Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([C:5]1[N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:9](=[O:11])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 28.8 %

Procedure:
To a solution of 2-butyl-6-methylpyrimidin-4(3H)-one (3.38 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (6.64 g) in acetonitrile (50 mL) was added cesium carbonate (8.61 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.09 g, 29%) as a colorless viscous substance.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12](C=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([C:17]([CH3:19])=O)[CH3:16]>>[CH:15]([C:17]1[CH:19]=[CH:1][C:14]2[C:8]3[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][C:5]=2[C:4]=1[CH:3]=[CH2:2])=[CH2:16]
Reactant: CCC(C)=O
Reactant: c1ccc2cc3ccccc3cc2c1
Product: C=Cc1ccc2c(c1C=C)Cc1ccccc1-2

Procedure:
To a solution of 2,7-Bis(diethylphosphonatomethyl)-9,9-dipropylfluorene (4) (26.8 g) and 3,5-dimethoxy-4-(1-methylpropoxy)-benzaldehyde (6) (26.2 g) in tetrahydrofuran (200 mL) was added potassium hydroxide (8.4 g) and dimethylsulfoxide (5.0 mL). The suspension was stirred at 70° C. for 4 hours and then isopropanol (150 mL) was added. The solvent of the supernatant solution was removed at reduced pressure and the resultant oil was stirred in methanol (200 mL). The precipitate was filtered off and purified by stirring in boiling ethanol (200 mL) two times. After drying, (II-2) was obtained as a pale yellow powder (25.8 g, 72%). The UV/VIS spectrum of (II-2) in methyl ethyl ketone (MEK) has two maxima at 382 nm and at 402 nm with a molar extinction coefficient of 93092 Mol−1 cm−1 and 75139 Mol−1 cm−1 respectively. Under UV irradiation in MEK, (II-2) shows a strong blue fluorescence with fluorescence peaks at 419 nm and 444 nm. The fluorescence quantum yield of (II-2) relative to the anthracene standard is 0.66 (in MEK solvent, not degassed). The 1H-NMR data in CDCl3 are summarized in table 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].C1COCC1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[NH:12][CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(Br)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1nc2cc[nH]c2cc1Br
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 6-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine 5-carbonitrile (2.46 g, 6.54 mmol), THF (6 mL) and MeOH (6 mL) was added 1N NaOH (3 mL). The reaction mixture was stirred for 30 minutes and then neutralized with 1N HCl and extracted with EtOAc (2×). The organic phase was dried over MgSO4 and concentrated in vacuo to give crude intermediate 6-bromo-1H-pyrrolo[3,2-b]pyridine 5-carbonitrile, which was subsequently dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60%, 314 mg, 7.85 mmol) was added, and the reaction mixture was stirred 30 minutes. Next, iodomethane (0.49 mL, 7.85 mmol) was added, and the reaction mixture was stirred for 30 minutes while warming to RT. The solution was subsequently diluted with EtOAc (100 mL), quenched and washed with brine. The aqueous layer was back-extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (2% MeOH/DCM) to give the title compound as a white solid (1.05 g, 68%). 1H NMR (500 MHz, CDCl3) δ ppm 7.90 (s, 1H), 7.43 (d, 1H, J=3.5 Hz), 6.76 (d, 1H, J=3.5 Hz), 3.85 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C9H6BrN3, 236, 238; found 236, 238.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH:15](O)=O>>[CH2:9]([N:6]1[C:7]2[N:8]=[CH:15][NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[S:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Reactant: O=CO
Product: CC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.22 g, 1.0 mmol) was suspended in formic acid (1.5 mL) and this solution was heated at 100° C. for 1 h. Excess formic acid was evaporated off under reduced pressure. 10% Sodium hydroxide (1.5 mL) was added to the orange solid and the resulting solution was heated at 100° C. for 15 minutes. Water was added and the pH of the solution adjusted to pH 4 with dilute acetic acid. The resulting slurry was stirred for 0.5 h at ambient temperature, then the precipitate was collected by filtration and washed with water. Yield: (0.21 g, 90%).
