Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:4]=1[F:21])=[O:29]
Reactant: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 49.7 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (0.059 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.041 g, 0.090 mmol, 49.6% yield) as a white solid. The mother liquor was concentrated to small volume, diluted with IPA, stirred for 30 minutes, and filtered to give a second batch of 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.011 g, 0.024 mmol, 13.31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.25 (t, J=5.56 Hz, 1H), 7.88-7.99 (m, 1H), 7.78 (s, 1H), 7.37-7.57 (m, 2H), 7.30 (s, 1H), 4.55 (d, J=5.49 Hz, 2H). LC-MS (ES−) m/z 455.10, 457.03 [M−1]. LC-MS (ES+) m/z 456.99, 459.87 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]([CH3:24])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]2([CH3:23])[CH3:22])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:24])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2([CH3:23])[CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CN(C)C2CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(C)C2CCNCC2(C)C)cc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-((4-methoxybenzyl)(methyl)amino)-3,3-dimethylpiperidine-1-carboxylate (1.87 g, 5.17 mmol, 1 eq) was dissolved in dichloromethane (4 ml); TFA (4 ml) was added at 0° C., and stirring was carried out for 2 h at RT. The reaction solution was concentrated under reduced pressure, taken up in toluene and dried again. The crude product was used in the next stage without being purified further.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:10](OC)=[O:11]>CO>[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]=[O:11])[CH2:6][CH2:5]1
Reactant: COC=O
Reactant: NCCN1CCNCC1
Solvent: CO
Product: NCCN1CCN(C=O)CC1
Yield: 48.2 %

Procedure:
Corresponding to Example 1, 774.3 g (6.00 mol) of N-2-aminoethylpiperazine in 300 ml of methanol were reacted with 120.0 g (2.00 mol) of methyl formate and 151.6 g (48% of theory) of N-2-aminoethyl-N'-formylpiperazine were obtained at 0.1 mm Hg between 115 and 120° C. in the form of a yellowish liquid
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=3)=[C:22]([O:33][CH3:34])[CH:21]=2)[N:7]=1)=[CH2:5])C.O.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.[Cl-].[Na+].O>[CH3:34][O:33][C:22]1[CH:21]=[C:20]([NH:19][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[N:9]=2)[CH:25]=[CH:24][C:23]=1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=1
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-c1cnnc(C)c1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
4-(1-Ethoxyvinyl)-N-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-2-amine (65 mg, 0.14 mmol) was dissolved in dioxane (10 mL). Water (0.5 mL) and hydrochloric acid (conc., 0.035 mL, 0.41 mmol) were added. The mixture was heated at 40° C. for 20 min. Sodium bicarbonate (s, 0.5 g) and brine (2 mL) were added and mixture was stirred for 10 min. The mixture was extracted with EtOAC (×2). The organic phase was dried (sodium sulfate) and evaporated to give the title compound as a solid 60 mg (98%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1>CC(=O)OCC.[Pd]>[NH2:11][C@@H:12]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:25][CH:26]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)OC(C)(C)C)cc3)nc2)cc1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-8 (591 mg, 0.95 mmol) in EA (25 ml) was added Pd/C (101 mg, 0.09 mmol) and the suspension degassed with H2. The mixture was stirred vigorously under an atmosphere of H2 overnight then filtered through celite and the filtrate was concentrated to give 405 mg (83%) of (S)-tert-butyl 2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-9. LCMS-ESI (m/z) calculated for C30H39N3O3: 489.3. found: 490.2 [M+H]+, tR=2.35 min (Method 8).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][C:8]([NH:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[C:37]([Cl:38])=[C:36]([C:39](Cl)=[O:40])[S:35][C:34]=2[CH:42]=1)=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[C:37]([Cl:38])=[C:36]([C:39](=[O:40])[N:16]([C:8]3[CH:9]=[CH:10][C:11]4[S:12][C:13]5[C:4](=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=5)[C:5](=[O:18])[C:6]=4[CH:7]=3)[CH3:17])[S:35][C:34]=2[CH:42]=1)=[O:29]
Reactant: COC(=O)c1ccc2c(Cl)c(C(=O)Cl)sc2c1
