Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10](Cl)(=[O:12])=[O:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([OH:25])=[C:17]([C:26]([N:28]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:27])[CH:16]=1.N1C=CC=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([OH:25])=[C:17]([C:26]([N:28]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:27])[CH:16]=2)(=[O:12])=[O:11])=[CH:4][N:3]=1
Reactant: COc1cc(S(=O)(=O)Cl)cnc1Cl
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(N)c2ccccc2c1O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2cnc(Cl)c(OC)c2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-5-chlorosulfonyl-3-methoxypyridine (0.65 g, 2.68×10-3 mole) (see Example 9), 4-amino-N,N-dioctadecyl-1-hydroxy-2-naphthamide (1.40 g, 1.98×10-3 mole) and pyridine (0.20 g, 2.5×10-3 mole) was stirred overnight at room temperature. Additional pyridine (7 drops) was employed after the first 21/2 hours of stirring. The reaction mixture was concentrated in vacuo and diluted with water to precipitate an oil which changed to a waxy solid upon trituration with water. The waxy solid was dissolved in toluene and purified by column chromatography on silica gel using toluene. The toluene fraction was concentrated to a solid which was recrystallized from ethanol; yield, 0.40 g (22 percent), m.p. 85° to 87° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([F:10])=[CH:4][C:3]=1[CH2:11][C:12]#N.[OH-:14].[K+].O.C(O)[CH2:18][OH:19]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([F:10])=[CH:4][C:3]=1[CH2:11][C:12]([O:19][CH3:18])=[O:14]
Reactant: COc1cc(F)cc(CC#N)c1F
Reactant: OCCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1cc(F)cc(OC)c1F
Temperature: 120 °C
Yield: 59 %

Procedure:
To a stirred solution of 2,5-difluoro-3-methoxyphenylacetonitrile (5.92 g, 30 mmol) in ethylene glycol (150 ml) was added potassium hydroxide (85%; 3.0 g, 45 mmol). The mixture was heated at 120° C. for 1 hr and then the mixture was poured into water (100 ml) and washed with ether (100 ml). The aqueous layer was acidified with 6N HCl (10 ml) and extracted with ether (200 ml). The extract was washed with water (50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated. The residual solid was dissolved in methanol (200 ml) and to the solution was added conc. sulfuric acid (2 ml). The resulting mixture was heated at reflux for 1 hr, cooled and concentrated in vacuo. The residue was dissolved in ether (100 ml), washed with water (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml), brine (100 ml) and dried over magnesium sulfate. Removal of solvent gave 3.80 g (59%) of the titled compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH3:16])[CH2:5][C:6]#[C:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH:26]1[C:31]([O:32][C:33](Cl)=[O:34])=[CH:30][CH:29]=[C:28]([Cl:36])[CH:27]=1>O1CCOCC1.C([O-])(O)=O.[Na+].CCOCC>[Cl:36][C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33](=[O:34])[N:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([C:7]#[C:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:16])[CH2:9][CH2:10]2)[CH3:15])=[CH:26][CH:27]=1
Reactant: C=CCN(C)CC#C[C@H]1CC[C@H](NC)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C)CC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Reaction time: 0.08 h

