Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>C1C=CC=CC=1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:15][C:11]2[CH:12]=[N:13][CH:14]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Oc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-aminophenol (Aldrich; 1.0 equiv.) in benzene (1 M) was added 3-pyridenecarboxaldehyde (Aldrich; 1.0 equiv.). The flask was fitted with a Dean-Stark trap and heated to reflux overnight. (A solid mass formed on the bottom of the flask, which was difficult to break up). The reaction was cooled to ambient and concentrated in vacuo. The solid was taken up in methanol (0.2 M), cooled to 0° C., and treated with sodium borohydride (1.5 equiv.) in 4 portions. The cooling bath was removed and stirring continued for 2 hours. A small amount of was added to quench unreacted hydride. The reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude solid was recrystallized from hexanes/ethyl acetate to give N-(4-hydroxyphenyl)pyridin-3-ylmethylamine. 1H NMR (400 MHz, DMSO d6) 4.16 (2H, s), 6.41 (2H, m), 6.48 (2H, m), 7.28 (1H, ddd, J=0.73, 4.8, 7.7 Hz), 7.7 (1H, td, J=2.2, 7.3 Hz), 8.38 (1H, m), 8.39 (1H, s), 8.52 (1H, d, J=1.5 Hz).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH3:10][C:11]([C@@H:45]([OH:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][SH:56])=[O:52])=[O:47])([CH2:13][O:14][P:15]([O:18][P:19]([O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])([OH:21])=[O:20])([OH:17])=[O:16])[CH3:12].C[O:59][C:60]1C(O)=C(OC)[CH:63]=[C:62](/C=C/C(O)=O)[CH:61]=1>FC(F)(F)C(O)=O.C(#N)C>[C:60]([S:56][CH2:55][CH2:54][NH:53][C:51](=[O:52])[CH2:50][CH2:49][NH:48][C:46](=[O:47])[C@H:45]([OH:57])[C:11]([CH3:10])([CH3:12])[CH2:13][O:14][P:15]([OH:17])(=[O:16])[O:18][P:19]([OH:21])(=[O:20])[O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])(=[O:59])/[CH:61]=[CH:62]/[CH3:63]
Reactant: COc1cc(/C=C/C(=O)O)cc(OC)c1O
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C/C=C/C(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
The assay mixture contained 50 mM Tris-HCl (pH 7.5), 1 mM CoA ester, and about 1 μg cell free extract. Reactions were allowed to proceed at room temperature and were stopped by adding 1 volume 10% trifluroacetic acid (TFA). The reaction mixtures were purified prior to MALDI-TOF MS analysis using Sep Pak Vac C18 50 mg columns (Waters, Inc.). The columns were conditioned with 1 mL methanol and then equilibrated with two washes of 1 mL 0.1% TFA. The sample was applied to the column, and the flow through was discarded. The column was washed twice with 1 mL 0.1% TFA. The sample was eluted in 200 μL 40% acetonitrile, 0.1% TFA. The acetonitrile was removed by centrifugation in vacuo. Samples were prepared for MALDI-TOF MS analysis by mixing 1:1 with 110 mM sinapinic acid in 0.1% TFA, 67% acetonitrile. The samples were allowed to air dry.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=3[N:12]2[CH:11]=[C:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.[CH3:31][CH2:32][O:33]C(C)=O>OS(O)(=O)=O.C(OC(=O)C)(=O)C>[C:32]([C:11]1[N:12]2[C:13](=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=32)[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])[CH3:31]
Reactant: COc1ccccc1-n1c(-c2ccccc2)cn2c3c(=O)[nH]c(=O)n(C)c3nc12
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1-n1c(-c2ccccc2)c(C(C)=O)n2c3c(=O)[nH]c(=O)n(C)c3nc12
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of commercially available 8-(2-methoxyphenyl)-1-methyl-7-phenyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (5, 200 mg, 0.516 mmol) in concentrated H2SO4 (0.103 mL) and acetic anhydride (1.29 mL) was refluxed for 2 h. The reaction was cooled to room temperature, poured into 10 mL of water, and extracted with CH2Cl2 (2×10 mL). The organic extracts were dried over MgSO4 and evaporated under reduced pressure. Purification by column chromatography on silica gel using a gradient CH2Cl2:EtOAc from 5:1 to 1:1 afforded the desired compound as a white solid (88 mg, 39% yield). 1H NMR (500 MHz, DMSO-d6): δ=11.03 (s, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.30-7.37 (m, 5H), 7.08 (d, J=7.9 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 3.60 (s, 3H), 3.30 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, DMSO-d6, CDCl3): δ=187.6, 154.4, 153.6, 153.0, 150.6, 146.8, 135.7, 131.4, 130.7, 129.8, 129.6, 127.5, 126.4, 121.2, 120.6, 120.1, 112.5, 101.0, 55.5, 29.6, 28.8; IR (film): ν=3160, 3050, 1668, 1490, 1292, 1211, 1023, 751, 555 cm−1; HRMS (ESI): m/z: calcd for C23H19N5O4Na+: 452.1335, found: 452.1338.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:25]3[CH:26]=[CH:27][C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1

Procedure:
-Benzyl-5-[4-(tert-butyl)phenyl]-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (1.44 g, 5.03 mmol), and 4-(tert-butyl)phenylboronic acid (1.08 g, 6.07 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.204 g, 0.250 mmol), and potassium carbonate (1.39 g, 10.1 mmol) in dioxane (50 mL) and water (5 mL) following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using 0-5% chloroform in hexane as an eluant yielded the title compound as an aqua solid (0.741 g, 43%), mp: 136-137° C. 1HNMR (200 MHz, DMSO-d6): δ 7.8 (s, 1H), 7.2-7.6 (m, 12H), 6.55 (d, 1H, J=2.6 Hz), 5.45 (s, 2H), and 1.3 ppm (s, 9H).
