Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: c1c[nH]cn1
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Nc1ccc(OS(=O)(=O)c2ccc(-n3ccnc3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 57.8 %

Procedure:
15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 20.7 g imidazole in 100 ml dimethylformamide in a round bottom flask. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. Reaction mixture was then precipitated by addition of water filtered and precipitate was washed with water and dried. Residue was resolubilized in hot ethyl glycol, crystallized by cooling and the crystals were washed with methanol and dried, yielding 10.4 g of 2-amino-5-(4-[1-imidazolyl]-phenylsulfonyloxy)nitro-benzene (melting point 209° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][CH:5]=[C:6]([NH:7][C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1
Reactant: Nc1cc(F)c(C(F)(F)F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#CNc1ccc(C(F)(F)F)c(F)c1
Yield: 96.1 %

Procedure:
To a solution of 3.27 g of 5-fluoro-2-iodo-4-trifluoromethyl-aniline (10.7 mmol) in 20 ml triethylamine were added 3763 mg of Pd(PPh3)2Cl2 (0.5 mmol), 102 mg of CuI (0.5 mmol) and 1.63 ml of ethinyltrimethylsilane (11.8 mmol). The reaction mixture was stirred over night at rt before most of the triethylamine was removed under reduced pressure. Then DCM was added and the resulting suspension was filtered. The filtrate was then concentrated and the residue purified by chromatography (silica gel; cyclohexane/EtOAc 9:1) to yield 2.83 g (96%) of 5-fluoro-4-trifluoromethyl-2-trimethylsilanylethynyl-phenylamine contaminated with triethylamine as a dark red liquid. 1H-NMR (CDCl3, 300 MHz): δ 0.26 (s, 9H), 4.68 (br s, 2H), 6.44 (d, J=12 Hz, 1H), 7.51 (d, J=8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([O:16]CC)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][NH2:21]>CCO>[NH:20]([C:14](=[O:16])[CH2:13][CH:11]1[CH2:12][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1)[NH2:21]
Reactant: CCOC(=O)CC1CC(NC(=O)OC(C)(C)C)C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(CC(=O)NN)C1
Yield: 96.2 %

Procedure:
A solution of ethyl 2-(3-(tert-butoxycarbonylamino)cyclobutyl)acetate (1.2 g, 4.7 mmol) and hydrazine hydrate (1.4 g, 23.5 mmol) in EtOH (8 mL) was heated at 80° C. for 17 hrs. The reaction mixture was concentrated and the residue was dissolved in DCM (20 mL). The organic phase was washed with saturated sodium chloride (10 mL) and water (10 mL). The water layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated to afford tert-butyl 3-(2-hydrazinyl-2-oxoethyl)cyclobutylcarbamate (1.1 g, 97%). ESI-MS (EI+, m/z): 244 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1

Procedure:
Add 20% palladium hydroxide on carbon (Pearlman's catalyst) (232 mg) to a solution of 5-(R)-[1-(S)-benzyloxy-2-(S)-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(S)-(2-cyclohexylethyl)-morpholine-4-carboxylic acid tert-butyl ester (232 mg, 0.31 mmol) in methanol (5 mL). Stir under 1 atmosphere of hydrogen gas at room temperature overnight, filter through a pad of Celite® and concentrate to give the desired compound as a colorless oil which is used directly without further purification (138 mg, 93%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([NH2:17])=[O:16])=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]#[N:34])[CH:31]=2)[NH:26][CH:25]=1>>[C:33]([C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15](=[O:16])[NH2:17])=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5]1)#[N:34]
Reactant: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: NC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1

Procedure:
5-(1-piperazinyl)benzofuran-2-carboxamide or a corresponding salt is reacted with 3-(4-chlorobutyl)-5-cyanoindole to give 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine and optionally then converted into its acid addition salt.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=[O:5])[CH3:2].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[C:17]([C:16]1[C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=[CH:20][C:19]=1[O:9][CH2:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])([CH3:10])[CH3:11])#[N:18]
Reactant: CCNC(=O)NC(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCNC(=O)NC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 65 %

