Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].C([O-])([O-])=[O:27].[K+].[K+].[F:32][C:33]1([F:43])[CH2:38][CH2:37][N:36]([CH2:39][C:40](Cl)=O)[CH2:35][CH2:34]1>CC#N>[F:32][C:33]1([F:43])[CH2:38][CH2:37][N:36]([C:39](=[O:27])[CH2:40][N:8]2[C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[C:3]([C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:16][CH2:15]4)=[O:13])[S:4][C:5]=3[N:6]=[CH:7]2)[CH2:35][CH2:34]1
Reactant: O=C(Cl)CN1CCC(F)(F)CC1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)N2CCN(c3ccccc3)CC2)sc2nc[nH]c(=O)c12
Agent: [K+]
Solvent: CC#N
Product: Cc1c(C(=O)N2CCN(c3ccccc3)CC2)sc2ncn(CC(=O)N3CCC(F)(F)CC3)c(=O)c12
Yield: 49.8 %

Procedure:
To a suspension of 5-methyl-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (0.4 g, 1.13 mmol) in CH3CN (5 mL) was added K2CO3 (0.156 g, mmol), KI (0.182 g, 1.13 mmol), and 2-(4,4-difluoropiperidin-1-yl)acetyl chloride (0.223 g, 1.13 mmol). The reaction mixture was refluxed overnight and then quenched with H2O (20 mL). The resultant precipitate was filtered and dried to provide a crude solid which was purified by flash chromatography (Et2O:DCM, 1:1) providing 0.29 g of pure 3-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5-methyl-6-(4-phenyl piperazine-1 carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (yield: 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[C:6]([CH3:20])=[CH:5]2.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[OH:25][CH:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:19]=[CH:18][C:14]([C:15](=[O:17])[NH:24][CH:21]5[CH2:23][CH2:22]5)=[CH:13][CH:12]=3)[C:6]([CH3:20])=[CH:5]4)=[O:37])=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Cc1cc2cc(N)ccc2n1-c1ccc(C(=O)O)cc1
Reactant: NC1CC1
Product: Cc1cc2cc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)ccc2n1-c1ccc(C(=O)NC2CC2)cc1

Procedure:
Compound 959 was prepared according to the procedure described in Scheme IV from 4-(5-amino-2-methyl-1H-indol-1-yl)benzoic acid, cyclopropaneamine, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C31H32N4O3: 509.25; found: 509.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:21](OC(=O)C)(=[O:23])[CH3:22].CO>N1C=CC=CC=1>[C:21]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:20])[C:17]([CH3:19])=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 49 was suspended in pyridine (6 ml), and acetic anhydride (0.18 ml) was added to the suspension. The mixture was stirred at room temperature for 40 minutes and a small amount of methanol was added dropwise to the reaction mixture. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol and ether in succession to obtain the title compound (160 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCN(C(C)C)C(C)C.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CN([CH:45]=[O:46])C>C(Cl)Cl>[F:9][C:8]([F:11])([F:10])[C:45]([OH:46])=[O:36].[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:17]=[CH:16][N:15]=2)[NH:13][C:39]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:40])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: CN(C)C=O
Reactant: O=C(Cl)N1CCOCC1
Reactant: N[C@@H](c1ccc(C(F)(F)F)c(F)c1)c1ncccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)c(F)c1)c1ncccc1C(F)(F)F)N1CCOCC1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methanamine (Intermediate 7) (100 mg, 0.296 mmol) and DIPEA (0.101 mL, 0.591 mmol) in DCM (1.0 mL) was added morpholine-4-carbonyl chloride (66.3 mg, 0.443 mmol). The resulting reaction mixture was stirred at rt for 19 h. The reaction was then diluted with DMF (2 mL), filtered through a syringe filter, and purified by reverse phase HPLC (Phenomenx Gemini Axia™-5μ C-18 column (150×30 mm) 10-100% MeCN/0.1% TFA in H2O ). The product-containing fractions were combined, and the solvent was removed by lyophilization to give the title compound as a white solid. 1H NMR (300 MHz, d4-MeOH) δ ppm 8.66-8.43 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.38-7.12 (m, 2H), 7.07-6.83 (m, 2H), 6.26 (s, 1H), 3.35 (peak obscured by solvent), 3.08 (br. s., 4H), 2.98 (br. s., 2H). MS (ESI pos. ion) m/z: 452.0 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOC(CCl)C1)C1C=CC=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@:33]2([C:51]3[C:42](=[CH:43][C:44]4[O:49][CH2:48][CH2:47][O:46][C:45]=4[CH:50]=3)[O:41][CH2:40]2)[C:32]1=[O:52].N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)OC2)C1=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@@:33]3([C:51]4[C:42](=[CH:43][C:44]5[O:49][CH2:48][CH2:47][O:46][C:45]=5[CH:50]=4)[O:41][CH2:40]3)[C:32]2=[O:52])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: ClCC1CN(Cc2ccccc2)CCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: O=C1N(C[C@@H]2CN(Cc3ccccc3)CCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.60 and making non-critical variations using (S)-4-benzyl-2-(chloromethyl)morpholine (Toshiya, M. et al., Heterocycles (1994), 38(5):1033-1040) to replace 4-benzyl-2-(chloromethyl)morpholine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (99%): MS (ES+) m/z 485.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(N)c1Cl
Yield: 103.5 %

