Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:37](OC(N1C(C(O)=O)C2CC1CC2)=O)(C)(C)[CH3:38]>>[CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH:12]([C:16]2[NH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([B:27]4[O:28][C:29]([CH3:34])([CH3:35])[C:30]([CH3:33])([CH3:32])[O:31]4)=[CH:25][CH:26]=3)=[CH:19][N:20]=2)[CH:13]2[CH2:14][CH:15]1[CH2:37][CH2:38]2)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C

Procedure:
This compound was synthesized using the procedure used to make [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester using 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester. LCMS-ESI+: calc'd for C28H39BN4O5: 522.30 (M+); Found: 523.31 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Product: CCCOc1ccc(CN2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1

Procedure:
The title compound was prepared form 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one and 1-methylpiperazine, following the procedure of Example 34, and was obtained as a colourless solid (36%), m.p. 149°-150° C. Found C,65.68; H,7.83; N,19.10. C24H34N6O2 requires C,65.73; H,7.81; N,19.16%
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:25]([O:27][CH3:28])=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:46](N)[CH2:47]N(CCN)CCN>C(OCC)(=O)C>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:25]([O:27][CH2:28][CH:46]=[CH2:47])=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:15]=1)=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCCN(CCN)CCN
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)COC(C)(C)C
Yield: 88 %

Procedure:
According to the general procedure for Fmoc-cleavage, 9 g Fmoc-Ser(tBu)-Tyr(tBu)-OMe, 22 ml TAEA in ethyl acetate yielded 4.7 g of crude product (yield based on HPLC: 88%).
Reaction SMILES: [OH:1]O.[CH:3]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH2:5][CH:4]=1>>[O:1]1[CH:4]2[CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH:3]12
Reactant: OO
Reactant: C1=CCCC=CCCC=CCC1
Product: C1=CCCC2OC2CCC=CCC1

Procedure:
Also, in the process of the present invention, the total molar amount of hydrogen peroxide fed during the entire monooxidation procedure in the oxidation apparatus is preferably controlled to 0.04 to 0.55 times, more preferably 0.10 to 0.55 times, still more preferably 0.10 to 0.30 times the molar amount of 1,5,9-cyclododecatriene fed into the first reactor, to produce the target 1,2-epoxy-5,9-cyclododecadiene at a high selectivity thereto.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[C:13]1([C:19]2[C:23]([CH:24]=O)=[C:22]([CH3:26])[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[CH:24][C:23]1[C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:20][O:21][C:22]=1[CH3:26])[CH2:6]2
Reactant: Cc1onc(-c2ccccc2)c1C=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC(=Cc1c(-c3ccccc3)noc1C)C2=O
Yield: 48.7 %

Procedure:
5-Methoxy-1-indanone (1 g, 6.2 mmol) and 3-phenyl-5-methyl-4-isoxazolecarbaldehyde (1.14 g, 6.2 mmol) were dissolved in EtOH (30 ml) and NaOH(4 drops of a 4M solution in water) was added. The reaction mixture was heated to reflux for 17 h. The reaction mixture was cooled and filtered to obtain the title compound as a yellow solid (1.0 g, 49%).
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1([CH2:17][CH:18]([OH:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1.C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[N:8]1([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ncc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ncc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.07 g (10.5 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.100 g (0.263 mmol) 1-(indazol-1-yl)-3-(4-octylphenoxy)propan-2-ol in 10 ml absolute DMSO. Having stirred for 20 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.18 g, 6 mmol) and 5% palladium carbon (1.0 g) in tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred, under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give tert-butyl[4-(3-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.54 g, 96.2%) as crystals.
Reaction SMILES: O.S(=O)(=O)(O)O.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH2:12][CH2:13][CH2:14][OH:15].CC([OH:22])C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH2:12][CH2:13][C:14]([OH:22])=[O:15]
Reactant: OCCCOc1cccc(F)c1
Reactant: CC(C)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCOc1cccc(F)c1
Yield: 90 %

