Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22]3([N:25]4[CH:29]=[N:28][C:27]([Cl:30])=[N:26]4)[CH2:24][CH2:23]3)[CH2:21][O:20]2)=[CH:15][CH:14]=1>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2([N:25]3[CH:29]=[N:28][C:27]([Cl:30])=[N:26]3)[CH2:24][CH2:23]2)([OH:20])[CH2:21][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Yield: 44.3 %

Procedure:
15.6 g (0.276 mol) of 1,2,4-triazole and 1.7 g (0.015 mol) of potassium tert. butoxide are initially introduced into 40 ml of abs. dimethylformamide and 21 g (0.071 mol) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane in 30 ml of absolute dimethylformamide are added dropwise at 80° C. The mixture is allowed to react at 100° C. for 6 hours and the solvent is then evaporated in vacuo. The residue is taken up in ethyl acetate/toluene, the solution is washed with water and dried over sodium sulphate, and the solvent is stripped off in vacuo. Chromatography on silica gel (eluent dichloromethane/ethanol =98/2) yields 11.5 g of the title compound of m.p. 156° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(F)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.O.O.Cl[Sn]Cl>Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1ccc2cc(N)ccc2n1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2-methyl-6-nitroquinoline (12 g, 63.84 mmol) in HCl (1N, 450 mL) was added a solution of SnCl2.2H2O (72 g, 0.32 mol) in HCl (1N, 150 mL) slowly. The reaction mixture was heated to reflux for 15 min, then cooled to room temperature. The precipitate was filtered. The filtrate was basified by aqueous KOH and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give 6.9 g of 2-methylquinolin-6-amine (68.3%). MS [M++1]=159, LC-MS: tR=0.255 min.
Reaction SMILES: [CH3:1][C:2]1[C@@H:3]([C:15]([OH:17])=O)[N:4]2[CH2:9][C@@H:7]([CH:8]=1)[N:6]([O:10][CH2:11][CH:12]=[CH2:13])[C:5]2=[O:14].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[C@@H:3]([C:15]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:17])[N:4]2[CH2:9][C@@H:7]([CH:8]=1)[N:6]([O:10][CH2:11][CH:12]=[CH2:13])[C:5]2=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (20 mL), crude of (2S,5R)-3-methyl-7-oxo-6-(prop-2-en-1-yloxy)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 150, 700 mg, 2.94 mmol, 1.00 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (1.17 g, 5.84 mmol, 1.99 equiv), HATU (1.67 g, 4.39 mmol, 1.49 equiv), DIEA (1.51 g, 11.68 mmol, 3.98 equiv) at 0° C. The resulting solution was stirred for 12 h at 25° C. The resulting solution was diluted with 150 mL of ethyl acetate and it was washed with 3×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:2). This resulted in 0.500 g (40%) of the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C-]#N.[Na+].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[CH2:14].C(O)(=O)C>CN(C)C=O.O>[O:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)OCCCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCOC(=O)CCC(=O)c1cccnc1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (26.8 g) in dimethyl formamide (DMF, 100 mL) was added over 10 min. to a stirred solution of sodium cyanide (7.0 g) in DMF (200 mL) at room temperature under dry nitrogen. The solution was stirred for 30 min. and n-butyl acrylate (32 g) in DMF (200 mL) was added dropwise over 60 min. The reaction mixture was stirred for 3 h. Acetic acid (20 mL) and water (80 mL) were added and stirring was continued for 10 minutes. The solution was concentrated under reduced pressure, dissolved in ethyl acetate (600 mL), washed with water (3×200 mL), brine (200 mL) and dried (Na2SO4). The solution was filtered, concentrated and distilled at 140° C. at 0.5 mm/Hg to give 18.2 g of the title compound as an oil; ESMS (M+1)+236.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[C:16]=1[CH3:36])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[C:16]=1[CH3:36])#[N:14]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1nc(-c2c(C)c(C#N)c3nc(C(=O)N(C)C)oc3c2F)cs1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C(=O)N(C)C)oc3c2N2CC[C@H](N(C)C)C2)cs1
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (442 μl, 3.48 mmol) was added at 140 to 150° C. to a dimethyl sulfoxide (56 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-2-carboxamide (I-129) (1.00 g, 2.90 mmol) and triethylamine (525 μl, 3.77 mmol), followed by stirring at the same temperature for 10 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diethyl ether to obtain the entitled compound (670 mg, 53%) as a yellow solid. The fraction containing impurities and the filtrate in suspension washing were recovered and purified in the same manner to obtain 145 mg of the entitled compound, 815 mg (64%) of the entitled compound was obtained in total.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:24]1[C:33]2[N:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:34]([C:27]3[C:28]4[N:29]=[CH:30][CH:31]=[N:32][C:33]=4[C:24]([C:18]4[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=4[CH3:16])=[CH:25][CH:26]=3)=[O:35])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(-c4c(C)cccc4C)c4nccnc34)cc2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carbox-ylic acid (Example 71). Title compound: ESI-MS: 466.2 [M+H]+; tR=3.67 min (System 3).
