Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:21])[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][C:9](=[N:11][C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2cc[nH]n2)C=C(C(C)(C)C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(Nc2cc[nH]n2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.5 g quantity of 2,6-di-tert-butyl-4-(3-pyrazolylimino)-2,5-cyclohexadien-1-one (Compound 34a) was dissolved in 21 ml of tetrahydrofuran. To the solution was added a solution of 21 g of sodium hydrosulfite in 63 ml of water. The mixture was stirred at room temperature for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting crude product was washed with hexane, giving 1.3 g of title compound (Compound 34) as a colorless solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:13](=[O:32])[C:14]4[O:31][CH:30]=[CH:29][C:15]=4[N:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[CH:27][CH:26]=[N:25]5)=[CH:20][CH:19]=4)[N:17]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([N:7]2[C:11]([C:12]3[C:13](=[O:32])[C:14]4[O:31][CH2:30][CH2:29][C:15]=4[N:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[CH:27][CH:26]=[N:25]5)=[CH:20][CH:19]=4)[N:17]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2)c2ccoc12
Agent: [Pd]
Solvent: CCO
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2)c2c1OCC2
Yield: 32.7 %

Procedure:
A solution of 3-(1-phenyl-1H-pyrazol-5-yl)-1-[4-(1H-pyrazol-1-yl)phenyl]furo[3,2-c]pyridazin-4(1H)-one (64 mg) and 10% palladium on carbon (100 mg) in ethanol (80 mL) was stirred at 50° C. for 12 hr under a hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (21 mg).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=O)=[CH:21][CH:20]=1)[CH3:17]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:6]3=[N:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[C:11]3[N:12]=[C:26]2[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)[CH2:2][CH2:3]1
Reactant: Nc1cc([N+](=O)[O-])cnc1NCC1CC1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])cnc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
To a solution of N2-(cyclopropylmethyl)-5-nitro-2,3-pyridinediamine (792 mg, 3.80 mmol) in dichloromethane (50 mL) at room temperature was added 4-ethoxy-benzeneacetyl chloride (795 mg, 4.00 mmol). The mixture was stirred for 10 hours. The mixture was concentrated in vacuo and the residue dissolved in dichloroethane (25 mL) and acetic acid (25 mL). The mixture was stirred for 48 hours at 85° C. The reaction was then cooled to room temperature and brought to pH=10 by addition of 1 M NaOH aqueous solution. The mixture was extracted with EtOAc (50 mL). The aqueous phase was back-extracted with additional EtOAc (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([2.5%. MeOH+0.5% NH4OH aq] in CH2Cl2) to provide 1.02 g of the title compound 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-6-nitro-3H-imidazo[4,5-b]pyridine (76.0% yield from N2-(cyclopropylmethyl)-5-nitro-2,3-pyridinediamine). 1H-NMR (400 MHz, CDCl3): δ 0.44 (m, 2H), 0.52 (m, 2H), 1.10 (m, 1H), 1.40 (t, J=6.8 Hz, 3H), 4.01 (q, J=6.8 Hz, 2H), 4.10 (d, J=7.2 Hz, 2H), 4.35 (s, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 8.80 (d, J=2.3 Hz, 1H) 9.26 (d, J=2.3 Hz, 1H). MS (ESI) (M+H)+: 353.
Reaction SMILES: C[Si](I)(C)C.[CH3:6][O:7][C:8](=[O:33])[C@H:9]([NH:22]C(OCC1C=CC=CC=1)=O)[CH2:10][C:11]1[C:20]([Br:21])=[CH:19][C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1.C(N(CC)CC)C>C(#N)C>[CH3:6][O:7][C:8](=[O:33])[C@H:9]([NH2:22])[CH2:10][C:11]1[C:20]([Br:21])=[CH:19][C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1
Reactant: COC(=O)[C@@H](Cc1cc2oc(=O)[nH]c2cc1Br)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](N)Cc1cc2oc(=O)[nH]c2cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyliodide (73 mL, 0.73 mmol) was added to a solution of azotropically dried (R)-2-benzyloxycarbonylamino-3-(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (146 mg, 0.33 mmol) in acetonitrile (10 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. Triethylamine (0.12 mL) was added and the mixture was stirred at room temperature for 15 min. The solvents were removed in vacuo, and the residue was extracted with ethyl acetate. The combined organics were washed with sodium bicarbonate and brine, dried over sodium sulfate and filtered. Solvents were removed and the residue was used directly in the next step. Mass spec. 315.10 (MH)+.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]([CH3:38])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:35](O)=[O:36])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:51][S:52]([NH2:55])(=[O:54])=[O:53].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]([CH3:38])=[N:17][O:18][C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:35]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:36])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Nc1cccc(Cc2ccccc2)n1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1Nc1cccc(Cc2ccccc2)n1
Temperature: 70 °C

