Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[N-:10]=[N+:11]=[N-:12].[Na+].O>CO>[N:10]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCN=[N+]=[N-]
Yield: 99.7 %

Procedure:
A solution of methyl 5-bromovalerate (5.00 g, 25.6 mmol), NaN3 (3.33 g, 51.2 mmol) and 15 ml of water in 40 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying and removal of solvent, methyl 5-azidovalerate (4.01 g, 99.7%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C1(C(N)C2CCCCC2)CCCCC1.[H][H]>CO>[CH3:17][C@H:13]([C:14]([OH:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: [H][H]
Reactant: C=C(C(=O)O)c1ccc2cc(OC)ccc2c1
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CO
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 84.7 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.45 g (2 mmoles) of 6-methoxy-α-methylene-2-naphthaleneacetic acid, 20 ml of methanol, and 0.39 g (2 mmoles) of dicyclohexylmethylamine. Then, 9.0 mg (0.010 mmole) of Ru((-)-T-BINAP)(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (-)-T-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 12 hours at a hydrogen pressure of 135 kg/cm2 and at a reaction temperature of 17° C. Thereafter, the solvent was distilled off to provide 0.39 g of naproxen. The yield was 84%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:20][CH2:19]1)[C:12](O)=[O:13])=[O:7].C(N(CC)CC)C.[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[C:38]1([CH2:44][CH2:45][CH2:46][NH:47][C:12]([C:11]2[CH:15]=[CH:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH2:19]3)=[C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:10]=2)=[O:13])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2NC(=O)c2ccco2)CC1
Reactant: NCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCc3ccccc3)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a suspension of 3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (0.1 g, 0.246 mmol) in methylene dichloride (5 ml), triethylamine (0.074 g, 0.74 mmol), (3-phenylpropyl)amine (0.044 g, 0.370 mmol) and 1-propane phosphonic cyclic anhydride (0.23 g, 0.74 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and extracted with dichloromethane (10 ml×1). The organic layer was washed with water (10 ml×2) and dried over anhydrous sodium sulfate. The organic layer was concentrated and the crude product obtained was purified by flash chromatography using silica gel column to get (0.070 g, 67.9%) of the titled compound as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]O)[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 85.4 %

Procedure:
The non-polydispersed alcohol 19 (0.835 g, 1.97 mmol) was dissolved in 3.5 ml dry dichloromethane and placed under a nitrogen atmosphere. Triethylamine (0.301 ml, 0.219 g, 2.16 mmol) was added and the mixture was chilled in an ice bath. After two minutes, the methanesulfonyl chloride (0.16 ml, 0.248 g, 2.16 mmol) was added. The mixture was stirred for 15 minutes at 0° C., then at room temperature for two hours. The reaction mixture was filtered through silica gel to remove the triethylammonium chloride, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 9/1 ethyl acetate/methanol) to give non-polydispersed compound 20 as a clear oil (0.819 g, 83%). FAB MS: m/e 503 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(O)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 77.1 %

Procedure:
6,7-Dimethoxy-quinazolin-4-ol (1.00 g, 4.85 mmol, 1 eq.), phosphorous oxychloride (4.07 mL, 43.6 mmol, 9.00 eq.) and triethylamine (6.08 mL, 43.6 mmol, 9 eq.) were refluxed for 2 hours. Stripped then restripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried and stripped in vacuo to give an amber oil. Purified over silica gel in 9:1 to 3:1 Hexanes/EtOAc. Obtained 0.84 g of off-white solids as product. LCMS detects (M+H)+=225.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1>>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:43][CH2:44][CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:48][CH2:47]3)[CH:10]=2)[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2ccccc2)CC1
Reaction time: 19 h
Yield: 45 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 19 h, and being recrystallized with EtOAc to obtain the title compound (45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH2:21][CH2:22][C:23](Cl)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:15]1([CH2:21][CH2:22][CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cccc([C@H]2CCCNC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc([C@H]2CCCN(CCCc3ccccc3)C2)c1