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[OH:13][C@@H:14]([C@H:16]1[C@@H:19]([C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[NH:18][C:17]1=[O:26])[CH3:15].C(N(CC)CC)C.Cl>O.C(O)C.C(OCC)(=O)C.ClCCl>[OH:13][C@@H:14]([C@@H:16]1[C@@H:19]([C:20]#[C:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[NH:18][C:17]1=[O:26])[CH3:15]
Reactant: C[C@@H](O)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
Trimethylsilyl trifluoromethanesulfonate (0.48 ml) was added to a mixture of (3R,4S)-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone (0.15 g), triethylamine (0.4 ml) and dichloromethane (7 ml) at 5° C. The mixture was stirred at ambient temperature for 3 hours and poured into a mixture of ethyl acetate (70 ml), ethanol (10 ml), 10% hydrochloric acid (10 ml) and water (50 ml). After stirring for 30 min. at ambient temp., the organic layer was separated, washed successively with brine, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitates were recrystallized from n-hexane to give 0.13 g of (3S,4S)-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[C@H:11]([F:27])[CH2:10]1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O.S(=O)(=O)(O)O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C@H:12]([OH:26])[C@H:11]([F:27])[CH2:10]1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1C[C@@H](F)C2=O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1C[C@@H](F)[C@H]2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
392 mg of 7α-(5-chloropentyl)-16α-fluoro-estra-1,3,5(10)-trien-3-ol-17-one, Example 15d), in 2 ml of anhydrous tetrahydrofuran is dissolved, and 1.1 ml of a 1-molar solution of lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran is added while being cooled in an ice bath. It is allowed to stir for 30 minutes at 0° C., then mixed with water and 8% sulfuric acid until a weakly acidic reaction is achieved, and it is extracted three times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness in a vacuum. The crude product is chromatographed on silica gel with hexane/ethyl acetate, whereby 118 mg of 7α-(5-chloropentyl)-16α-fluoro-estra-1,3,5(10)-triene-3,17β-diol and 138 mg of 7α-(5-chloropentyl)-16α-fluoro-estra-1,3,5(10)-triene-3,17α-diol is obtained, both as a solid foam.