Procedure:
1-{4′-[4-(6-benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (sodium salt; 0.050 g, 0.083 mmol), carbonyldiimidazole (0.0676 g, 0.417 mmol), MeSO2NH2 (0.0789 g, 0.83 mmol) and DBU (0.0248 mL, 0.166 mmol) were combined in THF (1 mL) and the mixture was heated to 70° C. in a capped vial for 25 hours. The mixture was purified by preparative HPLC to yield the title compound.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]=O)[CH:12]=[CH:11]2.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]=[N:2][CH3:1])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: CN=Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96 %

Procedure:
A mixture of an 8.03M solution of methylamine in ethanol (67 mL, 537 mmol) and 50 mL of methylene chloride was added dropwise under nitrogen to a mixture of 6-methoxy-naphthalene-2-carbaldehyde (20 g, 107.4 mmol), magnesium sulfate (20 g) and 200 mL of methylene chloride. The mixture stirred at room temperature under nitrogen for 17 h. The MgSO4 was removed by filtration and the solvent was removed under reduced pressure to give (6-methoxy-naphthalen-2-ylmethylene)-methyl-amine (20.59 g, 96%) as a yellow solid, mp 109-110° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(CC)C.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([O:46][CH:47]([CH3:49])[CH3:48])[C:32]([F:45])=[C:33]([CH:44]=1)/[CH:34]=[N:35]/[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1)[CH3:27]>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([N:35]([CH2:34][C:33]2[CH:44]=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=[C:31]([O:46][CH:47]([CH3:49])[CH3:48])[C:32]=2[F:45])[C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=2)=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Reactant: c1ccc(COCn2ccnc2-c2ccccc2)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2cnc(-c3ccccc3)n2COCc2ccccc2)c(F)c(OC(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
To a solution of Intermediate 15.1 (100 mg, 0.378 mmol) in 2 mL THF at 0° C., was added sec-BuLi (0.81 M in cyclohexane, 514 μL, 0.416 mmol). The mixture was stirred at 0° C. for 10 min, then a solution of Intermediate 7.3 (123 mg, 0.378 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at 0° C. for 30 min and rt 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 75% EtOAc/hexanes gradient) followed by preparative HPLC purification to afford 53.7 mg of Intermediate 15.2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[CH:4][C:3]=1[C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1.NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)[CH:4]=1)=[O:8])[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol) in tetrahydrofuran (1.644 ml) and methanol (1.644 ml) at 25° C. was added hydrazine (0.10 ml, 3.29 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (silica, 5% MeOH in DCM (1% NH4OH)). The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 mL) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (79 mg, 0.17 mmol, 53% yield) as a yellow solid: LCMS (ES) m/z=380, 382 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J=8.59 Hz, 1H) 8.10 (s, 1H) 7.99 (br. s., 3H) 7.55 (d, J=1.77 Hz, 1H) 6.48 (d, J=2.02 Hz, 1H) 4.22-4.28 (m, 1H) 3.81 (s, 3H) 2.90-2.95 (m, 2H) 1.74-1.78 (m, 1H) 1.62-1.65 (m, 4H) 1.48-1.51 (m, 1H) 1.37-1.39 (m, 2H) 1.09-1.13 (m, 2H) 0.92-0.96 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:30][CH:26]1[CH2:29][CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NC1CCC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NC1CCC1

Procedure:
5-Cyclobutylamino-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and cyclobutylamine. Mass spectrum (ES) MH+=391.
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C)C=O>[Cl:1][C:2]1[C:9]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5]
Reactant: C1CCNC1
Reactant: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c([N+](=O)[O-])ccc(N2CCCC2)c1Cl
Yield: 88.2 %

Procedure:
13.0 g of 2,3-dichloro-6-nitrobenzonitrile was dissolved in 50 ml of dimethylformamide, and 11.0 g of pyrrolidine was added to the solution, followed by stirring while externally cooling because of heat generation. After continuing the stirring for 30 minutes, the reaction mixture was poured into water. The precipitate thus formed was filtered, washed with water and then with methanol to obtain 13.3 g of 2-chloro-6-nitro-3-pyrrolidinobenzonitrile (melting point: 170°-173° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)=[CH:16][C:17]=1[O:22][CH2:23][CH3:24]
Reactant: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CCO
Product: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Yield: 56.2 %

