Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink solid (295 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:26]\[C@H:27]3[CH2:31][CH2:30][CH:29](O)[CH2:28]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:39])CC)C>ClCCl.O>[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:26]\[C@H:27]3[CH2:31][CH2:30][CH:29]([F:39])[CH2:28]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: Cn1ccc(NC(=O)/C(=C/[C@H]2CCC(O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cn1ccc(NC(=O)/C(=C/[C@H]2CCC(F)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-hydroxycyclopentyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide (124 mg) in dichloromethane (4 ml) was added diethylaminosulfur trifluoride (100 μl) under ice-cooling, followed by stirring at room temperature for 15 minutes. The reaction mixture was diluted with dichloromethane, and water was added thereto. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=7:3-1:0) to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-fluorocyclopentyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide (78 mg) as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+].[CH3:28][C:29]([CH3:31])=[O:30]>>[C:29]([C:31]1[CH:4]=[CH:5][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:12][CH2:11][CH:10]([O:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:15][CH2:14]2)=[C:16]([CH2:21][CH2:20][CH3:19])[C:22]=1[OH:25])(=[O:30])[CH3:28]
Reactant: CC(C)=O
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1c(OCCCN2CCC(OC(c3ccc(Cl)cc3)c3ccccn3)CC2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 6.5 h
Yield: 87 %

Procedure:
In 6 ml of acetone were dissolved 0.80 g (2.64 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 0.95 g (3.01 mmol) of 4-(3-bromopropoxy)-2-hydroxy-3-n-propylacetophenone. To the mixed solution was added 0.44 g (3.18 mmol) of potassium carbonate, and the mixture was heated and stirred at an oil bath temperature of at around 60° C. for 6.5 hours. After completion of the reaction, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography using a solvent mixture of chloroform and methanol in a volume ratio of 20:1 as an eluent to obtain 1.24 g (yield: 87%) of 1-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)propyl]-4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine as a slightly brown oily product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>CCOCC>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCC(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)NCC(=O)O
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of glycine in a 1 N-sodium hydroxide, an ether solution of n-dodecanoyl chloride and a 1 N-aqueous solution of sodium hydroxide were dropped simultaneously and the mixture was stirred for 1 hour. The reaction mixture was then neutralized with hydrochloric acid and ether was removed from the solution. N-n-dodecanoylglycine was obtained from the remaining reactant after the purification by column chromatography with the yield of 84.7 %. The melting point of the product was 115.5° to 116.7° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=1[C:26]([F:29])([F:28])[F:27]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([S:17][CH3:16])=[C:19]([C:26]([F:29])([F:27])[F:28])[CH:20]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CSc1ccc(CCl)cc1C(F)(F)F
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: CSc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1C(F)(F)F
Yield: 89 %

Procedure:
In the same manner as in Example 7 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 4-(methylthio)-3-(trifluoromethyl)benzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:23][CH3:24])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]([CH3:20])=[C:15]([CH3:21])[C:14]=2[CH:22]=1)(=O)=O.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>CO.C(O)C.C(O)(C)C>[CH3:24][O:23][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:14]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CO
Solvent: CCO
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 64 %

Procedure:
Method A (9 h at 60° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-3,4-dimethyl-2H-1-benzopyran-2-one (example 75) and 4-phenylpiperidine; yield 64%; fusion point 152°-153° C. (from ethanol and isopropanol). Fumarate (×0.5 C4H4O4): method E; yield 92%; fusion point 209°-210° C. (from ethanol and methanol).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([NH:31][S:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)(=[O:40])=[O:39])=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)=[CH:16][CH:17]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(N)cc4)n3)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(NS(=O)(=O)c5ccccc5)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-acetyl-4-[(4-{[4-(4-aminophenyl)pyrimidin-2-yl}amino}phenyl)carbonyl}piperazine (100 mg, 0.24 mmol) in pyridine (5 mL) containing a catalytic amount of DMAP is added benzenesulfonyl chloride (50 mg, 0.29 mmol) and the solution is stirred overnight at room temperature. The pyridine is removed under vacuum and the residue extracted into methylene chloride and washed with 1N HCl. Evaporation of solvent provides the crude piperazine which is purified by preparative HPLC (10-60% CH3CN over 25 min.) to give an analytically pure sample as a yellow solid: M+1; 557.3. HPLC Retention Time; 9.59 min (Method B).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[N:15][NH:16][C:17]3=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[CH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[CH3:30][C:27]1[N:26]=[C:25]([CH2:24][N:16]2[N:15]=[CH:14][C:13]3[C:18](=[CH:19][C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)=[CH:11][CH:12]=3)[C:17]2=[O:20])[O:29][N:28]=1
Reactant: O=c1[nH]ncc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: Cc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(Cn2ncc3ccc(-c4ccc(OC(F)(F)F)cc4)cc3c2=O)n1
Temperature: 80 °C