Reaction SMILES: CO[C:3](=[O:25])/[C:4](=[N:22]/[O:23][CH3:24])/[C:5](/[CH3:21])=[CH:6]\[CH2:7][O:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]=1.[CH3:26][NH2:27]>C1COCC1.O>[CH3:26][NH:27][C:3](=[O:25])/[C:4](=[N:22]/[O:23][CH3:24])/[C:5](/[CH3:21])=[CH:6]\[CH2:7][O:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]=1
Reactant: CN
Reactant: CO/N=C(C(=O)OC)\C(C)=C/COc1ccn(-c2ccc(Cl)cc2)n1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=N/OC)/C(C)=C\COc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
120 mg (0.33 mmol) (Z)-5-[1-(4-chloro-phenyl)-1H-pyrazol-3-yloxy]-2-[(E)-methoxyimino]-3-methyl-pent-3-enic acid methyl ester and 0.99 ml (1.98 mmol) of a 2-molar solution of methyl amine in THF have been stirred overnight at ambient temperature in 2.0 ml of THF and 0.5 ml of water. After removal of the solvent in vacuo the product (120 mg) was collected in quantitative yield and good purity. Melting point 129-130° C.
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:20](O)[CH2:21][CH2:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1](=[O:19])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=1
Reactant: CCCCO
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCOc1cc(OC(=O)OC(C)(C)C)ccc1C(C)(C)C
Yield: 55.4 %

Procedure:
tert-Butyl 4-tert-butyl-3-hydroxyphenyl carbonate (1.5 g, 5.6 mmol), n-butanol (0.5 mL, 5.4 mmol), triphenylphosphine (1.3 g, 5.0 mmol) and diethyl azodicarboxylate (DEAD) (0.78 mL, 5.0 mmol) were treated in the same procedure described in Example 31(a). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 9/1) to furnish 964 mg (66% yield) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Naphthalene-1-carboxylic acid. LC-MS (basic): tR=0.95 min; [M+H]+=502.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[O:25][CH2:24][CH2:23][O:22]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CN2C(=O)c3ccccc3C2=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2(CN3C(=O)c4ccccc4C3=O)OCCO2)cc1
Temperature: 25 °C

Procedure:
2-[2-(4-Methoxyphenyl)-2-oxoethyl]isoindole-1,3-dione (Preparation 37, 6.35 g, 21.5 mmol) was suspended in toluene (50 mL) and ethylene glycol (12 mL) added. p-Toluenesulfonic acid (300 mg, 1.58 mmol) was added and the resulting mixture heated under reflux for 40 h, removing water with a Dean-Stark trap. The reaction mixture was allowed to cool to rt then partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure, to give the title compound as an off-white solid. δH (d6 DMSO): 3.66 (2H, t), 3.72 (3H, s), 3.87 (4H, m), 6.88 (2H, d), 7.32 (2H, d), 7.83 (4H, m).
