Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=NO)[C:3]1=[O:15].[N+](=[CH2:18])=[N-].C[CH2:20][O:21]CC>C(Cl)Cl.CO>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:18])=[C:4]([O:21][CH3:20])[C:3]1=[O:15]
Reactant: CCOCC
Reactant: C=[N+]=[N-]
Reactant: CN1C(=O)C(=NO)C(=O)c2ccccc21
Solvent: CO
Solvent: ClCCl
Product: COc1c(OC)c2ccccc2n(C)c1=O

Procedure:
A suspension of 1-methyl-3,4-dihydroxy-2(1H)-quinolinone (0.2 gm, Example 7, obtained from Formula 1.02, see Example 1) in methylene chloride (5 ml) and methanol (5 ml) was treated with a solution of excess diazomethane in ether. The resulting solution was evaporated and the residue was chromatographed on silica gel (5 gm). The major product of the reaction was eluted with 1% methanol/methylene chloride and crystallized from ethyl acetate-hexane to give the title compound. That the expected product was obtained was confirmed by the spectral data: MS: m/e 219 (M.+ +1); NMR(CDCl3): δ3.71 (s, 3H, CH3 --N), 3.94 (s, 3H, OCH3), 4.22 (s, 3H, OCH3) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.C([N-:10][CH:11]([CH3:13])[CH3:12])(C)C.[Li+].[C:15](#N)CC>O1CCCC1>[NH2:10][C:11]([CH2:13][CH3:15])=[CH:12][CH:1]1[CH2:4][CH2:5][NH:6][C:2]1=[O:3]
Reactant: CC1=NCCO1
Reactant: CC(C)[N-]C(C)C
Reactant: CCC#N
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(N)=CC1CCNC1=O
Temperature: -78 °C
Yield: 70 %

Procedure:
A solution of 2-methyl-2-oxazoline (8.5 g; 0.10 mole) in 100 mL dry tetrahydrofuran (THF) was added via syringe to a stirred suspension of freshly prepared lithium diisopropylamide in 50 mL THF. The suspension was kept stirred under a nitrogen atmosphere at -78° C. for an additional hour after the addition was completed. At this point propionitrile (10 mL; 0.14 mole) was added to the stirred suspension which was then allowed to warm to room temperature with continued stirring. The reaction was then quenched with 25 mL saturated NH4Cl solution. The organic layer was separated and washed with water. The water wash was back extracted with ether and the organic portions combined and washed with brine. The organic solution was dried over K2CO3, filtered, and concentrated to 13 g of yellow liquid. Distillation (90°-95° C. at 1 mm Hg) yielded 6.5 g clear liquid as product (70% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (325 mg, 1.0 mmol) in MeOH (10 mL) was added dihydro-2H-pyran-4(3H)-one (88 mg, 1.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (630 mg, 10.0 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (200 mg, Yield 48.9%). 1H NMR (CD3OD, 400 MHz): δ 8.44 (brs, 1H), 7.32-7.20 (m, 3H), 7.20-7.13 (m, 2H), 7.13-7.09 (m, 1H), 7.08-7.00 (m, 1H), 6.86-6.77 (m, 1H), 4.39 (s, 2H), 4.35-4.25 (m, 1H), 4.03-3.89 (m, 2H), 3.63-3.40 (m, 7H), 3.31-3.07 (m, 4H), 2.06-1.92 (m, 2H), 1.55-1.40 (m, 2H). LCMS (m/z): 410.2 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1OC(OC1C=CC=C(C(C)(C)C)C=1)=S)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][C:54](N=NC(C#N)(C)C)(C#N)C.[CH:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[CH:53]=[CH:54][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: COCCO[C@@H]1[C@H](OC(=S)Oc2cccc(C(C)(C)C)c2)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reactant: c1ccccc1
Product: COCCO[C@@H]1[C@H](C=Cc2ccccc2)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 40 °C

