Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][NH2:20])=[O:18])[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:22]#[C:23]Br>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[O:18][C:23]([NH2:22])=[N:20][N:19]=4)=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)c1ccnc2[nH]c(CCc3ccccc3)cc12
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1nnc(-c2ccnc3[nH]c(CCc4ccccc4)cc23)o1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a solution of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbohydrazide (104 mg, 0.371 mmol) in N,N-dimethylacetamide (1 mL) was added a solution of cyanogen bromide (47 mg, 0.445 mmol) in N,N-dimethylacetamide (0.5 mL) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from N,N-dimethylformamide/water to give the title compound (50 mg, yield 44%) as pale-yellow crystals.
Reaction SMILES: [C@@H]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[CH2:21](Br)[CH:22]=[CH2:23].Cl.[OH-].[Na+]>CO.CS(C)=O>[NH2:18][C:17]1[NH:16][C:14](=[O:15])[C:13]2[N:12]([CH2:23][CH:22]=[CH2:21])[CH:11]=[N:10][C:20]=2[N:19]=1
Reactant: C=CCBr
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCn1cnc2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.9 %

Procedure:
A mixture of guanosine (20 g, 0.071 mol), allyl bromide (14.7 ml, 0.169 mol) and anhydrous DMSO (100 ml) was stirred at rt, under nitrogen, for 18 hours. Concentrated HCl (50 ml of 37%) was added in one portion and the mixture stirred for 45 minutes then poured into MeOH (600 ml). The methanolic solution was neutralised with 2M NaOH (aq) solution and the resulting white precipitate collected by filtration. The white solid was dried under vacuum at 50° C. for 18 hours to afford the title compound (16 g crude, 119%). m/z 192.2[MH+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].Cl.[CH2:11]([NH:14][CH:15]1[CH2:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16]1)[CH2:12][CH3:13]>C1C=CC=CC=1.C(N(CC)CC)C.O>[CH2:11]([N:14]([CH:15]1[CH2:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16]1)[C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH3:13]
Reactant: CCCNC1CCc2cc3c(cc2C1)OCC3
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(C(=O)Cc1cccs1)C1CCc2cc3c(cc2C1)OCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
A solution of (2-thienyl)acetyl chloride in 15 ml of benzene is added dropwise to a solution of 13 g of the compound of Example 34 in 160 ml of benzene and 10.2 g of triethylamine. After being stirred at room temperature for 3 hours, the mixture is diluted with water, extracted with anhydrous sodium acetate and then evaporated under vacuum. After passage through a silica column using a mixture of methylene chloride and ethyl acetate (95:5) as eluant, 4 g of oil are obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)nc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)nc1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.17 mmol) (from example 40, step 1) was dissolved in MeOH (1 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.051 mL, 0.17 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 10.66 μL, 0.17 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (0.896 mL, 5.38 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (60 mg, quant.) as a slightly yellow oil. MS m/z 372 (M+H)+
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexyl isocyanate (0.35 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclohexylamino)carboxamide (0.37 g, 49%) as a white solid: mp 208-210° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m. 3H), 6.34 (t, J=5.8 Hz, 1H), 6.04 (d, J=7.9 Hz, 1H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 3.37 (m, 1H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.76-1.02 (m, 10H); 13C NMR (DMSO-d6) δ 172.78, 169.84, 167.59, 167.04, 157.28, 141.13, 134.64, 133.42, 131.51, 126.98, 121.64, 48.82, 47.91, 38.66, 33.23, 30.94, 25.27, 24.47, 21.99; Anal. Calcd. For C21H24N4O5: C, 61.16; H, 5.87; N, 13.58. Found: C, 61.21; H, 5.79; N, 13.63.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39](=[O:53])[NH:40][C@@H:41]([CH2:51]O)[CH2:42][O:43][C:44]1[CH:45]=[N:46][CH:47]=[C:48]([Br:50])[CH:49]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1.CC#N.C1COCC1>[C:34]([O:38][C:39]([N:40]1[CH2:51][C@H:41]1[CH2:42][O:43][C:44]1[CH:45]=[N:46][CH:47]=[C:48]([Br:50])[CH:49]=1)=[O:53])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COc1cncc(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@H]1COc1cncc(Br)c1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