Procedure:
Acetone (600 mL) is chilled using an ice/salt water bath, then chromium trioxide (14.45 g, 145 mmol) is added, followed by water (32 mL) and concentrated sulfuric acid (16 mL). The mixture is allowed to stir several minutes, then a solution of 3-(3-fluorophenoxy)-propan-1-ol (6.15 g, 36.1 mmol) in acetone (300 mL) is slowly added via an addition funnel over ˜1 h. The reaction is stirred at 0° C. for 5 h, and then 2-propanol (70 mL) is added. The reaction is filtered over diatomaceous earth, rinsed with acetone (˜100 mL), and the filtrate evaporated under reduced pressure, reconstituted in diethyl ether (500 mL), and washed with brine (2×500 mL). The organic layer is then dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford the sub-title compound (6.00 g, 90%) as an off-white solid which is used without further purification: Rf 0.34 (95:5:0.5 dichloromethane/methanol/ammonium hydroxide); 1H NMR (300 MHz, CDCl3), δ2.85 (t, J=6.2 Hz, 2H), 4.23 (t, J=6.2 Hz, 2H), 6.59-6.70 (m, 3H), 7.18-7.24 (m, 1H), 7.30-9.60 (br s, 1H); 19F NMR (282 MHz, CDCl3), δ-112.01; APCI MS (negative mode) m/z 183 [C9H9FO3—H]−.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[NH:5]([C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[CH:8][CH:7]=1)[C:1]([CH3:2])=[O:3]
Reactant: CC(=O)Cl
Reactant: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(OC2(c3ccccc3)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 0.85 g of acetyl chloride in 5 ml of benzene is added dropwise to a solution of 2.8 g of 4-(4-aminophenoxy)-1-methyl-4-phenylpiperidine and 1.1 g of triethylamine in 10 ml of benzene. After stirring the mixture at room temperature for 6 hours, it is concentrated; the resulting residue is taken up with 30 ml each of water and diethyl ether; the obtained mixture is shaken thoroughly, and the organic phase is separated off, dried over sodium sulfate and concentrated. 2.8 g of the title compound remain as a viscous yellow oil which crystallizes (m.p. 143° to 144° C.) from diethylether after standing for several days.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1>C1COCC1.C(O)C>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[CH3:3])[CH:15]=1
Reactant: ClCc1cncc(Br)c1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nccn1Cc1cncc(Br)c1
Yield: 53 %

