Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.C(OCC)(=O)C.C(O)(C(F)(F)F)=O>[C:31]([NH:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1N1CCNCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
1-Boc-4-(2-Aminomethyl-phenyl)-piperazine (0.47 g, 1.6 mmol) was dissolved in methylene chloride (20 mL). DIPEA (1.5 mL, 8.5 mmol) was added, and the mixture was cooled to about 0° C. The mixture was treated with benzoyl chloride (0.20 g, 0.16 mL, 1.4 mmol). The resulting mixture was stirred for about 1 hour at 0° C., and then warmed to r.t. and stirred overnight. The mixture was diluted with ethyl acetate (500 mL), washed with water (45 mL), saturated aqueous sodium bicarbonate (45 mL) and brine (45 mL) and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and purified via silica gel chromatography (50% ethyl acetate in hexanes) to afford a clear oil, which was subsequently stirred in neat TFA (5 mL) for about 1 hour. The solvent was evaporated under reduced pressure to afford the title compound as a clear oil (0.30 g, 100%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([C:14]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[CH3:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:23]2[CH:22]=[N:21][C:20]([N:17]3[CH2:18][CH2:19][C:14]([CH2:12][CH3:13])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:15][CH2:16]3)=[N:25][CH:24]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3ccc(N)c([N+](=O)[O-])c3)cn2)CC1

Procedure:
To a solution of 4-bromo-2-nitroaniline (10.0 g, 46.07 mmol) in 1,4-dioxane (240 mL) and MeOH (140 mL) was added ethyl 4-ethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate (21.59 g, 55.28 mmol) and potassium phosphate (14.69 g, 69.10 mmol) and the mixture degassed by purging N2 for 15 min
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: BrCCCCBr
Reactant: COC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of diisopropylamine (150 mmol, 21 mL) in THF (100 mL) at −10° C. was added dropwise a 2.5M solution of n-butyl lithium in hexanes (145 mmol, 58 mL) while maintaining the temperature below 0° C. After the addition was complete, the solution was stirred for 30 min at 0° C., then it was cooled to −70° C. using a dry ice/acetone bath. A solution of methyl cyclopentanecarboxylate (100 mmol, 13.1 g) in THF (20 mL) was added dropwise at −70° C. maintaining the reaction temperature between −60 to −70° C. The mixture was then stirred for 1 h at −50 to −60° C. and a solution of 1,4-dibromobutane (100 mmol, 21.59 g) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. The cooling bath was removed and the reaction was allowed to equilibrate to room temperature and stirred overnight. The reaction mixture then was poured into a saturated solution of ammonium chloride (200 mL) and the mixture was extracted with diethyl ether (2×100 mL). The combined extracts were washed with brine (150 mL), dried (MgSO4), filtered and the solution was concentrated under reduced pressure. The resulting residue was distilled at 120-133° C./2.5 mm Hg to obtain 12.8 g (48%) of 1-(4-bromobutyl)cyclopentanecarboxylic acid methyl ester as a colorless oil. HR MS: Obs. mass, 262.0565. Calcd. mass, 262.0568, (M+).
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[CH:1]1([CH:8]=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC1CCCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
To a stirred solution of cycloheptyl-methanol (1.28 g, 0.01 mol) in CH2Cl2 (50 ml) at room temperature was added portionwise PCC (3.23 g, 0.015 mol). The reaction turned almost instantly dark brown as was stirred at room temperature for 4 hours. The reaction was then diluted with Et2O (50 ml) and the solvent decanted away from the solid residue. The residue was washed with further Et2O (2×25 ml). The reaction mixture and combined washing were then filtered through a 10 g SiO2 chromatography cartridge and washed through with further Et2O (25 ml). The solvent was then removed under reduced pressure to yield the desired compound (1.08 g) as a colourless, pungent oil which was used without further purification.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[C:29]([CH3:36])[N:28]=1.C(=O)([O-])O.[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>[F:26][C:27]1[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=[C:29]([CH3:36])[N:28]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)c(F)n1
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: COCCOC
Solvent: O
Product: Cc1ccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c(F)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6-methylpyridin-3-yl)boronic acid (233 mg), sodium hydrogen carbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a deaerated mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 2 hr. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3→1:4) to give the title compound as a colorless oil (yield 400 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:12])=[CH:4][N:3]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: ClCc1ccc(Cl)nc1
Reaction time: 4 h
Yield: 95.7 %