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[N:21]=[N:20][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)nn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)nn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
2-{[4-(2-{[6-(4-Fluorophenyl)pyridazin-3-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (400 mg) obtained in Example 123-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (290 mg) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:9]1[CH:14]=[C:13]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:12]=[C:11]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=1[OH:25])([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:1]([O:4][CH2:5][C:6]([C:9]1[CH:14]=[C:13]([N:15]([C:26](=[O:28])[CH3:27])[C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:12]=[C:11]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=1[OH:25])([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCC(C)(C)c1cc(Nc2nccs2)cc(C(C)(C)C)c1O
Product: CC(=O)OCC(C)(C)c1cc(N(C(C)=O)c2nccs2)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
A mixture consisting of 0.50 g of Compound 13 (prepared in Example 13) and 6 ml of acetic anhydride was heated at 100° C. for 1 hour. The reaction mixture was then cooled to ambient temperature and concentrated. The resulting crude product was purified by silica gel column chromatography (diethyl ether-hexane=1:2) to give 0.50 g of the desired compound as a colorless solid. The structure and physical properties of this product compound are shown in Table 2.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[C:5]([NH:10][CH3:11])[C:4]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH:6]=[C:5]([NH:10][CH3:11])[C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: CNc1cc(F)cc(NC)c1[N+](=O)[O-]
Reactant: NCCOCCO
Product: CNc1cc(NCCOCCO)cc(NC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.01 mole (2 g) of 2-methylamino-6-methylamino-4-fluoronitrobenzene in 8 ml of 2-(2-aminoethoxy)ethanol was heated to 100° C. After 30 minutes the reaction medium was diluted with 20 ml of ice water and the desired product precipitated out. After filtering and vacuum drying in the presence of P2O5, it was recrystallized from isopropanol and then from ethyl acetate. The product melted at 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:26])[F:24])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:54]2[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: CN1CCNCC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCN(C)CC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 500 mg of the compound obtained in Example 219 and 1-methylpiperazine (0.17 ml) as starting material, 287 mg of the title compound (light yellow amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:48])C=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:38])=[O:48])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCSC)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
180 mg 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-(methylsulfanyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (0.326 mmol, 1.0 eq.) were dissolved in 1.7 mL chloroform and cooled to 0° C. 80.3 mg 3-chlorobenzenecarboperoxoic acid and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with DCM and a solution of sodium thiosulfate (10% in water) was added and stirred for 5 minutes. The layers were separated and the aqueous layer was washed with DCM twice. The combined organic layers were washed with saturated sodium hydrogencarbonate solution, was dried over a silicon filter and concentrated in vacuo. The crude product was purified by flash chromatography to provide 136 mg of the analytically pure target compound as a racemate.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:27][CH:28]([CH3:34])[CH2:29][C:30]([NH:32]O)=[NH:31]>CN(C=O)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([C:12]2[O:14][N:32]=[C:30]([CH2:29][CH:28]([OH:27])[CH3:34])[N:31]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CC(O)CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of N-boc-amino-cyclopropanecarboxylic acid (500 mg, 2.49 mmol) in 2 mL of DMF at 0° C. was added carbonyldiimidazole (403 mg, 2.49 mmol). The reaction mixture was stirred at room temperature for 30 min, and 3,N-dihydroxy-butyramidine (480 mg, 4.06 mmol) was added as a solution in 2 mL of DMF. The pale yellow, faintly cloudy reaction mixture was stirred at room temperature for 30 min and then heated at 100° C. for 15 h. After cooling to room temperature, the reaction mixture was diluted with 15 mL of water and extracted with 50 mL of ethyl acetate. The organics were washed with 2×15 mL of water and 15 mL of brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel (0-8% MeOH/CH2Cl2) to afford 242 mg (34%) of {1-[3-(2-hydroxy-propyl)-1,2,4-oxadiazol-5-yl]-cyclopropyl}-carbamic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:7]2[CH2:6][CH2:5][NH:4][C:3](=[O:8])[C:2]2([CH3:9])[CH3:1])=[CH:14][CH:13]=1
