obtain crystals of trans-4-(4'-heptylphenyl)cyclohexanol. Yield: 41.6 g, 20.4%. M.p.: 80.2°-82.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:26])[CH:11]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C>[Cl:27][C:11]1[C:12](=[O:26])[N:13]2[C:17](=[C:18]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH2:16][CH2:15][CH2:14]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)cc(=O)n2c1CCC2
Solvent: CN(C)C=O
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c(Cl)c(=O)n2c1CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
Example 9 (22 mg, 0.047 mmol) was dissolved in DMF (2 mL) and N-chlorosuccinimide (8 mg, 0.056 mmol) was added and the reaction was allowed to stir at r.t. for 4 hr. The mixture was concentrated in vacuo and purified by preparative HPLC (25/35 water/acetonitrile) to give 5 mg (21%) of the title compound. 1H NMR (400 MHz, MeOD): δ 7.98 (s, 1H), 7.50 (dd, 1H, J=10.0, 1.6 Hz), 7.44 (m, 1H), 6.87 (t, 1H, J=8.6 Hz), 4.17 (t, 2H, J=7.8 Hz), 3.59 (m, 2H), 3.34 (m, 2H), 3.17 (t, 2H, J=7.4 Hz), 2.43 (m, 2H). MS (ES) [m+H] calc'd for C17H16 ClFIN3O4, 508. found 508.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]([NH:26][CH2:27][CH:28]2[CH2:30][CH:29]2[C:31](OCC)=O)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C[O:39]CC1>>[C:7]1([C:13]([NH:26][CH2:27][CH:28]2[CH2:30][C:29]2([CH3:31])[OH:39])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(O)CC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of lithium aluminum hydride (0.077 g; 2.04 mmol) in 10 ml THF is added ethyl 2-triphenylmethylaminomethylcyclopropane-1-carboxylate (0.714 g; 1.85 mmol) in 20 ml THF and stirred overnight. The reaction mixture is quenched with water, filtered, concentrated in vacuo and flash chromatographed using hexane:ethylacetate;3:l to obtain 2-triphenylmethylaminomethyl-1-hydroxy-methylcyclopropane as a clear oil which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9]I>CN(C=O)C.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([CH3:9])[CH:4]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-5-bromo-pyridine (3.00 g, 17.3 mmol) in anhydrous DMF (25 mL) is added MeI (2.95 g, 20.76 mmol, 1.2 eq.). The mixture is stirred overnight at rt. The solution is diluted with EtOAc (200 mL) and extracted with H2O (4×100 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by silica gel chromatography eluting first with hexane/acetone (4:1) followed by elution with hexane/acetone (1:1) to yield the title compound. MS (+VE) m/z 188.02 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C([O:20][C:21](=O)[C:22](OCC)=[O:23])C.CC(C)([O-])C.[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:17])[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:22]([OH:23])[C:21]2=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(Cc1ccccc1)Nc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
After the addition of anhydride THF (20 ml) to compound 5d (1.40 g, 7.34 mmol), the temperature was adjusted to 0° C. Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35 g, 11.9 mmol) were added thereto and the agitation for 3 hours was carried out. After the identification of the reaction progress with TLC, the solution was poured into the distilled water and acidified with 1N HCL aqueous solution. Three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4 and solvents were removed. Crude purification was carried out by the column chromatography but the next reaction was followed since the purified compound was small in quantity.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][N:13]=[N+]=[N-])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=NCc1ccc(COc2ccc(Cl)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NCc1ccc(COc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
4-(4-Chloro-phenoxymethyl)-benzylazide (3.2 g, 11.7 mmol) was dissolved in MeOH (50 mL). NEt3 (11.35 mL, 81.9 mmol) and SnCl2×2H2O (5.28 g, 23.4 mmol) were added and the exothermic reaction was stirred under reflux. When boiling ceased the mixture was heated to reflux for additional 45 min. After cooling to r.t. the mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in CH2Cl2 (300 mL) and this solution was washed with sat. aq. NaHCO3-solution (1×100 mL), dried over Na2SO4, filtered and evaporated to dryness to give the title compound, pure enough for further reaction.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])[CH:22]=[N:21]1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]O)[CH2:34][CH2:33]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])[CH:22]=[N:21]2)[CH2:34][CH2:33]1
Reactant: CN1CCC(CO)CC1
Reactant: COC(=O)/C=C/c1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnn(CC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Triphenylphosphine (393 mg, 1.5 mmol) and (E)-methyl 3-(1H-pyrazol-4-yl)acrylate, prepared as described above, (12 mg, 1 mmol) were added to a solution of N-methyl-4-hydroxymethyl-piperidine (165 mg, 1.25 mmol) in tetrahydrofuran (THF, 2 mL). After addition of di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol), the reaction was stirred overnight at room temperature. Solvents were evaporated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of Hexane in EtOAc from 1:1 to 0:100 v/v. Fractions containing product were pooled and evaporated to give 220 mg of pure material (0.84 mmol, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](O)([CH3:17])[CH3:16])=[C:13]([O:19][CH3:20])[C:12]([O:21][C:22]2[C:30]([CH3:31])=[CH:29][C:28]([N:32]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:27]3[C:23]=2[CH2:24][CH2:25][CH2:26]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:33]([N:32]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:28]1[CH:29]=[C:30]([CH3:31])[C:22]([O:21][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:14]([C:15]([CH3:17])=[CH2:16])[C:13]=2[O:19][CH3:20])=[C:23]2[C:27]=1[CH2:26][CH2:25][CH2:24]2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1c(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)ccc(OCc2ccccc2)c1C(C)(C)O
Agent: Cl
Solvent: ClCCl
Product: C=C(C)c1c(OCc2ccccc2)ccc(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)c1OC
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
2-[6-Benzyloxy-3-(7-dibenzylamino-5-methylindan-4-yloxy)-2-methoxyphenyl]-propane-2-ol (13.9 g) was dissolved in dichloromethane (100 mL). Adding concentrated hydrochloric acid (40 mL), the mixture was stirred for 20 min vigorously. The organic layer was separated, and the water layer was extracted with dichloromethane. The combined organic layers were washed with a 2 mol/L aqueous solution of sodium hydroxide and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1−3/1) to give the title compound (7.97 g).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[C:12]([Cu])#[N:13]>C(#N)CC.CCOC(C)=O>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 86.6 %