Procedure:
To a solution of 5′-O-(tert-butyldiphenylsilyl)-3′-O-(3-tert-butylphenoxythiocarbonyl)-2′-O-(2-methoxyethyl)-5-methyluridine (15.0 g, 20.0 mmol) in 150 mL of benzene was added PhCH=CHSnBu3 (18.7 g, 50 mmol). The resulting solution was degassed three times with argon at rt and 45° C. After AIBN (1.0 g, 6.1 mmol) was added, the resulting solution was refluxed for 2 h. Another portion of AIBN (1.0 g, 6.1 mmol) was added after cooling to about 40° C. and refluxed for 2 h. This procedure was repeated until the starting material disappeared. The solvent was evaporated and the residue was purified by flash chromatography on a silica gel column using 10:1 and 5:1 hexanes-EtOAc as eluent to give 1.74 g of 5′-O-(tert-butyldiphenylsilyl)-3′-deoxy-2′-O-(2-methoxyethyl)-3′-(2-phenylethenyl)5-methyluridine as a white foam.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:32])([CH3:34])[CH3:33])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)c(F)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccc(O)c(F)c1
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
To a solution of Boc-Tyr(3-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.19 g, 0.294 mmol) in methylene chloride (3 ml), TFA (1.5 ml) was added and stirred for 15 min. The reaction mixture was concentrated under reduced pressure, mixed with a saturated aqueous NaHCO3 solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The resultant was evaporated to remove the solvent under reduced pressure, giving the titled compound (136 mg, 85%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22].C(O)CCC>O>[F:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 20.1 %

Procedure:
A solution of 20.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine, 60 ml of hydrazine hydrate and 150 ml of n-butanol was refluxed for 48 hrs. The reaction was poured into 1 l of water, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. Recrystallization of the residue from isopropanol-water and then from isopropanol yielded 3.3 g (20.1%) of product, mp 214°-216° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([NH2:9])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[CH:1]1([N:4]2[C:8]([NH:9][C:18](=[O:20])[CH3:19])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: Nc1c(I)cnn1C1CC1
Reactant: CC(=O)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(=O)Nc1c(I)cnn1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A 100-mL round-bottom flask was charged with 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.250 g, 1.00 mmol), N,N-diisopropylamine (0.52 mL, 2.99 mmol) and dichloromethane (8 mL), and the solution was cooled to 0° C. A solution of acetyl chloride (0.085 mL, 1.19 mmol) in dichloromethane (2 mL) was added dropwise, and the resulting solution stirred for 1 h at 0° C. The reaction mixture was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (gradient elution with 0.5-50% ethyl acetate/petroleum ether) to afford N-(1-cyclopropyl-4-iodo-1H-pyrazol-5-yl)acetamide (0.300 g, 92%) as yellow oil. MS (ESI, pos. ion) m/z 292 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:3]=1.[CH3:20][O-:21].[Na+]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:4]1[N:3]=[C:2]([O:21][CH3:20])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: C[O-]
Reactant: Nc1cc(-c2c(Cl)cccc2Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2c(Cl)cccc2Cl)cc(N)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h