Procedure:
To a stirred suspension of sodium hydride (0.54 g, 12.3 mmol) in THF (40 ml) at 20° C. was added 2-methylimidazole in portions over 45 min. 3-Bromo-5-(chloromethyl)-pyridine (1 g, 4.1 mmol) in ethanol (8 ml) was then added and this mixture was heated under reflux for 1 h under an argon atmosphere. After cooling and evaporation of solvents the residue was suspended in MeOH, filtered and adsorbed onto silica gel. Chromatographic elution with CH2Cl2/(2M NH3 MeOH)=98:2 afforded the title compound (0.56 g, 53%) as a yellow oil. MS: m/e=251.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:3]=1[C:4]#[N:5].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20]>>[S:19]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:3]=1[C:4]#[N:5])(=[O:22])(=[O:21])[NH2:20]
Reactant: NS(=O)(=O)Cl
Reactant: CCOCCOCCOc1cccc(N)c1C#N
Product: CCOCCOCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 69 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(2-(2-ethoxyethoxy)ethoxy)benzonitrile (Example 250b) and sulfamoyl chloride in 69% yield. MS 330 (MH+).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[N+]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=1)([O-])=O.C(O)(=O)C>CN(C=O)C>[CH2:1]([S:3][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1)[CH3:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
Sodium ethanethiolate (1.6 g, 17.2 mmol) was added to a solution of methyl 5-nitropicolinate (2.8 g, 16 mmol) in DMF (30 mL), and the resulting mixture was stirred a room temperature. After 3 hours, acetic acid (1 mL) was added, and the mixture was evaporated to dryness. The residue was suspended in methanol (50 mL) and treated with 3N NaOH. The resulting mixture was stirred at room temperature for 16 hours and then evaporated. The residue was dissolved in water (100 mL), washed with ethyl acetate (2×100 mL), and acidified to pH 3-4 (conc. HCl), resulting in precipitation of the product. The precipitate was filtered, rinsed with water (100 mL) and dried under vacuum, providing 2.3 g of 5-(ethylthio)picolinic acid, in 79% yield; 1H NMR (DMSO-d6) δ 1.23 (t, 3H, J=7.3 Hz), 3.14 (q, 2H, J=7.3 Hz), 7.86 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.95 (dd, 1H, J=8.4 Hz, J=0.9 Hz), 8.57 (dd, 1H, J=2.4 Hz, J=0.9 Hz), 13.09 (br, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=3)[C:3]=12.CC(O)=O>Br.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: COc1ccc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccccc3)c3ncnc(N)c23)cn1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2ccc(O)nc2)c2c(N)ncnc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
3-(1-(4-amino-3-(6-methoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Example 60, 28 mg, 0.057 mmol) was dissolved in HBr 33% in CH3COOH (2 ml, 36.8 mmol) and stirred at 60° C. for 4 hr. The reaction was then diluted with 3 ml of water and the resulting mixture purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (6.9 mg, 25.4%) as yellowish solid.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[CH:19]([C:21]([CH3:23])=[O:22])=[CH2:20].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:19][C:21](=[O:22])[CH3:23])([C:7]#[N:8])[C:5]#[N:6]
Reactant: C=CC(C)=O
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.6 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 0.70 g of methyl vinyl ketone were dissolved in 15 ml of acetone, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.5 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3-oxobutyl)malononitrile.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Br:12])=[C:10]2[C:5]([CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]2=[O:13])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1>ClCCl>[Br:12][C:11]1[C:10]2[C:9](=[O:13])[C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:1][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CCc2ccc(N)c(Br)c2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CCc2ccc(NS(=O)(=O)c3ccccc3F)c(Br)c2C1=O
Yield: 84.5 %

Procedure:
A mixture of Example 362B (730 mg, 2.72 mmol) and 2-fluorobenzenesulfonyl chloride (0.396 mL, 2.99 mmol) in pyridine (2.20 mL, 27.2 mmol) and dichloromethane (10 mL) was reacted as described in Example 275C to yield 0.98 g of the desired compound. MS (ESI(−)) m/e 425 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.63-7.72 (m, 2H), 7.41 (t, 1H), 7.26-7.35 (m, 3H), 2.93 (t, 2H), 1.86 (t, 2H), 1.08 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH3:13])[C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH3:13])[C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([NH2:29])=[O:28])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccc(F)cc2)c1-c1ccnc(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(F)cc2)c1-c1ccnc(NC(N)=O)c1
Temperature: 50 °C
Yield: 100.4 %

Procedure:
4-[5-(4-Fluoro-phenyl)-3-methyl-3H-imidazol-4-yl]-pyridin-2-ylamine (13 mg, 0.048 mmol) and benzoyl isocynate (8.6 mg, 0.058 mmol) are mixed in DCM (0.5 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (0.5 mL) and potassium carbonate (10 mg, 0.073 mmol). The mixture is then heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is recrystallized in DCM to give 15 mg of the titled product.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([CH2:21][CH3:22])=[N:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:33]>CO>[ClH:33].[ClH:33].[NH2:7][C@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([CH2:21][CH3:22])=[N:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CCc1nnc2n1CCN(C(=O)C[C@@H](Cc1ccc(F)c(F)c1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: CCc1nnc2n1CCN(C(=O)C[C@H](N)Cc1ccc(F)c(F)c1)C2