Ph3P (1.13 g, 4.32 mmol) was dissolved in 9:1 THF/CH3CN (30 mL) and cooled to 4° C. with an ice/water bath. DIAD (850 μL, 4.32 mmol) was added slowly. After stirring 15 min, a solution of Example 273B (1.0 g, 2.88 mmol) in THF (4 mL) was added slowly. The solution was allowed to warm to rt and stirred for over night. The solution was concentrated and the residual oil was purified by flash chromatography (20-40% EtOAc in hexane) to give the desired product (1.0 g, 75%). MS (DCI) m/z 329, 331 (M+1)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[NH2:22][C:23]1[C:24]([Cl:32])=[C:25](Cl)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=1.C(N(C(C)C)CC)(C)C>C(O)CCC.CCOC(C)=O>[NH2:22][C:23]1[C:24]([Cl:32])=[C:25]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[C:26](=[O:30])[N:27]([CH3:29])[N:28]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Cn1nc(N)c(Cl)c(Cl)c1=O
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1c(Cl)c(N)nn(C)c1=O)c1nc2ccc(F)cc2n1-c1ccccc1
Yield: 13.3 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (1.0 g, 3.05 mmol), 6-amino-4,5-dichloro-2-methyl-2H-pyridazin-3-one (J. Het Chem, 5-10 37, 2000) (0.59 g, 3.05 mmol) and diisopropylethylamine (2.1 mL, 12.8 mmol) in butanol (5 mL) was heated to 115° C. in a sealed tube under argon for 19 h. The reaction mixture was cooled and diluted with EtOAc (50 mL) and washed with water (20 mL). The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 1-8% (9:1 MeOH/0.880 NH3) in DCM then gradient 20-100% EtOAc in cyclohexane). Fractions containing the less polar product were evaporated and freeze dried to give 341 as a yellow solid, (167 mg, 13%). LCMS (Method C): RT 4.01 min [M+H]+ 313.02. 1H NMR δ (ppm DMSO-d6): 7.76 (1H, dd, J=8.81, 4.85 Hz), 7.56-7.40 (5H, m), 7.13 (1H, ddd, J=9.85, 8.80, 2.53 Hz), 6.88 (1H, dd, J=8.91, 2.51 Hz), 5.70 (1H, d, J=9.37 Hz), 5.61-5.60 (1H, m), 5.52 (2H, s), 3.37 (3H, s), 1.59 (3H, d, J=6.56 Hz)
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].F[C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:17]=3[C:16]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[C@@H:30]([CH2:35][CH2:36][O:37][CH3:38])[CH2:29]3)=[N:15][C:14]=2[CH:39]=1.[Cl:40]C1C=CC2NC3C=CC(C(F)(F)F)=CC=3C(N3CCN[C@@H](CCOC)C3)=NC=2C=1>>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[Cl:40][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:17]=3[C:16]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[C@@H:30]([CH2:35][CH2:36][O:37][CH3:38])[CH2:29]3)=[N:15][C:14]=2[CH:39]=1
Reactant: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Reactant: COCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Agent: O=C(O)CCC(=O)O
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Yield: 100 %

Procedure:
Using a method similar to Example (S)-8-fluoro-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine succinate, using (S)-8-chloro-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.051 g, 0.12 mmol) to give 0.054 g (100% yield) of the free base as a yellow oil which is converted to the succinate salt as described previously: Mass Spectrum (m/e): 454(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[H][H]>CO>[CH3:17][C@H:13]([C:14]([OH:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: C=C(C(=O)O)c1ccc2cc(OC)ccc2c1
Reactant: [H][H]
Solvent: CO