Reactant: CNc1ccc2sc3ccc(Br)cc3c(=O)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(Cl)c(C(=O)N(C)c3ccc4sc5ccc(Br)cc5c(=O)c4c3)sc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To 0.51 g (1.6 mmol) of 2-bromo-7-methylamino-thioxanthen-9-one (14) and 10 mL of triethylamine in 15 mL of anhyd CH2Cl2 was added 0.61 g (2.1 mmol) of 3-chloro-2-chlorocarbonyl-benzo[b]thiophene-6-carboxylic acid methyl ester (12) dissolved in 10 mL of anhyd CH2Cl2 at 5-8° C. in an ice bath. A catalytic amount of DMAP was added. The reaction mixture was warmed at room temperature and stirred for 48 h under N2. The reaction mixture was filtered to remove triethylamine hydrochloride salt, the filtrate was washed three times with aq saturated NaHCO3, H2O, three times with aq. 2N HCl to remove unreacted amines, H2O, brine, dried over Na2SO4, and concentrated in vacuo to give crude ester 10. The crude ester 10 was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane to give 0.55 g (60% yield) of NMR pure 10 (LG−=Cl−) as a brown powder, mp 237-239° C. Found: C, 52.09; H, 2.64; N, 2.47%; calcd for C25H15NO4S2ClBr: C, 52.40; H, 2.62; N, 2.44%; 1H-NMR (400 MHz, CDCl3): 3.61 (3H, s), 3.92 (3H, s), 7.35-7.54 (3H, m), 7.66-7.80 (2H, m), 8.02 (1H, d, J=8.2 Hz), 8.40 (1H, s), 8.51 (1H, s), 8.69 (1H, s); 13C-NMR (100 MHz, CDCl3): 38.3, 52.6, 120.8, 120.9, 122.8, 124.9, 126.3, 127.3, 127.4, 127.8, 128.6, 129.6, 130.0, 131.0, 132.7, 134.1, 135.8, 136.1, 137.6, 138.7, 141.4, 162.5, 166.5, 178.1.
Reaction SMILES: [N:1]([O-])=O.[Na+].C(O)(=O)C.[CH3:9][O:10][CH:11]([O:30][CH3:31])[CH:12]([NH:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[NH2:29])[CH3:13]>O.C(COC)OC>[CH3:9][O:10][CH:11]([O:30][CH3:31])[CH:12]([CH3:13])[N:14]1[C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[N:29]=[N:1]1
Reactant: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: O
Product: COC(OC)C(C)n1nnc2ccc(OCc3ccccc3)cc21
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A solution of NaNO2 (34 g, 0.492 mole) in water is added to a cold (3° C.) solution of acetic acid and water. A cold (4° C.) solution of 2-[2-amino-5-(benzyloxy)anilino]-propionaldehyde dimethyl acetal in dimethoxyethane is then added in one portion to the vigorously-stirred NaNO2 acetic acid solution. The reaction temperature rises to 22° C. The reaction mixture is stirred at 18°-22° C. for 20 minutes, cooled to 5° C., and filtered. The solid filter cake is washed with water and dried at 50° C., to give the title product as a white solid, 75.7 g (65.7%). A sample is recrystallized twice from 1:1 toluene-heptane solution to a white solid, mp 101°-103° C. (sinter 100° C.), identified by elemental and NMR analyses.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:33][N:34](C=O)C>[Cl-].[NH4+].C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([C:33]#[N:34])[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)C=O
Reactant: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2cnn3-c2ccc(F)cc2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(C#N)cc3c2cnn3-c2ccc(F)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide (0.04 g, 0.08 mmol), Pd2(dba)3 (0.009 g, 0.01 mmol), 1,1-bis(diphenylphosphino)ferrocene (dppf) (0.005 g, 0.01 mmol), zinc cyanide (0.01 g, 0.09 mmol) and zinc powder (0.002 g, 0.02 mmol) were charged in a sealed tube with anhydrous DMF (3 mL) at room temperature. The reaction mixture was heated at 120° C. for 3 hours. The solution was cooled to room temperature and diluted with saturated aqueous ammonium chloride (10 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-70% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=O.[N-:19]=[N+]=[N-].[Na+]>C(O)CO>[N:19]1[O:18][N:16]=[C:3]2[CH:4]=[C:5]([C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])[CH:14]=[CH:15][C:2]=12
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)N1CCCCC1
Agent: [Na+]
Solvent: OCCO
Product: O=C(c1ccc2nonc2c1)N1CCCCC1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