Reactant: CC1(C)NCCNC1=O
Reactant: COc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCNC(=O)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of 3,3-dimethyl-piperazin-2-one (Step 108.4) (3.7 g, 28.9 mmol), 4-methoxybenzyl bromide (5.4 mL, 37.6 mmol, 1.3 equiv) and triethylamine (5.2 mL, 37.6 mmol, 1.3 equiv) in DCM (60 mL) was stirred for 48 h at rt. Additional 5.0 mL of 4-methoxybenzyl bromide were added and the mixture was stirred for 72 h at rt, then concentrated. The residue was diluted with DCM/saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in DCM to provide 3.95 g of the title compound as a white solid: ESI-MS: 249.2 [M+H]+; TLC: Rf=0.16 (Hex/EtOAc, 2:3).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:20][C:19]3[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=3[C:13]1=[C:12]([CH3:23])[C:11](=[O:24])[CH2:10][CH2:9]2)(=O)=O.[I-:25].[Na+]>CC(C)=O>[I:25][CH2:6][CH2:7][C:8]12[CH2:9][CH2:10][C:11](=[O:24])[C:12]([CH3:23])=[C:13]1[C:14]1[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=1)[CH2:20]2
Reactant: COc1ccc2c(c1)CC1(CCOS(C)(=O)=O)CCC(=O)C(C)=C21
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CC1(CCI)CCC(=O)C(C)=C21
Temperature: 60 °C
Yield: 63.6 %

Procedure:
A solution of 2-(2-methoxy-5-methyl-6-oxo-6,7,8,9-tetrahydro-8aH-fluoren-8a-yl)ethyl methanesulfonate (49.7 mg, 0.142 mmol) in acetone (2.0 mL) was treated with sodium iodide (85 mg, 0.57 mmol) and the resulting mixture was stirred and heated in an oil bath at 60° C. for 16 hours. After cooling, the mixture was diluted with acetone (2 mL) and filtered through a 0.45 Fm Acrodisc filter. The filtrate was evaporated under vacuum and the residue in CH2Cl2 (3 mL) was re-filtered. The filtrate was purified by chromatography on a Biotage Flash 12M KP-Sil column (12 mm×15 cm) which was eluted with 4:1 hexanes-EtOAc, collecting 6 mL fractions every 30 seconds. Fractions 9-11 gave 9a-(2-iodoethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (34.5 mg, 64% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[NH:4][N:3]=1.[CH3:10]OS(OC)(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[N:4]([CH3:10])[N:3]=1
Reactant: N#Cc1c(N)n[nH]c1N
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(N)c(C#N)c1N
Yield: 20.8 %

Procedure:
3,5-Diamino-4-cyanopyrazole (6.1 g) was dissolved in 1 M sodium hydroxide solution (50 ml), and dimethylsulphate (6.2 g) was added. The mixture was heated at reflux for 21/2 hours and then evaporated to dryness. The residue was extracted with 2-methoxyethanol, and the extracts were evaporated. The residue was triturated with a small amount of water to give 3,5-diamino-4-cyano-1-methylpyrazole (1.4 g), m.p. 194°-196° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][OH:21])[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH:20]=[O:21])[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)cc(Cl)c1Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(CC=O)cc(Cl)c1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1,1-Dimethylethyl cyclopropyl{[2,3-dichloro-5-(2-hydroxyethyl)phenyl]methyl}carbamate (1 eq.) from Step 3, Amine 6 and sodium bicarbonate (1 eq.) were suspended in CH2Cl2 (0.1 M). At 0° C., DMP (1 eq.) was added and the resulting mixture was stirred at 0° C. for 15 min and then at RT for 45 min. The reaction was quenched with 1 N aq. NaOH and extracted with ether. The combined organic extracts were then washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as an unstable, colorless oil.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:26])[C@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[OH:27]O>C1COCC1.O>[CH2:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:26])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CC[C@@H](CCCCCCC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](CCCCCCC)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 8.69 g (0.024 mol) of the product from Example 3 in 425 mL of THF/H2O (3:1), cooled to 0 degrees, was added 10.8 mL (0.097 mol) of 30% hydrogen peroxide solution followed by 2.03 g (0.049 mol) of LiOH--H2O. The resulting solution was stirred at 0° C. for 1.5 h and then quenched with a solution of 15.4 g of sodium sulfite in 100 mL of H2O. The reaction mixture was then acidified to pH 3 with aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.33 g (90%) of the desired product as a colorless oil. CI Mass Spec: 199 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:33]2[CH2:32][CH:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)[CH2:35][CH2:34]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(C2=CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(C2=CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC3CCCC3)CC2)cc1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid and 4-(4-Methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 503.9 (M+, 100%)