Procedure:
2-Chloro-3-nitroanisole C3 (1.38 g; 7.36 mmol) was dissolved in a mixture of glacial acetic acid (19 mL)/ethanol (19 mL). To this solution was added iron powder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 mL), neutralized with solid Na2CO3 and the product extracted with CH2Cl2(3×150 mL). The extracts were combined and washed with saturated brine and then dried over (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-chloro-3-methoxyaniline C4 (100%; 1.2 g) as a yellow oil. This material was used as such in the following steps. MS 157.9 (MH)+; Homogeneity by HPLC (TFA) @ 220 nm: 86%.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([OH:13])=[O:12])[N:6]=[CH:5][C:4]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24].[CH2:25](O)[CH3:26].C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2][C:3]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH2:25][CH3:26])=[O:12])[N:6]=[CH:5][C:4]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24]
Reactant: CCO
Reactant: CSc1c(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)cnn(CC(=O)O)c1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(SC)c1=O
Yield: 82 %

Procedure:
2-{5-Methylthio-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (105 mg, 0.299 mmol) in tetrahydrofuran (1 mL) was stirred with 1,1-carbonyldiimidazole (145 mg, 0.897 mmol) at room temperature for 1 hour and then with ethanol (0.2 mL) at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the resulting organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to give the desired product (93 mg, 82% yield).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH:15]([NH:16][CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.CC1C=CC(S(O[CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:13]12[CH:15]([N:16]([CH3:17])[CH2:29][CH2:30][CH2:31][NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=3)[CH:10]([CH2:11][CH2:12]1)[CH2:9][NH:8][CH2:14]2
Reactant: CNC1C2CCC1CN(Cc1ccccc1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCNc1ccc(C#N)cc1)C1C2CCC1CNC2
Temperature: 90 °C
Yield: 65.5 %

Procedure:
A mixture of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine (Preparation B; 4.0 g, 17.4 mmol), 3-(4-cyanoanilino)propyl 4-methyl-benzenesulfonate (Preparation G(ii); 5.74 g, 17.4 mmol), and potassium carbonate (2.40 g, 17.4 mmol) in DMF (85 mL) was heated at 90° C. under nitrogen overnight. The mixture was partitioned with water (200 mL) and diethyl ether (150 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered and then concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 3.40 g (50%) of the sub-title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1cc(C(=O)OC)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OC)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A solution of methyl 4-hydroxy-3-propylbenzoate (7.00 g, 36.0 mmol), benzyl bromide (11.48 g, 0.15 mol), and potassium carbonate (20.73 g, 0.15 mol) in N,N-dimethylformamide (20 mL) was heated and stirred at 80° C. for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (10.25 g, yield 100%) was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].[CH2:8]1[CH:12]2[CH:13]3C=CC([CH:11]2C=[CH:9]1)C3>>[OH:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]1[CH2:11][CH:12]2[CH2:13][CH:3]1[CH:9]=[CH:8]2
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CCOCCO
Product: OCCOCC1CC2C=CC1C2
Temperature: 190 °C