Reaction SMILES: [N:1]1([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].O.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:30]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(=O)c5ccccc5)CC4)ccc3c1=O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 1.2 g of sodium hydrogen carbonate were added to 30 ml of water and the mixture was stirred at room temperature for 30 minutes. 5 ml of acetone having dissolved therein 1.0 g of benzoyl chloride was added dropwise to the mixture while ice-cooling followed by stirring at the same temperature as above for 30 minutes and then at room temperature for 1.5 hours to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the crystals thus-treated from dimethylformamide gave 2.4 g of 8-(4-benzoyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][I:13]>C(O)C>[I-:13].[CH3:12][N+:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:7]=1
Reactant: CI
Reactant: c1cncc(-c2ncco2)c1
Solvent: CCO
Product: C[n+]1cccc(-c2ncco2)c1
Product: [I-]
Reaction time: 48 h

Procedure:
11.3 g of [(3-oxazol-2-yl)-pyridine] prepared as indicated in Helv. Chim. Acta 45 375 (1962) and 22.4 g of methyl iodide in 150 cm3 of ethanol are heated under reflux for 2 hours, then the reaction medium is left for 2 days. The solvent is evaporated, the residue is crystallized from 95° ethanol and 17 g of product is obtained. M.p.=241° C. (decomp.) after recrystallization from ethanol.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][CH:21]([NH:23][C:24](=[O:36])[C@H:25]([CH:33]([CH3:35])[CH3:34])[NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH3:22])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:20][CH:21]([NH:23][C:24](=[O:36])[C@H:25]([CH:33]([CH3:35])[CH3:34])[NH:26][C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])[CH3:22])=[O:9])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(CSc1ccc(F)cc1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Solvent: ClCCl
Product: CC(CS(=O)c1ccc(F)cc1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
1.3 g of m-chloroperbenzoic acid was added to a solution containing 2.5 g of N1 -[2-(4-fluorophenylthio)-1-methylethyl]-N2 -isopropoxycarbonyl-L-valinamide dissolved in 50 ml of methylene chloride, at 0° C. After the mixture was stirred for 5 hours at room temperature, the reaction mixture was filtered. The filtrate was washed successively with a saturated aqueous solution of potassium carbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel, thus obtaining 1.8 g of the desired product in the form of a colorless prism-shaped crystal (yield: 69%).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10]([O:18]CC)(=[O:17])[CH2:11][C:12]([O:14]CC)=[O:13].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)O[C:23]1C=CC=C[CH:24]=1.[CH2:43]([Sn](=O)CCCC)[CH2:44]CC>>[CH2:1]([CH:11]([C:12]([OH:14])=[O:13])[C:10]([OH:18])=[O:17])[CH3:3].[CH2:23]([CH:11]([C:12]([OH:14])=[O:13])[C:10]([OH:18])=[O:17])[CH3:24].[CH2:43]([CH:11]([C:12]([OH:14])=[O:13])[C:10]([OH:18])=[O:17])[CH3:44].[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: CCCC[Sn](=O)CCCC
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCC(CO)(CO)CO
Product: CCC(C(=O)O)C(=O)O

Procedure:
A 1000 ml. four-necked flask fitted with thermometer, nitrogen sparge tube and a 6" steam jacketed Vigreux with a Barrett trap on top was charged with 134.2 g. trimethylolpropane (1.0 mol), 800.0 g. diethyl malonate (5.0 mols), 1.0 g. triphenyl phosphite and 1.0 g. dibutyltin oxide. Steam was turned on in the condenser and heating was begun with a nitrogen sparge. The mixture cleared but became cloudy again at approximately 130° C. When the pot temperature reached 160° C. ethanol began distilling from the mixture. Heating was continued for a total of 50 minutes with a maximum pot temperature of 180° C. Vacuum was then applied and excess diethyl malonate was removed. Temperature was allowed to fall rapidly to 100° C. to avoid crossesterification reactions which could yield high molecular weight materials. Final stripping was at 100° C. with 1 mm. Hg. Yield of product was 412 g. (86% of theory). Proton NMR was consistent with the proposed structure.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]1.[N+:31](/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]>C1COCC1>[N+:31]([CH2:34][CH:35]([C:16]1([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18][CH2:19][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][CH2:15]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C[N+](=O)[O-])c2ccccc2)CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of diisopropylamine (667 ul, 4.68 mmol) in THF (dry) (4 ml) was treated with n-BuLi (1.6M in hexanes) (2.93 ml, 4.68 mmol). After 5 minutes, the mixture was allowed to warm to RT and then re-cooled to −78° C. This mixture was added dropwise to a cooled (−78° C.) solution of 1-tert-butyl 4-methyl azepane-1,4-dicarboxylate (step 1) (927 mg, 3.6 mmol) in THF (4 ml). The reaction mixture was stirred at −78° C. for 40 minutes. To this mixture was added (E)-(2-nitrovinyl)benzene (537 mg; 3.6 mmol) in THF (4 ml) and the resulting mixture was allowed to warm slowly to RT. The reaction was quenched with saturated ammonium chloride solution and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane/EtOAc followed by 10-100% TBME in iso-hexane afforded the title compound as a diastereomeric mixture.
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=O)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH:3]=[CH:2]1.[CH2:16]1[CH:25]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH:17]1[CH2:26]N.C([N:32]1CCC(CNC(C2C3C(=CC=CC=3)NC=2)=O)CC1)CCC>>[CH2:16]1[CH:25]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH:17]1[CH2:26][C:2]1[S:1][C:5]2=[C:6]([C:13]([NH2:32])=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH:3]=1
Reactant: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Reactant: O=C(O)c1c2ccccc2n2ccsc12
Reactant: NCC1CCN2CCCCC2C1
Product: NC(=O)c1c2ccccc2n2cc(CC3CCN4CCCCC4C3)sc12

Procedure:
Thiazolo[3,2-a]indole-9-carboxylic acid (D16) is converted to its acid chloride and reacted with eq-quinolizidin-2-ylmethylamine (D12) using a procedure analogous to that described in Description 1b.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1O
Agent: Cl
Product: COC(=O)c1ccc(N)c(O)c1
Reaction time: 48 h

Procedure:
Through a solution of 4-amino-3-hydroxybenzoic acid (75 g, 0.49 mol) in 2.0 L of dry CH3OH at room temperature was bubbled anhydrous HCl gas until the solution was saturated. The solution was stirred for 48 hr, then concentrated in vacuo. The product was partitioned between EtOAc and saturated aq. NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the title. 1H NMR (CDCl3, 400 MHz): d 7.51 (dd, 1H, J=8.1 and 1.9 Hz, ArH); 7.46 (d, 1H, J=1.9 Hz, ArH); 6.66 (d, 1H, J=8.1 Hz, ArH); 5.31 (bs, 1H, OH); 4.13 (bs, 2H, NH2) and 3.85 (s, 3H, OCH3).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](CCN)=[CH:28][CH:27]=1.C(O[C@@H](CC1C=CC(O[C@@H:52]([C:54](=O)[NH:55]CCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:55][CH2:54][CH2:52][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:31]=2)[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reactant: NCCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(4-trifluoromethyl-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H28F3NO5 [M−H]−: 466.