4-Chloro-3-nitro-benzoylpiperidine (539.2 g, 2.00 mol) was dissolved in 2.93 L ethylene glycol in a 5-L flask with stirring and heating to 50° C. To this solution, sodium azide (137.0 g, 2.10 moles) was added in portions over 40 min. When the addition was complete, the temperature was increased to 120° C. during 2.5 hr and maintained at this temperature for 3 hr. The solution was allowed to cool to 50° C., at which time additional sodium azide (65.3 g, 1.00 moles) was added over 5 min. The temperature was increased to 120° C. during 2.5 hr and maintained at this temperature for 4.5 hr until gas evolution had ceased. The solution was allowed to cool to room temperature, at which time the mixture was partitioned between water and ethyl acetate (1.5 L each). The aqueous phase was extracted three times with ethyl acetate (300 mL). The combined organic phases were washed with 30 mL water, twice with saturated NaCl (200 mL), and finally dried over anhydrous Na2SO4. The filtered solution was evaporated to yield 345.5 g of crude 1-(benzofurazan-5-ylcarbonyl)piperidine.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])=[CH:26][CH:25]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(F)cc4)CC3)nc21

Procedure:
Pipemidic acid (35 mg, 0.1154 mmol) and 4-fluorophenyl isothiocyanate (17.7 mg, 0.1154 mmol) were used. Purification on silica yielded compound 23 in Table 1, below (30 mg, 57%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.69 (s, 1H), 7.33 (s, 1H), 7.25-7.16 (m, 2H), 7.13-7.03 (m, 2H), 4.34 (q, J=7.00 Hz, 2H), 4.28-3.96 (m, 8H), 1.50 (t, J=7.36 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH:8]1[CH:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9]1=[O:21])([CH3:4])[CH3:3].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].C(O)(=O)C>O1CCCC1>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH:8]1[CH:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][CH:9]1[OH:21])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(=O)C1CO[Si](C)(C)C(C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCC1CC(O)C1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Yield: 61.5 %

Procedure:
2,3-Bis(((1,1-dimethylethyl)dimethylsilyl)oxymethyl)cyclobutanone (10.2 g, 28.4 mmol) from Step B was dissolved in tetrahydrofuran (THF) and the solution was cooled to -78° C. under a nitrogen atmosphere. To the THF solution at -78° C. was slowly added, with stirring, 31 mL (31 mmol) of potassium tri-sec-butylborohydride (sold by Aldrich Chemical Company as a 1 M solution in THF under the registered trademark K-Selectride®. After stirring for 0.5 h at -78° C., the reaction mixture was allowed to warm to 0° C. and it was stirred for 40 minutes at 0° C. One equivalent (1.9 mL) of glacial-acetic acid was added and the reaction mixture was concentrated in vacuo to approximately 50 mL. The concentrate was diluted with 1 L of methylene chloride and the resultant solution was washed with 400 mL of 5% aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to a syrup. The syrup (15.5 g) was chromatographed on a 4.5×45 cm silica gel column eluted @2-5 psi with 2 L of methylene chloride. All fraction containing the desired product were combined and concentrated. The residue (10 g) was rechromatographed as described above to give 6.3 g (62% yield) of the title compound as a syrup; 1H NMR (CDCl3) δ 0.07 (d, 12H), 0.92 (d, 18H), 2.01 (m, 1H), 2.13 (m, 2H), 2.25 (m, 1H), 2.40 (m, 1H), 3.35 (d, 1H), 3.55 (m, 2H), 3.86 (dd, 1H), 3.98 (dd, 1H); MS DCI-NH3M/Z: 361 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][CH2:12][CH2:13][C:14](Cl)([F:16])[F:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([CH2:11][CH2:12][CH:13]=[C:14]([F:16])[F:15])[C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH3:10]
Reactant: CCOC(=O)C(CCCC(F)(F)Cl)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(CCC=C(F)F)C(=O)OCC

Procedure:
150 g of 2-(4-chloro-4,4-difluoro-but-1-yl)malonic acid diethyl ester, 160 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 250 ml of toluene are stirred for 15 hours at reflux temperature. After cooling, 200 ml of toluene are added and the reaction mixture is washed with 500 ml of water and then with 500 ml of 2N NaCl solution, dried over sodium sulfate and the solvent is evaporated off. The residue is distilled at 65° and 0.052 mbar. The title product is obtained in the form of a colourless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][N:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CS(C)=O>[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[N:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2ccc(=O)n(CCN(C)C)n2)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