Procedure:
To a mixture of 7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (50 mg, 0.163 mmol), 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (47.5 mg, 0.359 mmol), and potassium carbonate (68 mg, 9.68 mmol) was added DMF (1 mL) and the reaction was heated to 80° C. overnight. The reaction was diluted with EtOAc and water, the layers were separated, and the organic layer was concentrated to an oil. The residue was purified by flash chromatography (Rf=0.32, 1:1 hexanes/ethyl acetate) to afford 2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white solid. C19H13F3N4O3. 403.1 (M+1). 1H NMR (DMSO) δ 8.58 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.34 (dd, J=2.0, 8.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.98-8.02 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 5.67 (s, 2H), 2.31 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:38])=[CH:15][C:14]=2[O:39][CH3:40])[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[N:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=5)[S:27][C:21]=4[C:20]3=[O:38])=[CH:15][C:14]=2[O:39][CH3:40])[CH2:9]1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CNC1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Dissolve 3-{2-methoxy-4-[4-oxo-2-(4-trifluoromethyl-phenyl)-4H-thiazolo[5,4-c]pyridin-5-yl]-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.27 mmol) in dichloromethane (12 mL) and slowly add trifluoroacetic acid (6 mL). Stir the mixture for one hour and then evaporate. Apply the residue to a 10 g SCX column with dichloromethane. Wash the column with methanol then elute the material using 1:1 dichloromethane:2N ammonia/methanol. Concentrate to give 0.909 g (85%) of the desired product as a white solid. MS/ES m/z 474.0 [M+1]+.
Reaction SMILES: [F:1][CH:2]([C:8](=O)[CH2:9][F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:16].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2](=[C:8]([NH2:16])[CH2:9][F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CCOC(=O)C(F)C(=O)CF
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(F)=C(N)CF
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.4 %

Procedure:
A mixture of ethyl 2,4-difluoro-3-oxobutanoate (24.6 g, 0.148 mol), ammonium acetate (200 g, 2.6 mol) and anhydrous methanol (400 mL) is stirred at room temperature for 3 days. The solution is poured into a saturated aqueous solution of sodium bicarbonate (1L) and extracted four times with ether. The combined organic phases are washed with brine and dried over magnesium sulfate. The solvent is evaporated to yield ethyl 2,4-difluoro-3-amino-2-butenoate (11.1 g, 45%)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]3[C:25]([O:27]CC)=[O:26])=[CH:4][C:3]=2[O:2]1.[OH-].[K+]>CCO.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (1RS,2SR,3SR)-1-(3,4-methylenedioxyphenyl)-3-phenylindane-2-carboxylate (650 mg, 1.68 mmol) in EtOH containing a few drops of THF was added 6M KOH (1.68 ml, 10.1 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from EtOAc/hexanes. The title compound was obtained as a solid (305 mg, 51%); m.p. 186°-187° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=O)[C:5](=[CH:8][C:9]=1[F:10])[CH:6]=O.[C:13]1(=[O:20])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]2[C:4](=[CH:11][C:18]3[C:13](=[O:20])[C:14]4[C:15]([C:16](=[O:19])[C:17]=3[CH:6]=2)=[CH:11][C:4]2[C:5](=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=2)[CH:6]=4)[CH:3]=1
Reactant: O=C1CCC(=O)CC1
Reactant: O=Cc1cc(F)c(F)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc3cc(F)c(F)cc3cc2C(=O)c2cc3cc(F)c(F)cc3cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 4,5-difluorophthalaldehyde (Compound 22)(0.48 g, 2.8 mmol, 2 molar equivalents) and 1,4-cyclohexanedione (0.16 g, 1.4 mmol, 1 molar equivalent) in ethanol (40 ml) was added a solution of 5% aqueous NaOH (0.6 ml) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and then warmed to 60° C. After 1 hour at 60° C., the reaction mixture was cooled to room temperature. The resulting precipitate was filtered, washed with water (15 ml), ethanol (30 ml) and diethyl ether (30 ml) to give the title compound as a yellow powder (0.35 g, 64%) used as obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:29][O:28][CH:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:27][CH2:26]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: COC1CCN(CCCCl)CC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC1CCN(CCCOc2ccc(C3(CN(C)C)CCOCC3)cc2)CC1
Yield: 49.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-4-methoxy-piperidine (410 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM:MeOH:NH3) to give the title compound as a yellow oil (415 mg, 50%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.34 (s, 3H), 3.22 (m, 1H), 2.83-2.71 (m, 2H), 2.51 (t, 2H), 2.40 (s, 2H), 2.23-1.81 (m, 10H), 1.97 (s, 6H), 1.67-1.53 (m, 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C(OCC)(=O)C>ClCCl>[CH3:15][C:13]([CH3:12])([O:16][C:17]([N:19]1[CH2:23][CH:22]2[CH:21]([O:9]2)[CH2:20]1)=[O:18])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Reaction time: 4 h
Yield: 39.1 %