Reaction SMILES: [CH3:1][CH2:2]CCCC.[CH2:7]([Li])[CH2:8]CC.[CH:12]1([Ru:17][CH:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:16]=[CH:15][CH:14]=[CH:13]1.C(Br)C>O.O1CCCC1>[CH2:1]([C:18]1([Ru:17][C:12]2([CH2:7][CH3:8])[CH:13]=[CH:14][CH:15]=[CH:16]2)[CH:22]=[CH:21][CH:20]=[CH:19]1)[CH3:2]
Reactant: [Li]CCCC
Reactant: C1=CC([Ru]C2C=CC=C2)C=C1
Reactant: CCCCCC
Solvent: C1CCOC1
Solvent: CCBr
Solvent: O
Product: CCC1([Ru]C2(CC)C=CC=C2)C=CC=C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a nitrogen-replaced flask, 5.0 mL of a hexane solution containing n-butyllithium (concentration: 2.6 mol/L) was placed and cooled to −78° C. After 1.74 g of bis(cyclopentadienyl)ruthenium was added, 50 mL of tetrahydrofuran was added dropwise over one hour to react them. The reaction solution was allowed to stand for 2 hours to return the temperature to room temperature and thereafter a reaction was performed for 24 hours. The reaction solution was again cooled to −78° C., 9.81 g of ethyl bromide was added dropwise over one hour to react them, allowed to stand for 2 hours to room temperature, and the reaction was performed for 24 hours. After completion of the reaction, 100 mL of water was added and bis(ethylcyclopentadienyl)ruthenium was extracted with hexane and then hexane was evaporated from the extraction solvent to obtain 2.0 g of bis(ethylcyclopentadienyl) ruthenium.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.[CH:21]1[N:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH:27]=O.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[C:18]([CH2:27][C:22]5[CH:23]=[N:24][CH:25]=[N:26][CH:21]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Reactant: O=Cc1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(=O)c(Cc3cncnc3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 101, step 6 was suspended in ethanol (17 ml), and pyrimidine-5-carboxyaldehyde (157 mg) prepared by the procedure described in Syn. Commun. 24, 253 (1994) and sodium hydroxide (291 mg) dissolved in water (1.7 ml) were added to the suspension at room temperature. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The crystals precipitated were recovered by filtration, and the residue was purified by alumina flash column chromatography (eluent: methylene chloride containing 4% methanol) to obtain the title compound (300 mg, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([N:7]([CH3:8])[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CNc1ccc(OC)cc1
Reactant: Oc1ccc(OCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(N(C)CCOc2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 24.7 %

Procedure:
Compound 6a (0.20 g, 1.46 mmol) and compound 5a (0.32 g, 1.46 mmol) were stirred in acetonitrile (10.0 mL) for 30 mins and then diisopropylethylamine was added dropwise (0.40 mL, 2.92 mmol). The reaction was then stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 6 as a colorless oil (0.10 g, 0.36 mmol, 25% yield). MS (ESI, positive) m/z calcd. for C16H20NO3 [M+H]+: 274.14, found: 273.96. 1H NMR (CDCl3, 400 MHz) δ 6.86 (d, J=8 Hz, 2H), 6.70-6.78 (m, 6H), 4.06 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 3.64 (t, J=5.6 Hz, 2H), 2.98 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=O)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:5]([O:9][C:10]([N:12]1[CH2:13][C:14]2([CH2:2][CH2:1]2)[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC[Mg+]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C2(CC2)C1
Temperature: 5 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To EtMgBr (344 mL) in THF cooled to −78° C. was added Ti(OiPr)4 (39 g, 137.93 mmol), followed by commercially available 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (40 g, 137.93 mmol) and the resultant reaction mixture was heated to reflux for 1 h. After cooling the reaction mixture to 5° C., another portion of EtMgBr (344 ml) and Ti(OiPr)4 (39 g, 137.93 mmol) was added. The mixture was stirred for 16 h at RT. The reaction mixture was quenched with NH4Cl solution and stirred for 15 min and filtered through a celite bed and washed with EtOAc. The aqueous layer was again extracted with EtOAc (3×). The combined EtOAc layers were washed with water and dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography to afforded the title compound as a solid (24 g, 58%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:19][C:20]1[CH:21]=[C:22]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:23]([NH:26][C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][C:34]#[N:35])[N:31]=2)=[N:24][CH:25]=1.[Si]([N:47]=[N+:48]=[N-:49])(C)(C)C>C(Cl)Cl>[NH:47]1[C:34]([CH2:33][CH2:32][C:30]2[N:31]=[C:27]([NH:26][C:23]3[C:22]([O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:21][C:20]([Br:19])=[CH:25][N:24]=3)[S:28][CH:29]=2)=[N:35][N:49]=[N:48]1
Reactant: N#CCCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: Brc1cnc(Nc2nc(CCc3nnn[nH]3)cs2)c(Oc2ccccc2)c1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
To a nitrogen purged vial was added TBAF (0.249 mL, 0.249 mmol), 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanenitrile (0.200 g, 0.498 mmol) (Example 320), and TMSN3 (0.0992 mL, 0.748 mmol) were added, and the reaction was stirred at 120° C. for 24 Hr. The crude reaction mixture was dissolved in CH2Cl2 and washed with aqueous sodium bicarbonate solution. The organic layer was concentrated to a residue that was purified on silica gel by eluting with 7% MeOH/CH2Cl2 and further purified by triturating in refluxing EtOAc to give the title compound (0.128 g, 57.8% yield). 1H NMR (d6 DMSO) δ 3.03 (t, J=7.5 Hz, 2H), 3.25 (t, J=7.6 Hz, 2H), 6.70 (s, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.22 (t, J=7.3 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.2 Hz, 1H), 11.01 (s, 1H).