Procedure:
2-Chloro-6-(2,6-dichlorophenyl)-3-nitropyridin-4-ylamine (28.7 mg, 0.0901 mmol, prepared as described in the previous step) was placed in a 8 mL vial equipped with a stir bar and anhydrous MeOH (1 mL) was added via syringe. NaOMe (0.5 M in MeOH, (0.396 mL, 0.198 mmol) was added to the stirred mixture, which was then stirred at 65° C. for 4 h. The solvent was removed under reduced pressure and the residue was chromatographed on a 12-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/heptane to yield 6-(2,6-dichlorophenyl)-2-methoxy-3-nitropyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 7.37-7.41 (m, 2H), 7.25-7.30 (m, 1H), 6.35 (s, 1H), 6.15 (br. s., 2H), 4.01 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>C1COCC1.C1OCCOCCOCCOCCOC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:3][C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: CCOC(=O)C1(O)CC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Oc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
Sodium hydride (60%, 166 mg, 4.15 mmol) was added to a solution of ethyl 1-hydroxycyclopropanecarboxylate (0.41 mL, 3.59 mmol) in THF (10 mL) at room temperature. After 15 min, 3 drops of 15-crown-5 were added followed by 4-bromo-1-fluoro-2-nitrobenzene (0.42 mL, 3.41 mmol). Mixture was stirred at room temperature for 24 hours. After diluting with 50 mL of ethyl acetate, mixture was quenched by addition of brine (25 mL) and layers were separated. Aqueous phase was extracted with ethyl acetate and combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. Resulting residue was purified via silica gel column chromatography (0-30% ethyl acetate/hexanes) to yield ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropanecarboxylate 7.20 (750 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[C:14](=O)[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(C(=O)Cc1cccs1)[C@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(CCc1cccs1)[C@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A5-1 when using 340 mg (0.99 mmol) (S)-N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide ((S)-A4-1: R=OMe, Cy=2-thienyl). Flash chromatography was done using a mixture of hexane/ethyl acetate 40/1 in the presence of 0.5% (v/v) dimethylethylamine.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[N:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[CH:49]=[CH:48][CH:47]=1>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.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[N:51]=[C:50]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=5)[CH:49]=[CH:48][CH:47]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4cccc(-c5ccccn5)n4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
Under a stream of argon, 1.4 ml of a hexane solution containing 2.2 mmol of butyl lithium was slowly added to 40 ml of tetrahydrofuran cooled to −78° C. in which 1.00 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.61 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 20 ml portion of tetrahydrofuran prepared by dissolving 0.56 g of 6-bromo-2,2′-bipyridyl and 0.12 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 20 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (developing solvent hexane:chloroform=1:1 to 0:1) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 6-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,2′-bipyridyl (0.82 g, yield 71%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C)C=O>CCCCCC.C(OCC)(=O)C>[CH:24]1([CH2:30][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(CC3CCCCC3)c3ccccc3c2=O)cc1C
Yield: 58.2 %

Procedure:
The titled compound was prepared following the procedure described in Step 3 of Example 1. 63 mg (0.23 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one 3a, 12 mg (0.30 mmol) of 60% sodium hydride and 52 mg (0.30 mmol) of cyclohexylmethyl bromide and 0.9 mL N,N-dimethylformamide were combined at 90° C. for 5 h. Flash chromatography using 10-75% ethyl acetate in hexane yielded 50 mg of the product 4b as white solid: LC-MSD, m/z for C25H27NO2 [M+H]+=374.6; HPLC retention time: 2.8 min; 1H NMR (400 MHz, CDCl3): δ 1.0-1.3 (m, 6H), 1.7-1.85 (m, 4H), 1.9-2.0 (m, 1H), 2.3 (s, 3H), 2.35 (s, 3H), 4.0-4.05 (m, 2H), 7.15-7.2 (m, 1H), 7.4-7.5 (m, 2H), 7.5-7.6 (m, 1H), 7.6 (s, 1H), 7.65-7.75 (m, 1H), 8.05 (s, 1H), 8.45-8.5 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1C=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[C:20](=[O:23])([O-])[O-].[K+].[K+]>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:7]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:6]=2[CH:20]=[O:23])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(O)cc1
Agent: [K+]
Product: COc1ccc(Oc2ccc(F)cc2C=O)cc1