Reaction SMILES: CN([CH:4]=[N:5][C:6]([C:8]1[N:9]=[C:10]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12][N:11]2[CH:25]=1)=O)C.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:6]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:25]=2)=[N:5][CH:4]=[N:35]1
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)-c1nc(C(=O)N=CN(C)C)cn1CCO2
Agent: Cl
Product: COC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2
Yield: 59 %

Procedure:
Following the procedure in Example 22, methyl 2-((dimethylamino)methylenecarbamoyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate was coupled with 2-chlorophenylhydrazine hydrochloride to give methyl 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield 59%. MS (ESI+): 422.1
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:31]4[C:27](=[O:37])[C:28]5[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:30]4=[O:32])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: OCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
In a 250 mL flask, 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-ol (3.00 g, 8.24 mmol), phthalimide (2.50 g, 17.3 mmol) and triphenylphosphine (5.20 g, 19.8 mmol) were diluted with tetrahydrofuran (30 mL). The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (4.00 g, 19.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and loaded onto silica gel. The resulting slurry was purified by flash column chromatography using 10% ethyl acetate/petroleum ether as eluent to afford the title compound as white solid (2.50 g, 75%); mp 114-118° C.; 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.07 (d, J=8.1 Hz, 2H), 7.86-7.76 (m, 4H), 7.72-7.66 (m, 2H), 7.37 (d, J=8.7 Hz, 2H), 7.31 (d, J=7.5 Hz, 2H), 3.77 (t, J=6.9 Hz, 2H), 2.75 (t, J=7.8 Hz, 2H), 2.08 (t, J=6.9 Hz, 2H); ES+API m/z 493 ([M+H]+).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2]2.C(O)(=O)C.[CH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH2:15]>CO>[N:19]1[CH:20]=[CH:21][C:16]([CH2:14][CH2:15][N:4]2[CH:3]=[CH:2][N:1]3[CH:9]=[CH:8][CH:7]=[C:6]3[CH2:5]2)=[CH:17][CH:18]=1
Reactant: C=Cc1ccncc1
Reactant: C1CC2CNCCN2C1
Solvent: CC(=O)O
Solvent: CO
Product: C1=Cn2cccc2CN1CCc1ccncc1

Procedure:
A solution of 12 g (0.095 mole) 1,4-diazabicyclo[4.3.0]-nonane, 10 ml of acetic acid and 12.5 ml of 4-vinylpyridine in 225 ml methanol was heated at reflux for 20 hours. The solvent was removed under vacuum and the residue distilled to yield 5.1 g of 2(4-pyridylethyl)pyrrolo[1,2-a]pyrazine; b.p. 126°-130/0.01 mm.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[N:35]([CH2:37][C:38]1[O:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=1)[C:34](=[O:47])[C:33]2(O)[C:48]1[C:56]([OH:57])=[CH:55][C:51]2[O:52][CH2:53][O:54][C:50]=2[CH:49]=1>>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[N:35]([CH2:37][C:38]1[O:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=1)[C:34](=[O:47])[CH:33]2[C:48]1[C:56]([OH:57])=[CH:55][C:51]2[O:52][CH2:53][O:54][C:50]=2[CH:49]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc2C1(O)c1cc2c(cc1O)OCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1C(c2cc3c(cc2O)OCO3)c2cccc(F)c2N1Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 7-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one, the title compound was obtained (65%): MS (ES+) m/z 436.4 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([OH:15])[CH:13]3[CH2:14][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>Cl>[CH2:16]([O:22][C:2]1[C:3]([C:8]2([OH:15])[CH:13]3[CH2:14][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OC1(c2nccnc2Cl)CN2CCC1C2
Reactant: CCCCCCO
Agent: Cl
Product: CCCCCCOc1nccnc1C1(O)CN2CCC1C2
Temperature: 80 °C

Procedure:
A mixture of 4.8 g of (26) (0.021 mol) and 125 ml of hexanol that had reacted with 1.5 g of Na (0.065 mol) was heated to 80° C. for 45 min. The reaction was cooled to ambient, 100 ml of 1N HCl was added, and the hexanol was azeotroped off with water. The residue was made basic with 1N NaOH and extracted 3× with 50 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a dark solid. Recrystallization of the solid from ether gave 3.83 g of 3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (26a) as a floculent yellow solid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.65 (7H, m), 1.85 (2H, m), 2.25-3.07 (6H, m), 3.1 (1H, d), 3.75 (2H, d), 4.45 (2H, t), 8.01 (1H, d), 8.07 (1H, d). A solution of 1.5 g of (26a) (0.0052 mol) in 75 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1.5 h the reaction was heated to reflux for 45 min. The