Procedure:
In a 300 mL autoclave equipped with a thermal couple and a mechanical stirrer, a mixture of 2-allyloxyethanol (109.5 g, 1.07 mol) and dicyclopentadiene (35.4 g, 0.27 mol) was stirred and heated to 190° C. The reaction was cooled after 3 h. Three such reactions were run and the reaction mixtures were combined. The mixture was distilled using a short-path distillation column under vacuum at 70° C. at 500 mTorr. The distillate (170 g) was dissolved in a mixture of 250 mL of CH3OH and 150 mL of H2O. Hexane (3×125 mL) was added to the mixture in order to extract out cyclopentadiene impurities. To the remaining methanol/water solution NaCl was added to force the product to oil out from solution. Ethyl acetate (200 mL) was added to extract the oil from water. After the solvents were removed by rotovaporation the product was dried under vacuum. Yield 157 g (58%). 1H NMR (500 MHz, CDCl3): Endo isomer: 6.13 (m, 1H); 5.93 (m, 1H); 3.72 (t, 2H); 3.52 (m, 2H); 3.22 (t, 1H); 3.10 (t, 1H); 2.90 (s, 1H); 2.80 (s, 1H); 2.37 (m, 1H); 2.09 (br s, 1H); 1.82 (m, 1H); 1.43 (d, 1H), 1.26 (d, 1H), 0.50 (d of t, 1H). Exo isomer: 6.10 (m, 1H); 6.07 (m, 1H); 3.75 (t, 2H); 3.36 (m, 2H); 3.50 (t, 1H); 3.40 (t, 1H); 2.80 (s, 1H); 2.74 (s, 1H); 2.09 (br s, 1H); 1.71 (m, 1H); 1.33 (d, 1H), 1.30 (d, 1H); 1.24 (m, partially obscured by endo isomer, 1H); 1.11 (d of t, 1H). Endo/exo ratio by 1H NMR was determined to be 82/18.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](N)=[O:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.Cl.[O:29]1CCOCC1>[OH-].[Na+]>[NH2:1][C:2]1[C:3]([C:25]([OH:29])=[O:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:23])[CH3:24])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: C1COCCO1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2-c2ccc(F)cc2)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccc(F)cc2)ccc1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3-Amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (30 g) was suspended in dioxane (60 ml) and 2N aq. NaOH (600 ml). The mixture was heated at 90° C. with stirring for 4 hours. The above reaction mixture was cooled to 25-30° C. The pH of the suspension was adjusted to 2.5 with 35% HCl (105 ml). The precipitate was collected by filtration and washed with water and dried in vacuo at 50° C. for 15 hours to give 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid as yellow powder. (29.6 g)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C)C=O.CC(OC)(C)C>[CH2:14]([N:9]1[CH:10]=[CH:11][C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[N:8]1)[CH3:15].[CH2:14]([N:8]1[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[CH:11][CH:10]=[N:9]1)[CH3:15]
Reactant: CCI
Reactant: Cc1csc(-c2cc[nH]n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCn1ccc(-c2cc(C)cs2)n1
Product: CCn1nccc1-c1cc(C)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68 %
Yield: 23 %

Procedure:
3-(4-methyl-2-thienyl)-1H-pyrazole (9.3 mmol) was dissolved in 20 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (14.0 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, ethyl iodide (18.6 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:MTBE 100:0 to 90:10) to afford 1.21 g 1-ethyl-3-(4-methyl-2-thienyl)-1H-pyrazole (68% yield) and 406 mg of 1-ethyl-5-(4-methyl-2-thienyl)-1H-pyrazole (23% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC1C(O)=C(F)C(F)=C(F)C=1F.[CH3:34][N:35]1CCOCC1.CN.C(O)C>C(Cl)Cl>[CH3:34][NH:35][C:19](=[O:21])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: CN
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of N-Boc-4-cyanophenylalanine (1.92 g, 6.6 mmol) and pentafluorophenol (2.43 g, 13.2 mmol) in CH2Cl2 (30 ml) at 0° C. was treated with 4-methylmorpholine (0.74 g, 7.3 mmol). After stirring the reaction mixture for 3 hours, 8M methylamine in ethanol (15 ml, 19.8 mmol) was added and the reaction mixture left to stir at room temperature for 16 hours. The solvent was removed under pressure, the residue dissolved in CH2Cl2 (50 ml) and washed with saturated sodium bicarbonate (2×50 ml), 1M citric acid (2×50 ml) and brine (50 ml). The CH2Cl2 layer was dried over MgSO4 and the solvent removed under pressure to yield the title compound as a white solid (1.84 g, 92%).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[CH3:7]O.[C:9](OC)(OC)([O:11]C)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+].CO>[CH3:7][O:6][C:3]([O:11][CH3:9])([CH2:4][CH3:5])[CH2:2][CH3:1]
Reactant: CCC(=O)CC
Reactant: COC(C)(OC)OC
Reactant: CO
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: CCC(CC)(OC)OC
Temperature: 5 °C
Reaction time: 2 h
Yield: 895.9 %