Procedure:
A solution of 66 mg (0.3 mmol) of trans-{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-cyclohexyl}-methyl-amine in 0.3 ml dioxane was treated with 0.103 ml (0.6 mmol; 2 equivalents) Huenig's base and dropwise with a solution of 0.042 ml (0.27 mmol) 4-chlorophenylchloroformate in 0.16 ml dioxane (during 10 min). After 5 min at RT, the mixture was dissolved in aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 97:3) yielded 68 mg (61%) of trans-{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-cyclohexyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 375 (MH+, 1Cl).
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[NH2:7][CH2:8][C@@H:9]([SH:11])[CH3:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14]>CCOCC.O>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:7][CH2:8][C@@H:9]([SH:11])[CH3:10])=[O:14])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: C[C@H](S)CN
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C[C@H](S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
Saturated aqueous NaHCO3 (8 ml) was added dropwise to an ice-cold, stirring mixture of (S)-(+)-1-amino-2-propanethiol hydrochloride (363 mg, 2.85 mmol) in Et2O (75 ml) and H2O (8 ml) and the resulting slurry was stirred in the cold for 30 min. A solution of p-nitrobenzyl chloroformate (693 mg, 3.21 mmol) in Et2O (25 ml) was then added dropwise over 35 min. After having been stirred in the cold an additional 50 min., the reaction mixture was transferred to a separately funnel and the layers were separated. The organic portion was washed with ice-cold 0.025N HCl and brine, dried with MgSO4, filtered, and evaporated under a vacuum to a yellow oil (886 mg) which solidified on standing. The crude product was purified by preparative TLC on four 0.1×20×40 cm silica gel GF plates using 30:1 CH2Cl2 -EtOAc as developing solvent. The product band provided a yellow oil (667 mg) which crystallized on scratching. Recrystallization from Et2O-petroleum ether offorded the title compound B3) in two crops; crop 1 consisted of tiny, white crystals (216 mg) having mp 55.5°-60.5° and crop 2 afforded larger, off-white crystals (284 mg) having mp 55.5°-62°, [α]D +21.5° (Cl.32 in CHCl3).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@@H:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:5][CH2:4][C@@H:3]1[NH:13][C:14](=[O:25])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][N:39]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([C:48](O)=[O:49])[S:47][C:41]=2[CH2:40]1.Cl.CN(C)CCCN=C=NCC>CC(N(C)C)=O.O.C(N(CC)CC)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]([NH:13][C@H:3]2[CH2:4][CH2:5][C@H:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:7][C@H:2]2[NH:1][C:48]([C:46]2[S:47][C:41]3[CH2:40][N:39]([CH3:38])[CH2:44][CH2:43][C:42]=3[N:45]=2)=[O:49])=[O:25])=[N:19][CH:20]=1
Reactant: CN1CCc2nc(C(=O)O)sc2C1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)C(=O)Nc3ccc(Cl)cn3)sc2C1
Yield: 81.8 %

Procedure:
N1-{(1S,2R,4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N2-(5-chloropyridin-2-yl)ethanediamide (553.4 mg) was dissolved in dimethylacetamide (7 mL), and to the solution were added 1-hydroxybenzotriazole monohydrate (245.1 mg), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (386.0 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (345.0 mg) at room temperature. The resultant mixture was stirred for 13 hours, and triethylamine and water were added thereto. The precipitated crystals were collected by filtration, and were dried, to thereby give 674.1 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=2)[CH3:13])=[C:4]([CH3:28])[N:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.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>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:32]3[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=3)=[CH:18][CH:19]=2)[CH3:13])=[C:4]([CH3:28])[N:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 115 °C
Yield: 26.1 %

Procedure:
A solution of 2.0 grams (0.005 mole) of 2,4-diamino-5-[4-(4-trifluoromethylsulfonyloxyphenyl)pentyl]-6-methylpyrimidine (prepared in Step K of this Example), 2.4 grams (0.015 mole) of 3,5-difluorophenylboronic acid, and 0.3 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 90 mL of N,N-dimethylformamide was stirred, and 3.5 grams (0.025 mole) of potassium carbonate was added in one portion. Upon completion of addition, the reaction mixture was warmed slowly to 115° C. where it was maintained for about 40 hours. The reaction mixture was cooled and poured into 250 mL of water. The mixture was then extracted with three 150 mL portions of ethyl acetate. The combined extracts were washed with three 150 mL portions of an aqueous 10% lithium chloride solution and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on neutral alumina (deactivated with 6% wt/wt water), using 2-10% methanol in methylene chloride as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.5 gram of 2,4-diamino-5-[4-[4-(3,5-difluorophenyl)phenyl]pentyl]-6-methylpyrimidine, mp 129°-134° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[N:10]2[CH2:18][CH:17]=[CH2:16])=[CH:5][CH:4]=1
Reactant: C=CCI
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 7-(methyloxy)-2(1H)-quinolinone (5 g, 0.029 mol) in DMF (70 ml) at 0° C. under N2 was added NaH (60% dispersion in oil; 2.5 g, 0.063 mol) stirred for 10 min, warmed to ambient temperature and stirred for a further 30 min. To this reaction mixture was added allyl iodide (3.13 ml, 0.034 mol) and stirred overnight. The reaction was quenched with water (20 ml) and concentrated. The product was obtained after column chromatography (gradient-5% MeOH in DCM) to yield 4.2 g (68%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH:34][C:35](=[O:40])[CH2:36][CH2:37][CH2:38]Cl)[CH:6]=1)[CH3:2].[H-].[Na+].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:40])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(NC(=O)CCCCl)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)cc(N2CCCC2=O)c1
Yield: 45.5 %