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl]-3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine (30 mg, 0.067 mmol from Step C), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent afforded 28 mg of the title compound as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 1.45 (t, 3H), 2.93–3.07 (m, 6H), 3.90–4.31 (m, 5H), 5.08 (m, 2H), 7.16 (s, 1H), 7.31 (m, 2H). ESI-MS 350 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[CH3:12][C:13]1[C:14]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[C:10]([CH3:11])[CH:9]=3)=[O:8])[CH2:24][CH2:25]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(C(=O)O)cnc1F
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Yield: 103.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-5-methylnicotinic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (620 mg) described in Preparation Example 47, the title compound (1.1 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([N:17]=[C:18]=[O:19])=[N:14][C:13]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][CH2:22][CH2:23][OH:24]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18]([NH:21][CH2:22][CH2:23][OH:24])=[O:19])=[N:14][C:13]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NCCO
Reactant: Cc1nc(N=C=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NCCO)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 80 °C

Procedure:
5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole (88a) (0.58 mmol, 0.183 g) is dissolved in dioxane (5 ml) and treated with 2-aminoethanol (0.64 mmol, 0.039 ml) under argon. The reaction mixture is stirred and heated to 80° C. for 1 hour. The solvent is then removed and the residue dissolved in EtOAc and washed with water (2×20 ml) followed by brine (20 ml) and dried over MgSO4. After filtration, the solvent is removed in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate-methanol (9:1) to give the title compound.
Reaction SMILES: Cl.[CH2:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19]Br>CC(C)=O>[Cl:16][CH2:17][CH2:18][CH2:19][N:3]1[CH2:4][CH:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:2]1
Reactant: C1CC2CNCC2C1
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CC2CCCC2C1
Yield: 48.1 %

Procedure:
To a suspension of octahydrocyclopenta[c]pyrrole hydrochloride (5.00 g, 33.86 mmol) in acetone (150 mL) was added K2CO3 (35.68 g, 101.59 mmol) and 1-chloro-3-bromopropane (10.56 g, 67.72 mmol) in turn. The reaction mixture was heated to reflux for 12 h under N2. The solvent was removed, and the residue was treated with 200 mL of EtOAc. The mixture was washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 1:1 (v/v) PE/EtOAc) to afford the title compound (3.06 g, 56.63%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 188.7 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.24-1.28 (m, 1H), 1.38-1.40 (m, 2H), 2.06 (m, 1H), 2.46-2.50 (m, 2H), 2.56-2.57 (m, 3H), 2.63-2.68 (m, 2H), 2.70 (d, J=2.24 Hz, 2H), 2.71-2.73 (m, 2H), 3.60 (m, 2H) ppm.
Reaction SMILES: C([O:8][C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[C:29]([CH2:31][N:32]([CH:36]4[CH2:38][CH2:37]4)[CH:33]([CH3:35])[CH3:34])[CH:30]=2)[O:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24]3([CH3:42])[CH3:41])=[O:20])=[CH:14][CH:13]=1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[C:29]([CH2:31][N:32]([CH:36]4[CH2:37][CH2:38]4)[CH:33]([CH3:35])[CH3:34])[CH:30]=2)[O:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24]3([CH3:42])[CH3:41])=[O:20])=[CH:14][CH:13]=1)([OH:10])=[O:8]
Reactant: CC(C)N(Cc1cc(C(=O)Oc2ccc(CC(=O)OCc3ccccc3)cc2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1cc(C(=O)Oc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8-[(cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-benzyloxycarbonylmethyl-phenyl ester (Intermediate 40, 0.093 g, 0.17 mmol) in ethyl acetate (3 mL) was treated with a slurry of 10% palladium on carbon (20 mg) in ethyl acetate and the resulting reaction mixture was stirred under an atmosphere of hydrogen at ambient temperature for 2 h. The reaction mixture was filtered over a bed of celite and the filtrate was evaporated to a residue that was purified by flash column chromatography over silica gel to afford the title compound.