Procedure:
The title compound was prepared by acylation of 1.0 g (5.2 mmole) of the (R)(-)-3-(3-methoxyphenyl)piperidine from preparation 7, Part C, with 1.3 g (7.8 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 910 mg (24 mmole) of lithium aluminum hydride in tetrahydrofuran, using the procedure of Preparation 3. This afforded 1.9 g of an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[OH:22].[CH:23](N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[Br:1][C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[O:22][CH3:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1O
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
(7-Bromo-3-chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (7.0 g) was dissolved in 1-methyl-2-pyrrolidinone (35 ml) and di-isopropylethylamine was gradually added. The reaction solution was warmed at 80° C. for 3 hours. Then water (350 ml) was added. The reaction solution was stirred at room temperature for 30 minutes. The product was extracted into ethyl acetate. The organic phase was washed with 1M hydrochloric acid and a solution of sodium sulphate, evaporated and dried in vacuum. The product was purified by flash chromatography using heptane-ethyl acetate as an eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:13]2[C:5](=[CH:6][C:7]3[NH:8][C:9]([S:14][CH2:15][C:16]4[C:21]([CH3:22])=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=4)=[N:10][C:11]=3[CH:12]=2)[C:4]([CH3:27])([CH3:26])[C:3]1=[O:28].[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:15][S:14][C:9]2[NH:8][C:7]3[CH:6]=[C:5]4[C:13](=[CH:12][C:11]=3[N:10]=2)[C:2]([CH3:29])([CH3:1])[C:3](=[O:28])[C:4]4([CH3:27])[CH3:26])[C:21]=1[CH3:22]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
A solution of 4.4 g (0.011 mol) of 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl -4-nitro-2-pyridyl)methyl)thio]indeno[5,6-d]imidazol-6(1H)-one in 100 ml of abs. methanol is treated with 3 g of sodium methylate, whereupon the mixture is boiled at reflux for 18 houre under argon. After concentrating the reaction mixture in vacuo the residue is treated with methylene chloride, whereupon the mixture is buffered by means of glacial acetic acid; the methylene chloride phase is extracted several times with a sodium bicarbonate solution, dried and evaporated. By recrystallisation from ethyl acetate there is obtained 5,7-dihydro-2-[[(4-methoxy-3 -methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 222°-226°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=1[CH3:22]>>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1c(NCCN)c(=O)n(C)c(=O)n1C
Reactant: c1ccc(OCC2CO2)cc1
Product: Cc1c(NCCNCC(O)COc2ccccc2)c(=O)n(C)c(=O)n1C
Reaction time: 24 h

Procedure:
2.43 g. Phenyl glycidyl ether and 5.15 g. 5-(2-aminoethylamino)-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione are left to stand for 24 hours at ambient temperature, whereupon the reaction mixture is separated with silica gel using, as elution agent, methylene chlorideammoniacal methanol (95:5 v/v). The yellowish oil obtained by evaporation of the pure fractions is triturated with ethyl acetate. After subsequent recrystallization from ethyl acetate, there are obtained 2.55 g. (43% of theory) of the desired product in the form of colorless crystals; m.p. 92°-94° C.
Reaction SMILES: OO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1.N=O.[C:37]([OH:41])([CH3:40])([CH3:39])[CH3:38]>O>[OH:23][CH:24]1[CH2:29][C:28]([CH3:30])([CH3:31])[N:27]([O:32][CH2:38][C:37]([OH:41])([CH3:40])[CH3:39])[C:26]([CH3:34])([CH3:33])[CH2:25]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: N=O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 47.5 °C
Reaction time: 1 h