Procedure:
5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chloro-butanoylamino) -benzoic acid ethyl ester (140 mg, 0.24 mmol) and NaH (10.5 mg, 0.26 mmol, 60% dispersion in oil) in THF (3 mL), were stirred at room temperature for 4 hrs. The reaction mixture was poured into water and extracted with ethyl acetate (10×3 mL), the combined organic layers were dried over MgSO4 and concentrated. Purification was carried out on a Biotage® using 40% of ethyl acetate in iso-hexane to give the required product as an orange oil (60 mg, 46%). 1H NMR (CDCl3): 1.26(3H,t,J=7.1), 2.01–2.18(4H,m), 2.52(2H,t,J=6.7), 2.88(2H,t,J=7.6), 2.97(2H,t,J=7.4), 3.44(2H,t,J=7.0), 4.26(2H,q,J=7.2), 5.06(2H,s), 6.96(1H,d,J=8.6), 7.18–7.58 (9H, m), 8.09(1H, s).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:21][CH2:22][CH:23]([OH:25])[CH3:24]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:21][CH2:22][CH:23]([OH:25])[CH3:24])=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: CC(O)CN
Product: CC(O)CNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 1-amino-2-propanol (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(2-hydroxy-propylamino)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (65 mg, 65%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O2 (M+H+) 333.2285, found 333.2282.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CO>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (2.37 g) in tetrahydrofuran (20 mL) was added 1,1′-carbonylbis-1H-imidazole (1.78 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1-methylpiperazine (2.0 mL), and the mixture was stirred at 40° C. for 3.5 days. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 1-(2-benzyloxycarbonylamino-2-methyl-propionyl)-4-methylpiperazine (1.99 g). This material was dissolved in methanol (10 mL). To the solution was added 10% palladium-carbon powder (0.4 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][CH2:12][C@@H:13]([OH:30])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1.CO>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[O:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][C@H:13]([OH:30])[CH2:12][NH:11][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])=[O:9])[CH2:20][CH2:19]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1NC(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 40.9 %

Procedure:
A solution of o-tolylisocyanate (64 ml, 0.51 mmol) in dichloromethane (1 ml) was added to a suspension of (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.15 g, 0.47 mmol) in dichloromethane (3 ml) over a five minute period. After 1 h methanol (1 ml) was added and the solvents removed under vacuum. The residue was purified by reverse phase chromatography (C8 Symmetry column) to give the title compound (87 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOC[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25](=[O:33])[C:26]4[C:31]([C:18]([C:19]=23)=[N:17]1)=[CH:30][CH:29]=[CH:28][C:27]=4[NH2:32].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[C:25](=[O:33])[C:24]1[C:19]3[C:18]2=[N:17][NH:16][C:20]=3[CH:21]=[CH:22][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCOCn1nc2c3c(cccc31)C(=O)c1c(N)cccc1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2c1C(=O)c1cccc3[nH]nc-2c13)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-7-aminoanthra[1,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0° C. The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate (×2). The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), washed with brine, dried, and evaporated. The reside is chromatographed on silica gel to furnish the desired amide as a yellow solid.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:8]\[C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[C:12]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:11][CH:10]=1)/[C:5]([OH:7])=[O:6])[CH3:2]>CO.C(Cl)Cl.[Pd]>[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccoc12)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1OCC2)C(=O)O
Yield: 55.5 %