Procedure:
Prepared as in Example 215c from 1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)urea (Example 230d) and 2,6-dinitrobenzonitrile in 65% yield. MS 307 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]([O:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:27]>CO>[CH3:18][C:16]1([CH3:19])[CH2:15][O:14][C:13]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:43]3[CH2:44][CH2:45][CH:40]([C:32]4[N:31]([CH2:30][CH2:29][O:28][CH2:26][CH3:27])[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=4)[CH2:41][CH2:42]3)=[CH:5][CH:6]=2)([CH3:12])[CH3:11])=[N:17]1
Reactant: CCOCCn1c(C2CCNCC2)nc2ccccc21
Reactant: CC1(C)COC(C(C)(C)c2ccc(CCCl)cc2)=N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C4=NC(C)(C)CO4)cc3)CC2)nc2ccccc21
Yield: 125.4 %

Procedure:
In a reaction vessel, 2-{1-[4-(2-chloro-ethyl)-phenyl]-1-methyl-ethyl}-4,4-dimethyl-4,5-dihydro-oxazole (1.9 g) prepared in the Example 9, sodium carbonate (0.8 g), 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzoimidazole (2.0 g) prepared in the Example 12 and methyl alcohol (20 mL) were introduced, and the mixture was reacted for 14 hours under reflux condition to obtain 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzoimidazole (4.4 g, yield 87%, HPLC purity 98% or more).
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.FC(F)(F)C(O)=O.CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.[OH-].[Na+]>ClCCl.O>[CH2:31]([N:25]1[CH2:26][C:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[C:5]([C:4]([OH:3])=[O:14])[CH2:24]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C#Cc1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.8 %

Procedure:
To a solution of (4-chloro-phenyl)-propynoic acid ethyl ester (92.65 g, 444.1 mmol) in dichloromethane (425 mL) was added trifluoroacetic acid (3.4, 44.4 mmol). The reaction mixture was cooled with a water bath and a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (164.7 g, 666.1 mmol) in dichloromethane (325 mL) was added dropwise over a period of 1.5 h. It was stirred for 22 h at ambient temperature. Further N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (27.5 g, 111.0 mmol) in dichloromethane (50 mL) was added and stirring was continued for 2 h at ambient temperature. The solvent was distilled off and the residue was taken up in dioxane (950 mL). After addition of water (475 mL) and sodium hydroxide (32%, 114.3 mL, 1.23 mol), it was stirred for 67 h at ambient temperature. After concentration the residue was diluted with water (400 mL) and extracted with tert-butylmethylether (400 mL). The organic layers were washed with water (400 mL). The aqueous layers were combined, cooled to 5° C. and set to pH=1.5 with aqueous HCl (25%, 172). After stirring for 1 h at 5° C., the solid was filtered off and was washed with water (1400 mL) and ethanol (400 mL). Drying (50° C., 25 mbar) afforded the title compound (109.85 g, 79%) as an off-white solid. MS m/e: 312.2/314.1 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=3)=[CH:24][C:23]=2[F:36])=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CS(Cl)(=O)=O.[CH3:48][O:49][CH2:50][CH2:51]O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=3)=[CH:24][C:23]=2[F:36])=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:51][CH2:50][O:49][CH3:48])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(CO)cc3)c(F)c2)ccn1
Reactant: COCCO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-[5-tert-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl)-urea (170 mg, 0.35 mmol) in anhydrous THF was added K2CO3 (52 mg, 0.38 mmol) followed by methanesulfonyl chloride (30 μL, 0.38 mmol). The mixture was stirred at room temperature for one day, and then 2-methoxy-ethanol (213 mg, 3.5 mmol) was added. The mixture was stirred at room temperature overnight, then EtOAc was added followed by saturated Na2CO3. The organic layer was washed with saturated Na2CO3 and brine, dried over MgSO4 and evaporated at reduced pressure. Purification by HPLC (10% to 90% aq acetonitrile afforded pure product (10 mg, 5%). 1H-NMR (CD3OD) δ 8.17 (d, J=6.0 Hz, 1H), 8.01 (t, J=9.3 Hz, 1H), 7.48-7.37 (m, 4H), 6.93-6.69 (m, 4H), 6.36 (s, 1H), 4.54 (s, 2H), 3.58 (m, 2H), 3.50 (m, 2H), 3.28 (s, 3H), 2.37 (s, 3H), 1.25 (s, 9H); MS LC-MS [M+H]+=548.1, RT=2.69 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=C(S(Cl)(=O)=O)C=C(Cl)C=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)cc(Cl)c1)CCC2
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 539.17 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3,5-dichloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:13]([O:20][C:21](=[O:38])[CH:22](Br)[CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N>[CH2:13]([O:20][C:21](=[O:38])[CH:22]([N:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:23][CH2:24][CH2:25][N:26]1[C:27](=[O:36])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]1=[O:35])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OCc1ccccc1)C(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: C1CNCCNCCNCCN1
Solvent: CC#N
Product: O=C(OCc1ccccc1)C(CCCN1C(=O)c2ccccc2C1=O)N1CCNCCNCCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
55 g of cyclen base (320 mmol) are dissolved in 550 ml of CH3CN, to which 119.8 g of brominated derivative (2-bromo-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid benzyl ester, 288 mmol) dissolved in 550 ml of CH3CN are added dropwise. The medium is stirred at ambient temperature overnight. The precipitate is filtered off and washed thoroughly with acetonitrile. 138 g of product are obtained in the form of a white powder (corrected yield 81.3%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.Cl>O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1cc2ccccc2c(N2CCOCC2)n1
Agent: Cl
Solvent: O
Product: c1ccc2c(N3CCOCC3)nc(N3CCNCC3)cc2c1
Yield: 26 %