Procedure:
A mixture of 70.3 g of 2-chloro-5-(hydroxymethyl) pyridine and 50 ml of 1,2-dichloroethane was dropwise added to a mixture of 87.4 g of thionyl chloride and 100 ml of 1,2-dichloroethane during 30 minutes in a water bath of 5°-20° C. The mixture was stirred for an hour and a half at room temperature and for 4 hours and a half under refluxing. After concentrating, to the residue were added 200 ml of chloroform and 60 ml of water and then added portionwise 20 g of sodium hydrogen carbonate under stirring. The organic phase was separated, treated with active carbon and concentrated to obtain 75.9 g of 2-chloro-5-(chloromethyl)pyridine as a yellowish brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:15][C:14]=2[CH3:30])[C:11]#[N:12])[CH:5]=[C:6]([F:8])[CH:7]=1.CSC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:15][C:14]=2[CH3:30])[CH2:11][NH2:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cc(F)cc(F)c2)c(C)c1
Solvent: C1CCOC1
Solvent: CSC
Product: COCCCc1ccccc1-c1ccc(C(CN)Cc2cc(F)cc(F)c2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-[2′-(3-methoxypropyl)-3-methylbiphenyl-4-yl]propanenitrile from step 3 (1 eq.) in THF (0.1M) was added borane-dimethyl sulfide complex (5 eq.). The mixture was refluxed for 5 h without a condensor to release the dimethylsulfide. The final concentration was 0.2M. The mixture was cooled to room temperature, quenched slowly with HCl (1N). The pH was set to 10 using NaOH (1N) and finally the mixture was extracted with CH2Cl2. The organic extract was dried over Na2SO4 filtered and concentrated. Purification by column chromatography on silica gel eluting with CH2Cl2/MeOH(NH3; 2M) 5% afforded the desired compound as a colorless oil. 1H NMR (500 MHz, CD3OD): δ 7.42 (d, 1H), 7.30-7.26 (m, 2H), 7.23-7.20 (m, 2H), 7.12 (d, 1H), 7.04 (s, 1H), 6.76-6.72 (m, 1H), 6.66-6.63 (m, 2H), 3.53-3.50 (m, 1H), 3.25-3.20 (m, 7H), 3.15 (dd, 1H), 2.88 (dd, 1H), 2.65 (d, 1H), 2.64 (d, 1H), 2.12 (s, 3H), 1.70-1.65 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)([CH3:20])[CH3:19]>>[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1)([CH3:20])[CH3:19]
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: CC(C)c1ccccc1B(O)O
Product: CC(C)c1ccccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-isopropylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=254.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.13 M) was added triethylamine (1.5 equiv.) followed by methanesulfonyl chloride (1.3 equiv.). The reaction was allowed to stir at room temperature for 15 h. The solution was then quenched with saturated NaHCO3, extracted with dichloromethane, dried with sodium sulfate, and concentrated to give the crude (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)piperidine-1-carboxylate in >95% yield. LCMS (m/z): 428.9/328.9 (MH+), Rt=3.81 min.
Reaction SMILES: C1[CH:6]=[C:5](Cl)[CH:4]=[C:3]([C:8]([O:10]O)=O)C=1.[C:12]([O:17]C(CC=C)C)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:12]([O:17][CH:5]([CH2:4][CH:3]1[O:10][CH2:8]1)[CH3:6])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=CCC(C)OC(=O)C(=C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OC(C)CC1CO1
Temperature: 23 °C
Reaction time: 6 h
Yield: 61.5 %

Procedure:
A solution of m-CPBA (32 g) in chloroform (150 ml) was cooled in cold water and then 4-penten-2-yl methacrylate (14 g) was added. The mixture was stirred at 23° C. for 6 hours. The post-reaction mixture was then poured into dilute potassium carbonate (300 ml) and the organic layer was separated. The organic layer was washed with three more portions of carbonate, finally with water and then dried. Remaining solvents were then removed and the residue was subjected to chromatography on silica gel. As a result pure 4,5-epoxypent-2-yl methacrylate (9.5 g) was isolated.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: Cc1ccc(NC2CCNCC2)c(C)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c(C)c1
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.097 g, 0.00040 mol) in DMF (1 mL) was added DIPEA (0.233 g, 0.00180 mol), HOBt (0.053 g, 0.00040 mol) and EDCI.HCl (0.138 g, 0.0007214 mol) at ambient temperature. After 2 minutes (2,4-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.12 g (77%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,4-dimethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 432.23 (M+1)+, 97.64%, 1H NMR (DMSO-d6): δ 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (t, 2H), 7.4 (d, 1H), 7.1 (s, 1H), 6.6 (d, 1H), 4.3 (m, 2H), 4.1 (t, 2H), 3.9 (d, 1H), 3.5 (bs, 1H), 3.2 (t, 1H), 2.8 (t, 1H), 2.2 (s, 3H), 2.1 (s, 3H), 1.9 (t, 2H), 1.5 (m, 1H), 1.3 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10]/[C:11](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:28]\[OH:29])=[CH:5][CH:4]=1
Reactant: NO
Reactant: Cc1cccnc1C(CC(=O)c1ccncc1)c1ccc(N(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccnc1C(C/C(=N\O)c1ccncc1)c1ccc(N(C)C)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(3-methyl-pyridin-2-yl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a yellow foam, MS (ESI+): m/z=361.3 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[C:4]([F:31])[CH:3]=1.Cl>CO>[F:31][C:4]1[CH:3]=[C:2]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]2[N:15]3[CH2:16][CH2:17][S:18][C:19]([CH2:22][OH:23])([CH3:21])[CH2:20][C:14]3=[N:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccccc5)cc4F)CC3)n2CCS1
Yield: 218.4 %

