Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](OCC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH2:34].C[Al](C)C.C(O)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]#[N:34])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC1CN(c2nc(C#N)co2)C1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 41 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-oxazol-2-yl)azetidine (357 g, 0.79 mmol) (obtained as described in Reference Example 21(3)) in benzene (8 ml) was added a solution of 0.67M methylamine-trimethylaluminium in benzene (2.8 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred in a water bath (60° C.) for 7 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (10 ml) was added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (5:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-cyano-1,3-oxazol-2-yl)azetidine (130 mg, yield 41%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[N:19]=[C:20]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:16][N:17]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccnc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 4-aminophenol (1.64 g, 15 mmol) in DMF (40 mL) was added potassium tert-butoxide (1.69 g, 15 mmol) and the resulting mixture was stirred at room temp for 15 min. 4-chloro-2-(trifluoromethyl)pyrimidine in DMF (10 mL) was then added and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified using Biotage flash 40M (2:1, Hexane, Ethyl acetate) to afford 4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (2.2 g, 63%). 1H NMR (DMSO-d6) δ 8.78 (d, 1H), 7.16 (d, 1H), 6.90 (d, 2H), 6.60 (d, 2H), 5.17 (brs, 2H); MS ES 256 (M+H)+, calcd 256, RT=2.42 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:16]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CO)c1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [2-(benzyloxy)-3-methylphenyl]methanol (30 g, 131.41 mmol, 1.00 equiv) and DMSO (300 mL). This was followed by the addition of 2-iodoxybenzoic acid (41 g, 146.42 mmol, 1.10 equiv) in several batches. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 1.5 L of ethyl acetate. The resulting mixture was washed with 3×800 mL of brine. The mixture was dried over anhydrous sodium sulfate. This resulted in 30 g (crude) of 2-(benzyloxy)-3-methylbenzaldehyde as orange oil. MS (ESI) m/z 227 ([M+H]).
Reaction SMILES: [C:1](Br)(=[O:7])[CH2:2]CCCC.[CH3:9][N:10]([CH2:14][C:15]([O-:17])=[O:16])[C:11]([NH2:13])=[NH:12].[Na+]>>[CH3:9][N:10]([CH2:14][C:15]([O:17][C:1](=[O:7])[CH2:2][N:10]([CH3:9])[C:11]([NH2:13])=[NH:12])=[O:16])[C:11]([NH2:13])=[NH:12]
Reactant: CCCCCC(=O)Br
Reactant: CN(CC(=O)[O-])C(=N)N
Agent: [Na+]
Product: CN(CC(=O)OC(=O)CN(C)C(=N)N)C(=N)N
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81 g (60 mmol) of the prepared hexanoyl bromide, and side arm water condenser fixed with a dry receiving flask, is placed 13.18 g (72 mmol) of sodium 2-(1-methylguanidino)acetate. The round bottomed flask is placed in an ice bath and the hexanoyl bromide is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield hexanoic 2-(1-methylguanidino)acetic anhydride.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[O:8][C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[C:11]=1[CH3:12]>C(Cl)Cl.N1C=CC=CC=1.O>[Cl:3][CH2:6][C:7]1[O:8][C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[C:11]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)oc2ccc([N+](=O)[O-])cc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(CCl)oc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (1.48 g, 12.4 mmole) was added dropwise to a solution of 2-hydroxymethyl-3-methyl-5-nitrobenzofuran (0.86 g, 4.15 mmole) in methylene chloride (10 ml) and pyridine (2 drops) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with water, the organic phase separated, and the aqueous phase re-extracted with methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate, dried (Na2SO4) and the solvent evaporated to leave the title compound, 0.93 g. A portion was recrystallised from ethanol, m.p. 141°-142°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C(O)C.[Na].[CH2:11]1[CH2:16][O:15][C:13]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=2)[CH:22]=O)([CH3:14])[O:12]1>C1(C)C(C)=CC=CC=1.O.C(O)(=O)C>[CH2:11]1[CH2:16][O:15][C:13]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:22]=[CH:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])[CH:24]=2)([CH3:14])[O:12]1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C2(C)OCCO2)cc1C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CCOC(=O)C=Cc1cc(C2(C)OCCO2)ccc1OC
Reaction time: 3 h

Procedure:
At 0° C., a mixture of 40 ml of ethyl acetate and 1 cm3 of ethanol is added drop by drop to a suspension of 3.5 g (0.15 mole) of sodium in balls in 200 ml of xylene. 22 g (0.1 mole) of 5-(1,1-ethylenedioxy-ethyl)-2-methoxy benzaldehyde dissolved in 50 ml of xylene are then added. The reaction medium is allowed to return to ambient temperature and is stirred for 3 hours. 50 ml of acetic acid are then added. After total disappearance of the sodium, 40 ml of water are added. After extraction with ether, washings with sodium hydroxide then with water up to neutrality, the ethereal phases are evaporated to obtain 24 g (oil) of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:34]C(OCC1C=CC=CC=1)=O)[CH2:5][NH:6][C:7]([C:9]1[CH:33]=[C:12]2[C:13](=[O:32])[N:14]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:15][CH2:16][N:11]2[N:10]=1)=[O:8]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH2:34])[CH2:5][NH:6][C:7]([C:9]1[CH:33]=[C:12]2[C:13](=[O:32])[N:14]([CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)[CH2:15][CH2:16][N:11]2[N:10]=1)=[O:8]
Reactant: COC(=O)[C@H](CNC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](N)CNC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Reaction time: 48 h