Procedure:
First, 43.11 g (50.1 mmol) of 3-pentanone, 43.11 g (1.35 mol) of methanol, and 0.43 g (2.26 mmol) of p-toluenesulfonic acid monohydrate were added to a 3-necked flask (300 ml volume) equipped with a thermometer, a mechanical stirrer and a dropping funnel, and cooled to 5° C. Next, 63.03 g (525 mmol) of trimethyl orthoacetate was added dropwise to this solution over a period of 90 minutes while keeping internal temperature at 10° C. or lower. Then the temperature of the reaction mixture was raised to room temperature and the reaction mixture was agitated for 2 hours. The reaction solution was neutralized with 1.0 g (4.63 mmol) of 25% sodium methoxide/methanol solution, and then distilled under reduced pressure to give 59.34 g of 3,3-dimethoxypentane (boiling point: 55-57° C./50 torr, yield of approximately 100%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[S:6](=[O:13])(=[O:12])[N:5]([CH3:14])[CH2:4]1.C([Li])CCC.CCCCCC.[S:26](=[O:28])=[O:27].O.O.O.C([O-])(=O)C.[Na+].[NH2:37]OS(O)(=O)=O>C1COCC1.O>[CH3:1][O:2][CH:3]1[C:8]2[CH:9]=[C:10]([S:26]([NH2:37])(=[O:28])=[O:27])[S:11][C:7]=2[S:6](=[O:13])(=[O:12])[N:5]([CH3:14])[CH2:4]1
Reactant: O=S=O
Reactant: COC1CN(C)S(=O)(=O)c2sccc21
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1CN(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step D (1.73 g, 7.42 mmol) in THF (15 mL) cooled to -60° C. was added via syringe n-butyllithium in hexane (2.5 M, 3.56 mL, 8.91 mmol) over 5 min. After the addition was completed, the mixture was warmed to 0° C. and stirred for 20 min. The mixture was re-cooled to -60° C. and a stream of sulfur dioxide was passed through the surface of the mixture for 20 min. The mixture was warmed to ambient temperature and the volatiles were evaporated. To the residue was added sodium acetate trihydrate (3.03 g, 22.3 mmol) and water (50 mL) and the mixture was cooled to 0° C. Hydroxylamine-O-sulfonic acid (1.51 g, 13.4 mmol) was added and the mixture was allowed to stir for 30 min. The reaction mixture was extracted with ethyl acetate (3×100 mL), dried over molecular sieves and concentrated to give an orange oil (2.25 g) which solidified on standing. The solid was crystallized from methanol-methylene chloride to give a colorless solid (1.21 g, 52%, first crop): mp 161°-162° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1.C(OCC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccc(Oc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A 0.5 M solution of 4-phenoxy-phenylmagnesium bromide in tetrahydrofuran (30 mL, 15 mmol) was introduced into a flame-dried flask placed under an argon atmosphere. A solution of 1-benzyl-4-piperidone (2.84 g, 15 mmol) in dry tetrahydrofuran (12 mL) was then added dropwise, while the temperature was maintained at less than 20° C. with an ice bath. After completion of the addition, the mixture was allowed to reach room temperature and further stirred for 2 hr. Ice was then added to the mixture, and 1 N HCl was added until the resulting precipitate was completely dissolved. The reaction was then diluted with diethyl ether (100 mL) and washed with water (50 mL). The aqueous layer was extracted with diethyl ether (2×50 mL), and the combined organic layers were sequentially washed with saturated aqueous sodium hydrogencarbonate (2×50 mL) and water (50 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (dichloromethane and then diethyl ether). The desired product was then isolated as a colorless solid (1.74 g, 33% yield).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:22](=[O:63])[CH2:23][CH2:24][C:25](=[O:62])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:33](=[O:53])[CH2:34][CH2:35][C:36](=[O:52])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:72](Cl)(=[O:74])[CH3:73]>C(Cl)Cl>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:22](=[O:63])[CH2:23][CH2:24][C:25](=[O:62])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:33](=[O:53])[CH2:34][CH2:35][C:36](=[O:52])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:72](=[O:74])[CH3:73])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)OC(C)(C)C)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
NEt3 (0.16 mL, 1.15 mmol) was added to (11) (0.87 g, 0.98 mmol) in CH2Cl2 (40 mL) and the solution was cooled to 0° C. Acetyl chloride (0.074M in CH2Cl2, 14 mL, 1.04 mmol) was added by syringe over 4 minutes and stirring was continued (0° C. to room temperature) for 24 hours. The aqueous phase was extracted with CH2Cl2 (4×50 mL) and the organic phase was washed with 40 mL portions of cold 0.25M citric acid, 5% NaHCO3 and H2O. Solvent removal and flash column chromatography with 60% acetone/hexane gave 0.79 g (87%) of (12) as an oil: 300 MHz NMR δ 1.23-1.69 (m+s, 27 H), 2.09 (s, 3 H), 2.44-2.53 (m, 4 H), 2.76-2.84 (m, 6 H), 3.03-3.24 (m, 6 H), 3.57-3.68 (m, 6 H), 4.7 (br s, 1 H), 4.81 (s, 2 H), 4.85 and 4.86 (2 s, 4 H), 6.35 (br s, 1 H), 7.38 (s, 15 H). Anal. calcd. for C51H74N6O10 : C, 65.78; H, 8.01; N, 9.03. Found: C, 65.89; H, 8.04; N, 8.95.