To DMSO (3.5 mL) is added 60% NaH dipersion in mineral oil (84 mg, 2.1 mmol) and the resulting mixture stirred for 5 min. To this solution is added 4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoic acid methyl ester (460 mg, 2 mmol reference example 36e) and the mixture stirred for 10 min (till homogeneous). In a separate flask containing DMSO (3.5 mL) is added 60% NaH (101 mg, 2.5 mmol) and stirred 5 min. To this solution is added 2-dimethylaminoethylchloride hydrochloride (346 mg, 2.4 mmol) and let stir for 5 min. This solution is transferred to the reaction solution, heated to 50° C., let stir for 2 hours. Cooled to 20° C., quenched with sat NH4Cl soln (2 mL) and concentrated. The residue is purified by short path flash chromatography (eluting with 10% methanol in dichloromethane) to give 542 mg of title compound. 1H NMR (CD3OD) δ 2.35 (s, 6H), 2.88 (t, J=7 Hz, 2H), 3.93 (s, 3H), 4.42 (t, J=7 Hz, 2H), 7.08 (d, J=10 Hz, 1H), 8.06 (m, 5H). MS (EI) m/z 302 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:16])[CH3:15])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CC[C@@H](C(=O)C)[C@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([C@H:14]([OH:16])[CH3:15])[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CC(=O)[C@@H]1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Product: C[C@@H](O)[C@@H]1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of (RS)-1-[(3SR,4SR)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol (example 5 (d)) the title compounds were synthesized from 1-[(3R,4R)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone through reduction with LiAlH4. (R)-1-[(3R,4R)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol was obtained as off-white solid. MS (m/e): 330.1 [(M+H)+] and (S)-1-[(3R,4R)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol was obtained as colorless viscous oil. MS (m/e): 330.1 [(M+H)+]
Reaction SMILES: C([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([CH:30]=[O:31])CC(O)=O)=[O:23])[CH3:21])=[O:18])C1C=CC=CC=1.C=O.[C:34]([OH:37])(=[O:36])[CH3:35]>CO>[CH2:8]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:9]1[C:17]([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([CH:30]=[O:31])[CH2:35][C:34]([OH:37])=[O:36])=[O:23])[CH3:21])=[O:18])[C:16]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H](NC(=O)c1[nH]c2ccccc2c1Cc1ccccc1)C(=O)N[C@H](C=O)CC(=O)O
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: C[C@H](NC(=O)c1cc2ccccc2n1Cc1ccccc1)C(=O)N[C@H](C=O)CC(=O)O
Yield: 72 %

Procedure:
(3S)-3-[( -Benzylindole-2-carbonyl)alaninyl] amino-4-oxobutanoic acid, semicarbazone (176 mg, 0.37 mmol) was dissolved in methanol (4.5 mL), formaldehyde (1.5 mL, 37% wt. aq) and acetic acid (1.5 mL) and the resulting mixture was stirred for 4 hours under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated in vacuo, diluted with water, and extracted twice with ethyl acetate. The ethyl acetate solution was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was triturated with ether to afford the title product as a light green powder (113 mg, 72%). TLC: (methylene chloride:methanol:acetic acid, 20:1:1, silica gel): Rf=0.38; MS for C23H23N3O5; M+H+=422; M−H+420. 1H-NMR (CD3OD): δ7.65 (d, J=8.0, 1H), 7.37 (dd, J=8.2, 0.8, 1H), 7.24-7.04 (m, 8H), 5.87-5.73 (m, 2H) 4.60-4.49 (m, 2H), 4.32-4.23 (m, 1H), 2.69-2.44 (m, 2H), 1.41 (d, J=7.1, 2 sets, 3H).
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH:15][C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[C:11](Cl)(Cl)Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:1]1([S:7]([C:10]2[N:15]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:17][C:11]=2[NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(C(Cl)(Cl)Cl)S(=O)(=O)c1ccccc1)c1cccs1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1nc(-c2cccs2)oc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N(1-Phenylsulfonyl-2,2,2-trichloroethyl)thiophene-2-carboxamide (0.4 g, 1.003 mmol) is dissolved in tetrahydrofuran, mixed with benzylamine (0.428 g, 4.012 mmol) and stirred overnight at room temperature. The resulting precipitate was filtered off with suction and discarded, the mother liquor was concentrated in a rotary evaporator and the residue was crystallized in 15 ml of petroleum ether, filtered off with suction and dried in air.