Procedure:
A suspension of 100 mg of 2Z-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-7-yl}-acrylic acid and 25 mg of Pd/C (10%) in 2 ml of MeOH and 2 ml of CH2Cl2 was hydrogenated at 22° C./1bar overnight. The suspension was filtered and the filtrate was again hydrogenated with 25 mg of fresh catalyst overnight. The suspension was filtered, the filtrate evaporated and the residue purified by prep. HPLC (RP-18, CH3CN/H2O, gradient) to give the title compound (56 mg, 56%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:20])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-Benzylpiperidine-4-carboxylic acid (29 g, 0.13 mol) dissolved in DCM (300 ml), cooled to 0° C. and added oxalyl chloride (17.3 ml, 0.2 mol). Catalytic amount of DMF was added to this mixture and stirred at rt for 2 h. After 2 h, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 1-benzylpiperidine-4-carbonyl chloride quantitatively. 2-Amino-4-bromophenol (23 g, 0.12 mol) dissolved in DCM and added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 1-benzylpiperidine-4-carbonyl chloride (29 g, 0.12 mol) in DCM (100 ml). After continuing stirring at rt for 2 h, DCM was removed on the rotavapour to obtain the titled compound (47.6 g), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([N:48]=[C:49]=[O:50])=[CH:44][CH:43]=1>>[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:4]3[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]4[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=4[O:17][CH3:18])=[CH:6][N:5]=3)[CH2:25][CH2:24]2)=[O:50])=[CH:44][CH:43]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)Nc3ccc(N(C)C)cc3)CC2)nc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of the compound of Example 59 in the form of its trifluoroacetic acid salt (45 mg), triethylamine (150 μL, 1.08 mmol) was added followed by 4-dimethylamino-phenyl-isocyanate (Aldrich, 33 mg, 0.20 mmol), and the solution was stirred at room temperature for 1.5 hours. The solution was then concentrated and the residue was purified by reverse phase HPLC to give a solid, (34 mg). MS(ES) (M+H)+=508.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:4](=[O:17])[CH:3]=1.C1CCN2C(=NCCC2)CC1.[C:29](Cl)(=[O:31])[CH3:30].O>C1(C)C=CC=CC=1>[C:29]([O:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:4](=[O:17])[CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCC1CC(O)=CC(=O)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCC1CC(OC(C)=O)=CC(=O)O1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 4.5 g (0.019 mole) of 4-hydroxy-5,6-dihydro-6-nonyl-2-pyrone and 3.15 g (0.021 mole) of DBU in 60 ml of toluene was added dropwise. Then, 1.65 g (0.021 mole) of acetyl chloride with cooling in an ice-water bath. The mixture was stirred for 2 hours and water was added to the reaction mixture. The reaction mixture was extracted with toluene and the toluene layer was washed with an aqueous 5% Na2CO3 solution, with 2N-HCl and finally with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under a reduced pressure to obtain 4.7 g (yield: 89%) of 4-acetoxy-5,6-dihydro-6-nonyl-2-pyrone. The acyloxypyrone was dissolved in 30 ml of toluene and 0.13 g of 4-pyrrolidinopyridine was added to the solution. The mixture was refluxed for 3 hours. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography and recrystallized to obtain 2.4 g (yield: 51%) of 3-acetyl-6-nonyltetrahydropyran-2,4-dione.
Reaction SMILES: [C:1]12([CH2:11]O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)C1)[CH2:8]2.[C:13]([C:15]1[NH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)#[N:14].CC1C(B2OC(C)(C)C(C)(C)[O:28]2)=C(C)NN=1>>[CH3:20][C:17]1[N:16]([CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[O:28]2)[CH2:10]3)[C:15]([C:13]#[N:14])=[CH:19][CH:18]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(C#N)[nH]1
Product: Cc1ccc(C#N)n1CC12CC3CC(CC(C3)O1)C2

Procedure:
The title compound was prepared by substituting 1-hydroxymethyl-2-oxadamantane for 1-adamantanemethanol and 2-cyano-5-methylpyrrole for 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 2A.