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 91.2 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.45 g (2 mmoles) of 6-methoxy-α-methylene-2-naphthaleneacetic acid and 20 ml of methanol. Then, 3.6 mg (0.004 mmole) of Ru2C14((-)-T-BINAP)2 (NEt3) prepared in Referential Example 1 was added to the mixture to perform hydrogenation for 24 hours at a hydrogen pressure of 40 kg/cm2 and at a reaction temperature of 20° C. Thereafter, the solvent was distilled off to provide 0.42 g of naproxen. The yield was 92%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.[C:12](=N)(OCC)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:13]([C:12]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][OH:10])=[CH:3][C:2]=2[N:1]=1)[CH2:14][CH3:15]
Reactant: CCCC(=N)OCC
Reactant: Nc1ccc(CO)cc1N
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cc(CO)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.9 parts of 3,4-diaminobenzenemethanol, 8.3 parts of ethyl butanimidate hydrochloride and 80 parts of ethanol is stirred first for 2 hours at room temperature and further for 2 hours at reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with ammonium hydroxide and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated, yielding 6.2 parts of 2-propyl-1H-benzimidazole-5-methanol as a residue.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:11]([N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)=[N:3]1)[CH3:12]
Reactant: CCn1nc(Br)c2ncccc21
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCn1nc(-c2ccc(O)cc2)c2ncccc21
Yield: 36.9 %

Procedure:
A mixture of 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (904 mg), (4-hydroxyphenyl)boronic acid (690 mg), Pd(PPh3)4 (139 mg), Na2CO3 (1.48 g), DME (17.5 mL), and H2O (3.5 mL) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue purified by basic silica gel column chromatography (AcOEt) and crystallized from hexane/AcOEt to give the title compound (353 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 1.35 g (5.233 mmol) of the product of Example 50 dissolved in 20 mL of chloroform and 1.5 mL of pyridine was added 1.02 g (5.233 mmol) of 4-fluorobenzenesulfonyl chloride and the resulting mixture was stirred overnight at room temperature. The chloroform was removed in vacuo and the residue was diluted with ether and washed with water, 5% HCl solution and saturated sodium bicarbonate solution and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether/hexanes (1:1) and the solid was collected by filtration and dried in vacuo to provide 1.50 g (69%) of the sulfonamide as a white solid. Electrospray Mass Spec: 416.9 (M+H)+
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Si:13](/[CH:20]=[CH:21]/[CH2:22][OH:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>ClCCl>[Si:13](/[CH:20]=[CH:21]/[CH2:22][OH:23])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14].[CH3:8][S:9]([O-:11])(=[O:23])=[O:10]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)[Si](C)(C)/C=C/CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)[O-]

Procedure:
As for the preparation described in Example 39, 1.6 ml (11.4 mmol) of triethylamine and 0.74 ml (9.55 mmol) of methanesulfonylchloride in 15 ml of dry dichloromethane are added to 1.3 g (7.6 mmol) of (E)-3-(t-butyldimethylsilyl)-2-propen-1-ol. [Lipshutz et al., J. Org. Chem. 54(21), 4975 (1989)] in 20 ml of dry dichloromethane to give after purification by flash chromatography on silica gel and elution with petroleum ether: ethyl acetate 9:1 1.3 g (67%) of expected (E)-3-(t-butyldimethylsilyl)-2-propen-1-ol, methanesulfonate as a colorless liquid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([OH:56])=O)(=[O:44])=[O:43])=[C:37]([CH3:57])[CH:36]=1.[N:58]1([CH2:63][CH2:64][O:65][C:66]2([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:81])([F:80])[F:79])[CH:73]=3)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH2:62][CH2:61][CH2:60][CH2:59]1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:57])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([N:69]2[CH2:70][CH2:71][C:66]([O:65][CH2:64][CH2:63][N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:80])([F:79])[F:81])[CH:73]=3)[CH2:67][CH2:68]2)=[O:56])(=[O:43])=[O:44])=[C:39]([CH3:41])[CH:40]=1