Procedure:
To a stirred solution of 2,5-dibromo-3-nitro-pyridine (25 g, 88.68 mmol) in propionitrile (100 ml) was added CuCN (8.7 g, 97.55 mmol) and the mixture was heated to 90° C. for 17 h. Then it was allowed to cool to room temperature, diluted with EtOAc, washed twice with brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 95:5-85:15) to obtain the title compound as yellow solid (17.5 g, 68%).
Reaction SMILES: O=[C:2]([CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]2[C:15]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:10]=2[N:11]=1)=O.FC(F)(F)C([O-])=O.[NH4+:37]>O>[CH3:23][O:22][C:12]1[C:10]2[N:11]=[C:7]([C:5]3[NH:4][CH:3]=[C:2]([CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[N:37]=3)[S:8][C:9]=2[C:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)Cc3cccs3)nc12
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(Cc4cccs4)c[nH]3)nc12
Temperature: 25 °C
Yield: 13.1 %

Procedure:
A mixture of 0.04 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-3-thiophen-2-yl-propyl)-amide and 0.13 g ammonium triflouroacetate was melted at 165° C. for 60 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:1 gave 0.005 g (13%) 4-methoxy-7-morpholin-4-yl-2-(4-thiophen-2-ylmethyl-1H-imidazol-2-yl)-benzothiazole as yellow solid; MS (ISP): m/e=413 (M+H+).
Reaction SMILES: [CH3:1][Li].CI.[Li].Cl.[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH:14]2[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[CH2:17][CH2:16][N:15]2[CH3:23])=[CH:11][CH:10]=1>O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[C:19]([CH3:21])([CH3:20])[C:18]([CH3:1])([OH:22])[CH2:17][CH2:16][N:15]2[CH3:23])=[CH:24][CH:25]=1
Reactant: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Reactant: [Li]C
Agent: Cl
Agent: [Li]
Solvent: CI
Solvent: O
Product: COc1ccc(CC2N(C)CCC(C)(O)C2(C)C)cc1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a mechanically stirred and nitrogen flushed ethereal solution (200 ml) of methyl lithium (prepared in the usual manner from 43 g of methyl iodide and 4.8 g of lithium) there is added in small quantities 9 g of 2-(p-methoxybenzyl)-1,3,3-trimethyl-4-piperidone hydrochloride. During the addition, which takes some 1.5 hour, the mixture is cooled with water. It is stirred at room temperature for 16 hours and finally refluxed for 1 hour. Then the lithium compounds are hydrolysed by careful addition of water (cooling with ice) and the basic material is extracted from the mixture with the aid of 4 N hydrochloric acid. Basification of the aqueous solution followed by extraction with ether and processing of the ethereal solution as usual, gives crystals which after recrystallization from petroleum ether melt at 55°-65° C. Yield 84%. Evidently a mixture of epimeric piperidinols has been formed.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:26][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (22.1 g, 100 mol) in dichloromethane (500 mL) at 0° C. was added triethylamine (14 g, 138.6 mol) and cyclopentanamine (9 g, 105.9 mmol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, concentrated and purified by silica gel chromatography to afford the product N-cyclopentyl-2-nitrobenzenesulfonamide (23 g, yield 85.2%). 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.18 (m, 1H), 7.84-7.87 (m, 1H), 7.40-7.78 (m, 2H), 5.25-5.27 (d, 1H, J=7.6 Hz), 3.76-3.81 (m, 1H), 1.79-1.87 (m, 2H), 1.62-1.70 (m, 2H), 1.39-1.58 (m, 4H).
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](=[O:26])[CH2:11][C:10]1=[O:27]>C(Cl)Cl>[Br:1][CH:11]1[C:10](=[O:27])[N:9]([CH3:8])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:12]1=[O:26]
Reactant: BrBr
Reactant: CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)C(Br)C(=O)N(c2ccccc2)c2ccccc21