Procedure:
To 4-2 (6.3 g, 10.26 mmol) in 700 ml CH3OH was added 650 mg 10% Pd on C and the resulting mixture stirred under 1 atm of H2 for 48 h. The catalyst was removed by filtration through celite and the filtrate concentrated to give a colorless glass which was triturated with Et2 O and filtered to afford 4-3 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1>CN(C=O)C>[C:37]([O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][O:17][C:13]2[CH:12]=[C:11]([C:10]3[N:9]=[C:8]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=34)[CH:16]=[CH:15][CH:14]=2)=[CH:35][CH:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Reactant: CC(C)(C)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (200 mg, 0.71 mmol) in DMF (3.5 mL) was charged with Cs2CO3 (348 mg, 1.07 mmol) and stirred at rt for 30 min. A solution of 1-bromomethyl-4-tert-butoxy-benzene (162 mg, 0.71 mmole) in 0.5 mL of DMF, was added to the reaction mixture. After 15 h, the reaction was complete by LC/MS analysis. The product was an orange/brown solid. The crude product was chromatographed on silica gel [Jones Flashmaster, 5 g cartridge, eluting with 10% ethyl acetate]. The product was then recrystalized with ethyl acetate and hexanes yielding the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 9H), 2.11-2.23 (m, 2H), 2.45-2.52 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.85 (m, 1H), 5.08 (s, 2H), 5.49 (brs, 2H), 7.01-7.04 (m, 3H), 7.05 (dd, J=4.00 Hz, 1H), 7.10 (d, J=5.02 Hz, 1H), 7.23-7.25 (m, 1H), 7.29 (q, J=40 Hz, 1H), 7.34-7.36 (m, 2H), 7.41 (t, J=16 Hz, 1H); MS (ES+): m/z 443.04 (100) [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:39])[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](CC6C=CC=CC=6)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]3[CH2:14][CH:15]([NH:18][C:19](=[O:39])[C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(Cc5ccccc5)CC4)cc2)CO3)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(c2cccc3c2CC(NC(=O)c2ccc(N4CCNCC4)cc2)CO3)CC1
Temperature: 50 °C
Reaction time: 19 h
Yield: 93.3 %

Procedure:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl]-4-(4-benzylpiperazin-1-yl)benzamide (1.7 g, 3.2 mmol) was dissolved in methanol (100 mL). Palladium (10%) on activated carbon (510 mg) and ammonium formate (1.6 g, 26 mmol) were added and the reaction mixture was stirred at 50° C. for 19 h. The catalyst was filtered off and the solvent was evaporated in vacuo to give 1.3 g (92% yield) of the title compound as a pale yellow solid: mp >102° C. sinters; EIMS (70 eV) m/z (relative intensity) 435 (8, M+); [α]22D−102° (c 0.15, chloroform).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][CH:30]([F:46])[C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[N:33][CH:32]=[C:31]([CH:30]([F:46])[F:29])[CH:36]=1
Reactant: CC1(C)OB(c2cncc(C(F)F)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 3.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (81 mg, 0.18 mmol) was treated with 3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (237 mg, 0.93 mmol, prepared according to WO2012/087237), sodium carbonate (2M, 700 μl, 1.40 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.02 mmol) according to the method described in Example 3 to give 3 mg (3% yield) of the title compound. Purity 98%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>ClCCl>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][C:36]([NH:35][CH2:32][CH2:33][CH3:34])=[O:37])[CH2:3][CH2:4]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Reactant: CCCN=C=O
Solvent: ClCCl
Product: CCCNC(=O)N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (100 mg) in dichloromethane (3 mL) was added propyl isocyanate (21.8 mg), and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was triturated with ethyl acetate to give N-(3,4-dimethoxybenzyl)-5-nitro-2-[trans-4-(3-propylureido)cyclohexylamino]benzamide as yellow powders (118 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[O:6][C:7]2[C:13]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[O:6][C:7]2[C:13]([CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCOCC3)c2o1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Nc1nc2c(OC)ccc(C3CCOCC3)c2o1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.4 %