Procedure:
A solution of 32.3 g (475 mmol) of 50% aqueous hydrogen peroxide mixed with 35 mL of tert-butyl alcohol is added over six hours at 45-50° C. to a mixture prepared by adding sequentially 0.362 g (1.2 mmol) of ethylenediaminetetraacetic acid, 55 mL of tert-butyl alcohol and 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine to a solution of 0.80 g (4 mmol) of ferrous chloride dissolved in 5 mL of water. Analysis by gas chromatography shows 15% starting nitroxyl compound remains at the end of the peroxide addition. The reaction mixture is stirred for one hour at 45-50° C. and then for 72 hours at 25° C. to complete the reaction. Analysis by gas chromatography shows the reaction mixture contains a ratio of 7 parts of the title compound to 1 part of 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-4-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][CH3:19])=[CH:4][C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][NH:26][C:27]([C:29]2([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]2)=[O:28])=[CH:23][C:22]=1[N:38]=[C:39]=S.CC(C)N=C=NC(C)C>C1COCC1>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][NH:26][C:27]([C:29]2([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]2)=[O:28])=[CH:23][C:22]=1[NH:38][C:39]1[N:18]([CH3:19])[C:3]2[CH:4]=[C:5]([O:13][CH2:14][CH:15]([F:16])[F:17])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)n(C)c2cc1OCC(F)F
Temperature: 25 °C

Procedure:
A mixture of ethyl 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)benzoate (0.737 g; 2.68 mmol; crude material from step (g)) and N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (0.900 g; 2.68 mmol) in THF (100 mL) was stirred over night at rt. DIC (0.338 g; 2.68 mmol) was added and the mixture was stirred for 6 h at rt. Another portion of DIC (0.169 g; 1.34 mmol) was added and the mixture stirred for another 6 h at rt. The mixture was concentrated and purified by column chromatography to give the sub-title compound. Yield: 0.790 g (51%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCOCC.C1(C)C=CC=CC=1>[C:15]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: O=C1CCCC1
Reactant: c1ccc2occc2c1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C1=C(c2cc3ccccc3o2)CCC1

Procedure:
Benzofuran was treated with butyllithium in ether followed by cyclopentanone. The resulting alcohol was dehydrated with toluenesulfonic acid in toluene to afford 2-cyclopenten-1-ylbenzofuran. Treatment with maleimide gave a cycloadduct which was aromatized by treatment with tetrachloroquinone. 1H NMR (DMSO-d6) δ 11.29 (s, 1H), 8.60 (d, 1H), 7.82 (d, 1H), 7.66 (t, 1H), 7.52 (t, 1H), 3.23 (m, 4H), 2.30 (quintet, 2H). MS m/e 276 (M−H)−.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: Clc1ccc(Br)cn1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3ccc(Cl)nc3)[C@@H]2C1
Yield: 37.8 %

Procedure:
The product of Example 52D (0.23 g, 1.0 mmol) and 2-chloro-5-bromopyridine (0.29 g, 1.5 mmol) were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, hexane:ethyl acetate, 60:40, Rf 0.3) to provide the title compound (0.13 g, 38% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.24 (dd, J=12.9, 4.1 Hz, 1H), 3.30 (m, 1H), 3.40 (m, 1H), 3.65 (dd, J=7.8, 3.4 Hz, 1H), 4.08-3.92 (m, 3H), 4.70 (dd, J=5.7, 3.7 Hz, 1H), 5.10 (m, 2H), 6.90 (dd, J=8.5, 3.1 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.25 (m, 3H), 7.35 (m, 2H), 7.54 (d, J=3.0 Hz, 1H); MS (DCI/NH3) m/z 346 (M+2+H)+, 344 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:31]1[C:35]([CH:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[N:34][N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH:34]1[C:35]([CH:36]2[CH2:37][CH2:38][CH:39]([C:42]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]5[N:17]=[C:18]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[O:19][C:20]=5[C:21]([F:22])([F:24])[F:23])=[O:15])=[CH:9][CH:8]=4)[CH2:2][CH2:3]3)=[O:43])[CH2:40][CH2:41]2)=[N:31][N:32]=[N:33]1
Reactant: O=C(O)C1CCC(c2nnn[nH]2)CC1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(N2CCN(C(=O)C3CCC(c4nnn[nH]4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h
Yield: 48.8 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (130 mg, 0.31 mmol), 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid (61 mg, 0.31 mmol), DMAP (2 mg, 0.016 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.37 mmol) in anhydrous DMF (2 mL) was stirred at room temperature for 2.5 days. The reaction was diluted in water (100 mL) and extracted with dichloromethane (2×100 mL) and ethyl acetate (1×100 mL), the organic layers combined, dried over sodium sulfate and purified by flash chromatograph with increasing concentrations of methanol in dichloromethane (0 to 10% over 20 min) to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{4-[4-(1H-tetrazol-5-yl)-cyclohexanecarbonyl]-piperazin-1-yl}-phenyl)-amide (90 mg, 49%) as a light yellow solid. LCMS calcd for C29H29F3N8O3 (m/e) 594, obsd 595 (M+H).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15](OC)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:19])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([CH3:23])[O-:22].[Li+].O>CC(O)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:22][CH:21]([CH3:23])[CH3:20])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:19])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Reactant: CC(C)[O-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Temperature: 65 °C
Yield: 95.2 %