Procedure:
In a similar manner to the method described in Example 140a, 2,4-difluoro-benzaldehyde (Aldrich) was reacted with 4-methoxy-phenol and potassium carbonate to give a solid. MS (H+), 247.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12](F)=[CH:11][C:10]=2[F:19])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][OH:22].[H-].[Na+]>O1CCCC1>[N:1]1([C:6]([O:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])=[CH:11][C:10]=2[F:19])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CO
Reactant: O=C(Oc1cc([N+](=O)[O-])c(F)cc1F)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1cc(F)c(OC(=O)N2CCCC2)cc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
To a stirred, cold (-50° ) mixture of 7.00 g (0.0257 mole) of (2,4-difluoro-5-nitrophenyl) 1-pyrrolidinecarboxylate and 1.60 g (0.0283 mole) of methyl glycolate in 200 mL of tetrahydrofuran was added 1.02 g (0.0424 mole) of sodium hydride. The reaction mixture was stirred at -50° C. for approximately four hours. The mixture was allowed to gradually warm to room temperature. The reaction mixture was poured into ice-water, and the resultant mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield 4.5 g of (2-fluoro-4-methoxycarbonylmethoxy-5-nitrophenyl) 1-pyrrolidinecarboxylate. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([F:26])([F:25])[C:4]([F:24])([F:23])[C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7]([F:18])([F:17])[C:8]([F:16])([F:15])[C:9]([F:14])([F:13])[CH2:10][CH2:11]I.[P:29]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[O:30]CC>>[F:13][C:9]([F:14])([C:8]([F:15])([F:16])[C:7]([F:17])([F:18])[C:6]([F:19])([F:20])[C:5]([F:21])([F:22])[C:4]([F:23])([F:24])[C:3]([F:26])([F:25])[C:2]([F:28])([F:27])[F:1])[CH2:10][CH2:11][P:29](=[O:30])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Product: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 120 °C

Procedure:
1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-10-iododecane (1.02 g, 1.78 mmol) and P(OEt)3 (15 ml, excess) was added to 50 ml round bottom flask. The mixture was heated to 120° C. under nitrogen for 40 hours and then purified with FluoroFlash® SPE cartridge. The remaining light yellow oil was chromatographed with Ethyl Acetate/Hexane to give product. (0.96 g, 92%). 1H NMR (600 MHz, CDCl3): δ (ppm) 4.10-4.00(m, 4H, CH2CH3), 2.35-2.23 (m, 2H, CH2CF2), 1.92-1.86 (m, 2H, PCH2), 1.25 (t, J=7.2 Hz, 6H, CH2CH3). 13C NMR (150 MHz, CDCl3): δ (ppm) 121-106 (m, C—F coupling unsolved), 62.28 (d, 2Jcp=6 Hz, CH2CH3), 25.33 (t, 2JcF=23 Hz, CH2CF2), 17.24 (d, 2Jcp=148 Hz, PCH2), 16.38, 3Jcp=6 Hz, CH2CH3), HRMS calcd for C14H14F17O3P: [M+H]+, 585.0487; found: 585.0433
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.O>[C:25]([O:24][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[C:3]([OH:35])=[O:2])=[CH:7][CH:8]=2)=[CH:20][CH:19]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(CC(OCC(F)(F)F)C(=O)O)cc2)cc1
Yield: 87.5 %

Procedure:
3-[4-(2-{4-tert-Butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-tnifluoroethoxy)propanoic acid methyl ester (described in Example 60)(0.27 g; 0.52 mmole) was dissolved in tetrahydrofuran and water (2:1), lithium hydroxide (0.015 g; 0.62 mmole) was added and the reaction mixture was stirred over night. Water was added and tetrahydrofuran was evaporated. The remaining water residue was extracted once with diethyl ether, acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.22 g (85% yield) of 3-[4-(2-{4-tert-butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1(C)C=CC=CC=1>[CH:20]1([N:25]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NC1CCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1C1CCCC1
Reaction time: 10 h
Yield: 46 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 3.0 ml (0.0305 mol) of cyclopentylamine were added thereto and the mixture was boiled for 40 hours on a water separator. After concentration the residue was hydrogenated with 1.2 g of Raney-nickel in 500 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ether 1:1. There were obtained 2.0 g (46%) of rac-cis-3-cyclopentyl-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 84°-88°.