reaction was cooled to ambient, water was added, and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2 the washed with brine, dried, and the solvent evaporated to give a yellow oil. Radial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3 gave 1.2 g 3-chloro-3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptane (26b) as a pinkish liquid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.95 (10H, m), 2.25-3.9 (7H, m), 4.4 (2H, t), 8.0-8.1 (2H, m). A mixture of 1.2 g of (26b) (0.0039 mol) and 0.5 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi H2. The catalyst was removed, the solvent evaporated, the residue suspended in water, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. Tlc shows two major spots, 10% ethanol-1% NH4OH-CHCl3. The less polar of the two component was not well separated. The more polar component was treated with HCl in isopropanol and thoroughly evaporated. The residue was recrystallized from ether to give 0.15 g of (27) as slightly hygroscopic colorless crystals, mp 117°-118° C. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.55 (8H, m), 1.85 (3H, m), 3.2-3.75 (6H, m), 4.05 (2H, m), 4.38 (2H, m), 8.05 (1H, d), 8.08 (1H, d). Anal. C16H25N3O-HCl-0.5H2O requires C: 59.89; H: 8.48; N: 13.10%. Found C: 59.83; H: 8.31; N: 12.95%.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[O:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].Cl.C(#N)C.O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[O:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(C(=O)O)o1
Temperature: 60 °C

Procedure:
To a room temperature solution of methyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furoate (Example 660) (608 g, 1.30 mmol) in THF (8.0 mL) was added dropwise an aqueous solution of sodium hydroxide (3.0 M, 0.50 mL, 1.50 mmol). The reaction was then heated to 60° C. for 12.0 hours. The resulting suspension was then diluted with 500 mL of ethyl acetate and neutralized with an aqueous solution of hydrochloric acid (1.0 N, 1.5 mL, 10 mmol). The resulting biphasic solution was then concentrated in vacuo to a volume of 50 mL. At this time a white solid began to form and the resulting solid suspension was allowed to sit until precipitation appeared to stop (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to furnish the solid acid as an intermediate (500 mg, 85%). 1H NMR (300 MHz, d4-MeOH) δ 7.64 (app q, J=8.3 Hz, 1H), 7.18 (d, J=3.4 Hz, 1H), 7.10-7.02 (m, 2H), 6.54 (s, 1H), 6.50 (d, J=3.5 Hz, 1H), 5.42 (s, 2H), 5.37 (s, 2H), 2.64 (s, 3H); LC/MS C-18 column, tr=2.38 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0070 (M+H calcd for C19H15BrF2NO5 requires 454.0096).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+].O>O1CCCC1>[CH:1]1([CH2:7][C:8]([CH3:19])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(CC1CCCCC1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC1CCCCC1)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of Example 41A (4.02 g, 15.4 mmol) and potassium trimethyl silanolate (11.0 g, 77.2 mmol) in tetrahydrofuran (80 mL) was heated to reflux for 18 hours. The mixture was cooled to 25° C., treated with water (10 mL), and concentrated in vacuo to remove the tetrahydrofuran. The residue was dissolved in water and washed with hexane. The aqueous layer was acidified to pH 1 with 1N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound (3.80 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 1.10 (m, 6H) 1.57 (m, 8H) 1.82 (m, 1H) 2.04 (m, 1H) 7.32 (m, 5H).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH3:18].N#N.O=O>CC#N.Cl>[CH2:14]([C:15]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:17]([CH3:18])[CH:16]=1)[CH3:13]
Reactant: CC/C=C/C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: N#N
Solvent: CC#N
Product: CCc1cc(C)c(C#N)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
To a solution of t-BuOK (17.2 g, 153 mmol) and cyanoacetamide (13 g, 153 mmol) in CH3CN (225 mL) was added (3E)-3-hexen-2-one (15 g, 153 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred for 30 min. To the reaction mixture was added additional t-BuOK (51.4 g), and the N2 was displaced by oxygen. After stirring for 1 h without external cooling, the mixture was diluted with 4 N HCl, which was added slowly and with good stirring. The mixture was filtered, washed with EtOH, dried to give 6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (5 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 12.33 (br. s., 1H), 6.18 (s, 1H), 2.45 (q, 2H), 2.30 (s, 3H), 1.11 (t, 3H).