Procedure:
1-Morpholino-3-piperazino-isoquinoline was prepared analogous to Example 3 from 1 -morpholino-3-chloro-isoquinoline and piperazine. M.p. of its hydrochloride: 245°-247°C (from water); yield: 26% of theory.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1([CH2:19]O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:19][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1

Procedure:
The desired product was prepared using the method described in Example 1176A starting with N-hydoxyphthalimide and cyclohexylmethanol.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1CCC(O)=O.C1(Br)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC.CCOC(C)=O>[C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]([O:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1O
Reactant: O=C(O)CCc1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Brc1ccccc1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C(CCc1ccccc1Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
3-(2-Phenyloxyphenyl)propionic Acid. A mixture of 3-(2-hydroxyphenyl)propionic acid (0.57 g, 3.4 mmol), phenylbromide (0.4 ml, 3.37 mmol), and K2CO3 (2.5 g) in acetone (10 ml) was stirred at room temperature for 2 days. The mixture was diluted with 1:1 hexane/EtOAc (100 ml), washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (5:1 then 4:1 hexane/EtOAc) to yield phenyl 3-(2-phenyloxyphenyl)propionate (0.45 g, 1.30 mmol, 77%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11]CC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[N:3]=1.C(O)C>[Pd].O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[OH:11])=[C:4]([O:19][CH3:20])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1nc(N)nc2c1ncn2O
Reaction time: 0.75 h