Procedure:
To a stirred solution of 130 g (4.27 mmol) [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-benzooxazol-2-yl]-carbamic acid methyl ester in 250 ml methanol and 250 ml dichoromethane was added 1.00 g of 10% palladium on charcoal, and the mixture was then stirred for 10 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane/methanol (1/1), and the filtrate concentrated in vacuo to afford 1.30 g (100%) [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-carbamic acid methyl ester as an off-white solid. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([C:17]([OH:19])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:36][O:35][N:34]([CH3:33])[C:17]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[CH2:5]1)=[O:19]
Reactant: O=C(O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
To a stirred solution of [5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid (1 g, 3.66 mmol) in DCM (15 mL) was added 1,1′-carbonyldiimidazole (0.65 g, 4.02 mmol) portion wise over a period of 10 min at 10-15° C. N,O-dimethylhydroxylamine hydrochloride (0.42 g, 4.39 mmol) was added portion wise and stirred for 5 min at that temperature. To the reaction mixture triethylamine (0.66 ml, 4.75 mmol) was added drop wise and it was stirred for 2 hr at 20-25° C. The reaction mixture was diluted with water (10 ml) and aqueous layer was separated. The aqueous layer was extracted with DCM (2×25 ml). The combined organic layer was washed with 5% HCl (25 ml) and saturated brine solution (25 ml). The organic layer was dried over Na2SO4, evaporated under reduced pressure to obtain 5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (0.95 g, 83%) as a colorless sticky mass.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)Cl.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>O>[C:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:30])[CH2:28][CH3:29]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
A solution of benzyl piperazine-1-carboxylate (16, 10.0 g, 45.4 mmol), triethylamine (6.89 g, 68.0 mmol) and dry CH2Cl2 (150 mL) was cooled to 0° C. and propionyl chloride (4.62 g, 50.0 mmol) was added dropwise over 10 min. The reaction was kept under nitrogen and allowed to warm to room temperature. After stirring at rt for 17 h, water (50 mL) was added and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The solution was dried over Na2SO4, filtered and concentrated to a yellow oil. The product was purified by silica gel chromatography eluting with 0-3% CH3OH in CH2Cl2 to afford the title compound (9.08 g, 72%) as a clear, colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 5.15 (s, 2H), 3.70-3.35 (m, 8H), 2.35 (q, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:18])[S:5]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17])(=[O:7])=[O:6].[OH-].[Na+].[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].C1(C)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([S:5]([N:4]([CH2:3][CH2:2][O:1][CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])[CH3:18])(=[O:7])=[O:6])=[C:9]([CH3:17])[CH:10]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
n-Bu4NCl (39 g, 140.1 mmol) was added to a solution of N-(2-hydroxyethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (116 g, 424.4 mmol) in toluene (750 ml) and the mixture was cooled to 0° C. Aqueous 35% strength NaOH solution (1,000 ml) was then added. Bromoacetic acid tert-butyl ester (93 ml, 636.6 mmol) was then added dropwise to the reaction mixture and the mixture was stirred at room temperature for 2 hours. The organic phase was separated off, washed with water (3×750 ml), dried over Na2SO4 and concentrated in vacuo. Purification was carried out by chromatography on silica gel (heptane/ethyl acetate 4:1). The yield was 124.6 g (76%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[I-].[PH4+].[CH3:13][CH:14]1OC(C)OC(C)O1>I>[CH3:1][C:2]1[NH:3][C:4]([CH2:13][CH3:14])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC1OC(C)OC(C)O1
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: [I-]
Agent: [PH4+]
Product: CCc1[nH]c(C)c(C(C)=O)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dimethyl-3-acetyl-pyrrole (548 mg) in 10 ml of aqueous hydriodic acid containing a little solid phosphonium iodide was cooled in an ice-salt bath. Paraldehyde (0.35 ml) was added and the solution was stirred for 41/2 hrs. without further cooling. The solution was then added to 100 ml of ice water to precipitate the light brown product (385 mg, 58%), m.p. 153°-160° C. For analysis, it was sublimed in vacuo then recrystallized from ether (thimble) as grey needles, m.p. 163° C. after changing to plates at 140°. Anal. Calc. for C10H15O: C; 72.69, H, 9.15; N, 8.48. Found: C, 72.67; H, 8.88; N, 8.69.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])=[O:4].[OH-].[K+]>CO>[O:23]=[C:15]1[CH:14]([C:8]2[C:7]3=[C:6]([CH3:24])[C:5]([C:3]([OH:4])=[O:2])=[CH:13][N:12]3[N:11]=[CH:10][N:9]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: COC(=O)c1cn2ncnc(C3C(=O)Nc4ccccc43)c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Temperature: 60 °C
Yield: 92.2 %

Procedure:
To a solution of Example 77 (3.3 g, 10.2 mmol) in methanol (600 mL) was added potassium hydroxide (1N aqueous solution, 200 mL) and the mixture was deoxygenated by purging with argon. The reaction mixture was heated to 60° C. for 20 hrs. The reaction mixture was cooled and concentrated to about 50 mL and the residue was acidified with concentrated HCl to pH 4. The yellow solid was collected, washed with water, and dried in vacuo to afford the title compound (2.9 g, 92%). MS: [M+H]+ =307.1; 1H NMR (CD3OD): δ 7.94 (s, 1H), 7.71 (s, 1H), 7.18-7.10 (m, 2H), 6.94-6.86 (m, 2H), 2.45 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][S:33][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCCSc1cccc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCSc2cccc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(1-naphthylthio)pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(1-naphthylthio)pentyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.