Procedure:
The mixture of methyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (50.0 g, 0.194 mol) and lithium isopropoxide (16.2 g, 95%, 0.233 mol) in 2-propanol was stirred at 65±5° C. for at least 30 min for complete trans-esterification. The batch was cooled to 40±5° C. and water (600 g) was added at a rate to maintain the batch temperature at 40±5° C. After addition, the mixture was cooled to 20-25° C. over 2±0.5 h and held at 20-25° C. for at least 1 h. The batch was filtered and rinsed with 28 wt % 2-propanol in water (186 g), and water (500 g). The wet cake was dried in vacuo (≦200 Torr) at 40-45° C. until the water content was ≦0.5% to give isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (52.7 g, 95% yield) in 99.2 A % (240 nm).
Reaction SMILES: CO[C:3]([O:20]C)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:38])[CH3:37]>CN(C=O)C.O>[CH3:37][C:36]1[N:38]=[C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:20])=[CH:13][CH:12]=2)[O:11][N:35]=1
Reactant: COC(Cc1ccc(C(=O)O)cc1)(OC)c1ccccc1
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccc(CC(=O)c3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
To 4-(2,2-dimethoxy-2-phenylethyl)benzoic acid (1.1 g, 3.84 mmole) in DMF (15 mL) was added carbonyldiimidazole (0.68 g, 4.2 mmole). After 20 min, N-hydroxy ethanimidamide (0.33 g, 4.5 mmole) was added and the mixture stirred for 45 min. at r.t. followed by 100° C. overnight. The reaction was cooled, poured in H2O (30 mL) and extracted with hexane/ethylacetate 1:1. The organic phase was dried over Na2SO4 and concentrated. The residue was dissolved in 100 mL acetone and treated with p-toluene sulfonic acid (100 mg) for 2 h. Et3N (0.5 mL) was added, and the mixture was concentrated to dryness. The residue was dissolved in 2:1 hexane/ethyl acetate (10 mL) and passed through a pad of silica gel, eluting with 1: 1 hexane:EtOAc. The fractions were concentrated, and the residue was stirred with 4:1 hexane:EtOAc 10 mL to give 0.49 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:17]([C:18]1[C:19]([CH3:21])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[CH:8][CH:9]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCC3)c2c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) (21.63 g, 100.0 mmol) and ethyl acetoacetate (12.6 mL, 100.0 mmol) in anhydrous toluene (300 mL) was added SnCl4 (23.1 mL, 200.0 mmol) over a period of 25 minutes at room temperature under nitrogen. The stirred reaction mixture was then refluxed for 5 h under nitrogen. After it was cooled down to room temperature, the reaction solution was concentrated to remove most of the solvent under reduced pressure. The residue was re-dissolved in EtOAc (3.5 L) and carefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜130 mL) at 0° C. The resultant mixture was stirred at room temperature overnight. The precipitate was filtered off, and the organic layer was separated and washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 30% EtOAc in hexanes to give the title compound as a pale yellow solid (24.6 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.36 (m, 5H), 1.53-1.65 (m, 4H), 1.81-1.86 (m, 2H), 2.42-2.45 (m, 1H), 2.54 (s, 3H), 4.05 (d, J=7.2 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.21-7.23 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 329 (MH+).