Procedure:
A mixture of 2-amino-9-benzyloxy-6-methoxypurine (300 mg, 1.11 mmol), 10% palladium-on-charcoal (100 mg), ethanol (10 ml) and dioxan (5 ml) was stirred under an atmosphere of hydrogen for 45 minutes. The catalyst was then removed and the filtrate evaporated to a white solid 2-amino-9-hydroxy-6-methoxypurine (190 mg, 95%). IR: νmax (KBr) 3312, 1643, 1591, 1394 cm-1 ; 1H NMR: δH [(CD3)2SO] 3.95 (3H, s, CH3), 6.45 (2H, br.s, D2O exchangeable, NH2), 7.93 (1H, s, H-8), 11.75 (1H, br.s, OH). Found: m/e 181.0594. C6H7N5O2 requires: m/e 181.0596.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:48])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:48])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: CCOc1ccc(COC(=O)Cl)cc1
Product: CCOc1ccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
4-Ethoxybenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 4-ethoxybenzyl carbonochloridate (58.5 mg, 0.18 mmol) according to General Procedure H to give 65 mg (81%) of pale yellow solid. Anal. Calcd. for C28H36N4O3 m/z 476.3, found: 477.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (d, J=8.9 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 1H), 7.04 (d, J=8.6 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.92 (m, 2H), 3.98 (m, 2H), 3.86 (d, J=6.9 Hz, 1H), 3.75 (d, J=12.5 Hz, 1H), 3.07 (m, 1H), 2.76 (m, 1H), 2.35 (m, 2H), 1.89 (m, 1H), 1.78 (m, 2H), 1.64 (m, 3H), 1.44 (m, 1H), 1.30 (t. J=7 Hz, 3H), 1.17 (m, 4H), 1.02 (m, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[C:25]([O:53][CH2:54][CH3:55])=[N:26][O:27][C:28]=1[C:29]1[N:33]=[CH:32][N:31]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1>CN1CCCC1=O>[C:1]([NH:4][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:23][C:24]1[C:25]([O:53][CH2:54][CH3:55])=[N:26][O:27][C:28]=1[C:29]1[N:33]=[CH:32][N:31]([C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:30]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(Cc1c(OCC)noc1-c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of diethyl acetamidomalonate (1.3 g, 6.0 mmol) and potassium tert-butoxide (0.73 g, 6.5 mmol) in N-methylpyrrolidone (30 mL) was stirred at room temperature for 30 min. 3-[4-(Bromomethyl)-3-ethoxyisoxazol-5-yl]-1-trityl-1H-1,2,4-triazole (2.8 g, 5.4 mmol) in N-methylpyrrolidone (20 mL) was added (temp 22-28° C.) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured onto an ice/water mixture (250 mL) and the aqueous phase was extracted with EtOAc (3×250 mL). The organic extracts were washed with an aqueous solution of potassium tert-butoxide and brine, dried (Na2SO4) and concentrated in vacuo. Flash chromatography (silica gel, eluent: EtOAc/heptane/triethylamine=50:50:2) gave the title compound (2.2 g, 62%): mp 145-149° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:32]([C:27]3[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:34])=[O:33])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of [4-(4-Amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and 2-Methyl-benzenesulfonyl chloride (113 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 ml, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum. The residue was diluted with water (10 mL) and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (40 g) column, eluting with 5-30% ethyl acetate in hexanes, to afford {6-chloro-3-methyl-4-[4-(toluene-2-sulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 62.1%) as a white foam. HRMS calcd. for C27H23ClFNO4S [(M−H)−] 492.1042, obsd. 492.1042.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])(=[S:3])[NH2:2].Cl[CH2:16][C:17](=O)[CH3:18]>C(O)C>[CH3:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[C:1]1[S:3][CH:16]=[C:17]([CH3:18])[N:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(N)=S)c(C)c1
Reactant: CC(=O)CCl
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(C)cs2)c(C)c1
Yield: 69 %

Procedure:
Methyl 4-carbamothioyl-3-methylbenzoate (8.9 g, 42.5 mmol) and chloroacetone (3.94 g, 42.5 mmol) were dissolved in ethanol (50 mL), and refluxed for 12 hours. The solvent was evaporated, and the residue was purified on a silica gel column, eluting with 20%-40% ethyl acetate in hexanes, to get methyl 3-methyl-4-(4-methylthiazol-2-yl)benzoate as white waxy solids (contains some ethyl 3-methyl-4-(4-methylthiazol-2-yl)benzoate) (7.4 g, 69% yield). An aliquot amount of the methyl and ethyl ester mixture was separated for identification purpose.