Reactant: FC(F)(F)c1cccc(C2(OCCN3CCCC3)CCNCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCCC3)(c3cccc(C(F)(F)F)c3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Diisopropylethylamine (4 eq.), EDCl HCl (1.2 eq.) and HOBt (1 eq.) were added to a mixture of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (0.65 mmol) in methylene chloride (10 ml). A mixture of 4-(2-(pyrrolidin-1-yl)ethoxy)-4-(3-(trifluoromethyl)phenyl)piperidine [amine H] and DIPEA (2 eq.) in methylene chloride (3 ml) was added dropwise, while cooling with ice, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and with sat. sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by means of column chromatography (silica gel, methanol/methylene chloride) to obtain the desired product. Yield: 78%. MS, Rt=3.9 min, m/z=696.4 [MH]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[C:17]([O:25][C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:66]>C1COCC1.O1CCOCC1>[ClH:66].[F:22][C:21]([F:23])([F:24])[C:20]1[CH:15]=[CH:16][C:17]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidine carboxylate (1.0 g, 5.0 mmol) in anhydrous THF (5 mL) was added 4-[(4-trifluoromethyl)phenoxy]phenol (1.65 g, 6.5 mmol) in THF (5 mL) and triphenyl phosphine (1.57 g, 6 mmol) in THF (5mL). The resulting mixture was cooled to 0° C. using ice-water bath and purged with nitrogen. Diisopropyl azodicarboxylate (1.21 g, 6 mmol) was dissolved in 5 mL of THF and added to above solution drop wise over a period of 30 min under nitrogen. Reaction then was stirred at 0° C. for 0.5 h heated at 70° C. for 16 h. THF was removed in vacuo and crude mixture was purified by silica gel flash chromatography (10% EtOAc/Hexane) to obtain the product. To a solution of the product in dioxane (4 mL) was added 4M HCl in dioxane (10 mL) at rt and the resulting mixture was stirred for 2 h at that temperature. The solvent was removed in vacuo and residue was triturated with ether to obtain a white solid (1.21 g, 65%): MS; m/z 338.4 (M+H), 1H NMR (400 MHz, DMSO-d6); δ 1.83-1.90 (m, 2H), 2.09-2.14 (m, 2H), 3.03-3.09 (m, 2H), 3.20-3.26 (m, 2H), 3.32 (s, 1H), 4.62-4.66 (m, 1H), 7.06-7.10 (m, 7H), 7.70 (d, 2H, J=8.8 Hz), 9.08 (s, 2H); HPLC (UV); 97%.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[CH:13][CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Product: CC(N=Cc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
9.96 g (0.082 mole) of (R)-(+)-1-phenylethylamine and 10.54 g (0.086 mole) of p-hydroxybenzaldehyde were dissolved in 140 ml of ethyl alcohol, and the resulting solution was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, and the crystalline material thus formed was separated by filtration to give 13.0 g of (-)-N-(p-hydroxybenzylidene)-1-phenylethylamine. Yield: 70.4%.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([S:19]([NH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.7 %

Procedure:
3.8 g of N-aminomorpholine (36.9 mmol) and 5.1 ml of triethylamine (3.7 g, 36.9 mmol) were dissolved at room temperature in 40 ml of methylene chloride. Again at room temperature 4.8 ml of n-butanesulfonyl chloride (5.8 g, 36.9 mmol) were added dropwise to this solution over the course of one hour. After 20 h of stirring at room temperature the reaction mixture was extracted by shaking twice with 50 ml of water and the organic phase was dried over magnesium sulphate and concentrated. The 6.7 g of crude product obtained were recrystallized from 30 ml of tert-butyl methyl ether. The constitution of the target compound was verified by NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.Cl.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([Br:18])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Br)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccccc2)c(Br)c1

Procedure:
To a solution of 1-benzyloxy-2-bromo-4-nitrobenzene (50 mg, 0.16 mmol) in ethanol (5 mL) and H2O (0.5 mL) was added iron (134 mg, 2.43 mmol) and one drop of concentrated HCl. The mixture was refluxed for 6 hrs and filtrated. The filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonated solution, dried over sodium sulfate and concentrated to afford crude 4-amino-1-benzyloxy-2-bromobenzene.