Procedure:
While irradiating with a 500 watt lamp at about 40° C., a solution of 5 ml of bromine and 30 ml of carbon tetrachloride was introduced dropwise into a solution of 25 g of the product of Step A and 750 ml of carbon tetrachloride. At the end of the introduction, the lamp was extinguished, the mixture was cooled and 500 ml of methylene chloride were added. The organic phase was washed with a saturated sodium carbonate solution, then with water and the product obtained was chromatographed on silica. Elution with an ethyl acetate-methylene chloride mixture 7-3-yielded 10.5 g of the sought product melting at 132° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:33][NH:34][O:35][CH3:36]>O1CCCC1>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: CNOC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)Cc1ccc(N(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a 0° C. mixture of 4-(dimethylamino)phenylacetic acid (4.91 g, 27.40 mmol) in tetrahydrofuran (150 ml), were added 2-chloro-4,6-dimethoxy-1,3,5-triazine (5.05 g, 28.76 mmol) and 4-methylmorpholine (9.6 ml, 87.32 mmol). The reaction mixture was stirred for 1 hour at 0° C. N,O-dimethylhydroxylamine hydrochloride (5.35 g, 54.84 mmol) was added and stirred for 18 hours at room temperature. The reaction was quenched with saturated ammonium chloride solution, and extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 40% ethyl acetate in hexanes) to give 2.76 g (45%) of 2-(4-dimethylamino-phenyl)-N-methoxy-N-methyl-acetamide. 1H NMR (250 MHz, CDCl3) δ 7.15 (d, J=8.7 Hz, 2H), 6.67 (s, J=8.7 Hz, 2H), 3.65 (s, 2H), 3.58 (s, 3H), 3.16 (s, 3H), 2.89 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[CH3:18][O:10][C:9](=[O:11])[C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:12]
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1

Procedure:
A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid (19.98 g) in methanol (250 ml) containing concentrated sulphuric acid (1 ml) was heated under reflux for 6.5 h. The solution was cooled, neutralised with aqueous sodium bicarbonate solution, and concentrated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried, and evaporated to give the title compound (21.13 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:15][CH:14]=[CH:13][CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1
Reactant: O=C1C=C2C(CC=CCN2Cc2ccc(Cl)nc2)O1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1C=C2C(CCCCN2Cc2ccc(Cl)nc2)O1
Reaction time: 24 h
Yield: 79.7 %

Procedure:
10 mg (0.036 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-4,5,8,8a-tetrahydro-2H-furo[3,2-b]azepin-2-one (1-6) are dissolved in 10 ml of toluene, 5 mg (0.005 mmol) of tris(triphenylphosphine)rhodium(I) chloride and 4 mg (0.015 mmol) of triphenylphosphine are added and the mixture is hydrogenated under a hydrogen pressure of 3 bar and at 110-120° C. for 24 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1 to 4:1) gives 8 mg (79% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-4,5,6,7,8,8a-hexahydro-2H-furo[3,2-b]azepin-2-one.