Procedure:
80% m-Chloroperbenzoic acid (3.9 g, 0.0226 mole) was added to a solution of 2,5-dihydro-1H-pyrrole-1-carboxylic acid 1,1-dimethylethyl ester (3.55 g, 0.021 mole) in dichloromethane (70 ml) and the mixture was stirred for 24h when more peracid (0.27 g,0.00156 mole) was added and the stirring continued for a further 4h. Ethyl acetate was added and the mixture was washed with 10% sodium carbonate solution. The aqueous phase was extracted with ethyl acetate (50 ml) and the combined organic solution washed with water, dried (MgSO4) and evaporated to leave an oil which was purified by column chromatography on flash silica eluting with 30% ethyl acetate in cyclohexane to give the title compound (1.52 g) as an oil, nmr(δ,CDCl3) includes 1.45(s,9H), 3.42(dd,2H), 3.67(s,2H), 3.78(dd,2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH2:11][CH2:10]1)(=O)[CH3:7].[NH2:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:29][C:26]=1[C:27]#[N:28]>ClCCl>[CH2:36]([O:35][C:30]1[C:31]([O:33][CH3:34])=[CH:32][C:25]([N:24]=[C:6]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[CH2:11][CH2:10]2)[CH3:7])=[C:26]([CH:29]=1)[C:27]#[N:28])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychloride (0.81 ml, 0.0086 mol) was added to a solution of 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane (4.02 g, 0.0157 mol) in dichloromethane (25 ml) and the mixture stirred for 30 minutes at room temperature. A solution of 2-amino-5-benzyloxy-4-methoxybenzonitrile (2 g, 0.0078 mol) in dichloromethane (25 ml) was then added and the reaction stirred for 18 hours at 40° C. On cooling, the reaction mixture was poured carefully in to ice/water (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give a brown oil. The crude product was purified on silica gel eluting with a solvent gradient of methanol:dichloromethane (2:98 to 10:90 v/v) to give the subtitle compound. Rf 0.67 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 492 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][N:18](CC2C=CC=CC=2)[CH2:17]1)=[O:15].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][N:18]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Benzyloxycarbonyl chloride (10.2 mL, 71.5 mmol) was added to a solution of 1-benzyl-4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3-carboxylic acid methyl ester (14.0 g, 35.8 mmol) in dichloromethane (200 mL), and the mixture was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 13.9 g (89%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([CH2:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4].[OH-:21].[Na+].O.Cl>O1CCOCC1>[O:18]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([OH:4])=[O:21]
Reactant: [OH-]
Reactant: O=C(Cn1cccc1C(=O)C(Cl)(Cl)Cl)c1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Cn1cccc1C(=O)O)c1ccccn1
Temperature: 25 °C

Procedure:
To a solution of 2,2,2-trichloro-1-{1-[2-oxo-2-(pyridin-2-yl)ethyl]-1H-pyrrol-2-yl}ethanone (600 mg, 1.8 mmol) in 1,4-dioxane (20 ml) was added a solution of a aqueous solution of sodium hydroxide (1 M) (3.6 mL, 3.6 mmol) at 0° C. The mixture was allowed to warm to room temperature. After completion (30 minutes; reaction monitored by LCMS) water was added (40 mL). The mixture was then acidified with aqueous HCl (1 M) and extracted with EtOAc (3×40 mL). The organic layers were dried (Na2SO4), filtrated and concentrated in vacuo to give 1-[2-oxo-2-(pyridin-2-yl)ethyl]-1H-pyrrole-2-carboxylic acid as a pale brown solid that was used such as in the next step without purification (500 mg). ESI-MI m/z [M+H]+ 245.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(c2ccccc2)CCNCC1
Yield: 110.8 %

Procedure:
To a cooled suspension of 10% Pd-C (0.5 g) in 10 mL methanol was added a solution of 1-benzyl-4-methyl-4-phenyl piperidine (4.5 g, 17.0 mmol) in 40 mL of methanol and the resulting suspension was hydrogenated in a Parr bomb under 250 psi of hydrogen for two days. The suspension was filtered through a pad of celite and the solvent was removed from the filtrate to obtain 4-methyl-4-phenyl piperidine as a yellow solid (3.3 g, 99% yield).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:9]([N:16]1[C:23](=[O:24])[C:20]2([CH2:22][CH2:21]2)[NH:19][C:18](=[O:25])[CH:17]1[CH2:26][OH:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:9]([N:16]1[C:23](=[O:24])[C:20]2([CH2:21][CH2:22]2)[NH:19][C:18](=[O:25])[CH:17]1[CH2:26][O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NC2(CC2)C(=O)N(Cc2ccccc2)C1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1C(=O)NC2(CC2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4-dimethylaminopyridine (660 mg, 5.00 mmol) and tert-butyldimethylchlorosilane (4.90 g, 32.0 mmol) were added to a dimethylformamide (100 ml) solution of the compound (7.15 g, 27.0 mmol) obtained in Step 4 above and triethylamine (4.5 ml, 32.0 mmol). The resulting mixture was stirred at room temperature for 16 hours, then ice water (200 ml) was added to the reaction mixture and the precipitated solid was collected by filtration. The solid obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=3:1 (v/v)] to give the title compound (8.63 g, 85%) as a colorless solid.