Procedure:
A solution of the compound (191 mg, 0.36 mmol) obtained in Example 14-6) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (3 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (161 mg, quant.) as a colorless solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>CS(C)=O>[O:9]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 559.2 %

Procedure:
A mixture of trimethylsulfoxonium iodide (65.2 g, 29.6 mmol) and anhydrous DMSO (300 ml) was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was then cooled to 0° C. and NaH (60% in mineral oil) (14.2 g, 35.5 mmol) was added in small portions over the course of 1 hour. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was then cooled to 0° C., tert-butyl 4-oxo-1-piperidinecarboxylate (59.0 g, 29.6 mmol) added, then allowed to react at room temperature for 16 hours. The reaction mixture was then poured onto 1.2 liters of ice water and extracted with ether (4×400 ml). The organic layers were washed with water (2×500 ml) and brine (2×500 ml). The organic extract was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in hexanes to 40% EtOAc in hexanes) to afford the product as white crystalline solid (35.3 g, 56%). M.p.=48-50° C.; 400 MHz 1H NMR (CDCl3) δ: 3.77-3.68 (m, 2H), 3.45-3.36 (m, 2H), 2.68 (s, 2H), 1.83-1.74 (m, 2H), 1.5-1.4 (m, 11H); LCMS: 214 [M+H].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:31])[C@@H:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[CH2:10][NH:11]C(=O)OCC2C=CC=CC=2)=[CH:4][C:3]=1[C:32]1[N:36]([CH3:37])[N:35]=[CH:34][C:33]=1[Cl:38]>C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:11][CH2:10][C@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[C:8]([NH:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:32]2[N:36]([CH3:37])[N:35]=[CH:34][C:33]=2[Cl:38])[CH:4]=1)=[O:31]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)[C@H](CNC(=O)OCc2ccccc2)Cc2ccc(F)c(F)c2)sc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)[C@H](CN)Cc2ccc(F)c(F)c2)sc1Cl
Reaction time: 4 h

Procedure:
Phenylmethyl {(2S)-3-{[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-2-[(3,4-difluorophenyl)methyl]-3-oxopropyl}carbamate (91 mg, 0.157 mmol) was dissolved in a solution of thioanisole (0.286 ml) in trifluoroacetic acid (2.855 ml). After 4 h at 25° C., the reaction mixture was dry loaded onto silica and neutralized/purified through silica chromatography (0-15% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:8])=[C:5]([N+:31]([O-])=O)[CH:4]=1>[Ni].CCO>[NH2:31][C:5]1[CH:4]=[C:3]([N:2]([CH3:34])[CH3:1])[CH:30]=[CH:29][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: CN(C)c1ccc(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: CN(C)c1ccc(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
Step 4): The mixture of 4-dimethylamino-2-nitro-N-(1-diphenylmethylpiperidin-4-yl)-bezamide (1.60 g, 3.5 mmol) and Raney Nickel in EtOH (75 ml) was stirred under H2 at room temperature for 4 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified with chromatography on silica gel (30-50% AcOEt in hexane) and recrystallized from diisopropyl ether to obtain 2-amino-4-dimethylamino-N-(1-diphenylmethyl-piperidin-4-yl)benzamide 1.18 g (79%): mp 118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH:57]=[CH:56][N:55]=[CH:54]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:37]=[C:38]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:53]3[CH:57]=[CH:56][N:55]=[CH:54]3)=[CH:44][CH:45]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCn2ccnc2)CCC3)cc1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
A solution of 0.220 g (0.298 mmol) (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 9(a)] and 0.30 g (0.446 mmol, 1.50 equiv.) of imidazole in 1.8 ml of absolute N,N-dimethylformamide was stirred for 4 h at 80° C. The reaction was allowed to warm to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of diethyl ether. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 20:1 v/v mixture of dichloromethane/methanol as the eluent to yield 0.067 g (0.094 mmol, 31.5% of theory) of (3R,4R)-3-[1-(2-imidazol-1-yl-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 711 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:5][O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH2:3][OH:4].Br[CH2:20][C:21]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([CH3:32])[C:22]=1[O:23][CH2:24][C:25]#[N:26]>>[Cl:31][C:29]1[CH:28]=[C:27]([CH3:32])[C:22]([O:23][CH2:24][C:25]#[N:26])=[C:21]([CH2:20][O:4][CH2:3][C:2]([CH3:18])([CH3:1])[CH2:5][O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:30]=1
Reactant: CC(C)(CO)COCc1ccc2ccccc2n1
Reactant: Cc1cc(Cl)cc(CBr)c1OCC#N
Product: Cc1cc(Cl)cc(COCC(C)(C)COCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 439 (M+H)+. Prepared from 2,2-dimethyl-3-(quinolin-2-ylmethoxy)-propan-1-ol (EXAMPLE 34e) and (2-bromomethyl-4-chloro-6-methyl-phenoxy)-acetonitrile.