Procedure:
A solution of [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.78 g, 2.12 mmol) in ethanol (10 mL) and 4 M HCl (15 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (50 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure yielding 0.32 g (57%) of a white solid. The crude material was directly used in the following reaction step without further purification. MS (ISP): 269.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C-:30]#[N:31].[K+]>CN(C)C=O>[Br:20][C:18]1[CH:19]=[C:14]([C:5]2[C:6]3[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=3)[N:8]=[C:3]([CH2:2][C:30]#[N:31])[C:4]=2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=[N:16][CH:17]=1
Reactant: [C-]#N
Reactant: CCOC(=O)CCCCc1c(CBr)nn2c(CC)ccc2c1-c1cncc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(CC#N)nn2c(CC)ccc2c1-c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 45.9 %

Procedure:
A mixture of ethyl 5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and potassium cyanide (13.1 mg) in N,N-dimethylformamide (1 mL) was stirred for 28 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times), brine, dried over magnesium sulfate, and evaporated to give ethyl 5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (28.8 mg, 45.9%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=O)[NH2:17])=[O:10])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C(N)=O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C#N
Temperature: -35 °C
Yield: 84.8 %

Procedure:
In a dry three-neck flask under a nitrogen atmosphere, 286 mL of pyridine, [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (13.5 g, 49.8 mmol) and imidazole (7.11 g, 104.6 mmol) were added successively. The reaction system was cooled down to −35° C., and phosphorus oxychloride (19 mL, 204.2 mmol) was then added dropwise to the solution with stirring. After stirring for 1 hour at −35° C., the reaction mixture was allowed to increase to room temperature, and stirred for another 0.5 hour. Pyridine was evaporated under low temperature, and the reaction mixture was diluted with water, then extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound [2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1e (10.7 g, yield 84.9%) as a white powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][NH2:14])=[O:12])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:26](=O)[CH3:27])[CH:25]=1>CO.C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](/[C:26](=[N:14]/[NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][CH:17]=[C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:18])[CH2:3][CH2:4]3)[CH:9]=2)/[CH3:27])[CH:25]=1
Reactant: NNC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.5 %

Procedure:
3-(1,1-dioxidothiomorpholino)benzohydrazide (30 mg, 0.111 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (19.00 mg, 0.111 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(1,1-dioxidothiomorpholino)benzohydrazide (15 mg, 0.035 mmol, 31.3% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.65 (d, 1H, J=2.0 Hz), 7.47 (m, 1H), 7.41 (t, 1H, J=7.6 Hz), 7.36-7.27 (m, 3H), 6.94 (d, 1H, J=8.8 Hz), 3.87 (m, 4H), 3.17 (m, 4H), 2.48 (s, 3H). Mass [M+H]+: 422.2
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23]([C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1)=[O:24])[CH3:27]
Reactant: FC(F)(F)c1ccc(-c2csc(Cl)n2)cc1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of 5.0 g (19.0 mmole) of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole and 57 mL of tetrahydrofuran at −78 degrees, was added, over 10 minutes, 9.5 mL of 2.5 M n-butyl lithium in hexanes solution. After 30 minutes, 1.1 mL of 2.5 M n-butyl lithium in hexanes solution was added The mixture was stirred for 2 hours and then 10.63 mL (107.8 mmole) of ethyl chloroformate was added quickly to a rapidly stirring solution. After 15 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 22 minutes. The reaction was quenched by the addition of 75 mL of 1M hydrochloric acid, stirred for 5 minutes and then diluted with 500 mL of ethyl acetate. The ethyl acetate layer was washed twice with 75 mL of water, once with 75 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting dichloromethane-hexanes (gradient 10:90-50:50) to give 4.94 g of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a light yellow solid.
Reaction SMILES: [CH3:1][C@@:2]1([OH:14])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]1([CH3:13])[CH3:12].[C:15](Cl)(=[O:17])[CH3:16]>>[CH3:1][C@@:2]1([O:14][C:15](=[O:17])[CH3:16])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]1([CH3:13])[CH3:12]
Reactant: CC(C)=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Reactant: CC(=O)Cl
Product: CC(=O)O[C@]1(C)CC[C@@H](CC=C(C)C)C1(C)C

Procedure:
Using the procedure of Example 15, 2 g of (1R,S) 1,2,2-trimethyl-3-(3-methyl-2-butenyl)-cyclopentanol and 3 ml of acetyl chloride were reacted and the product was chromatographed over silica gel and was eluted with a 95-5 cyclohexane-ethyl acetate mixture to obtain 1.5 g of (1R,S) 1,2,2-trimethyl-1-acetyloxy-3-(3-methyl-2-butenyl)-cyclopentane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([O:33]CC)=[O:32])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([OH:33])=[O:32])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Yield: 64.4 %

Procedure:
To a solution of ethyl 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetate (0.09 g, 0.2 mmol, obtained in example 32) in EtOH (4.2 mL), a solution of KOH (0.09 g, 2.5 mmol) in water (0.5 mL) was added. This was heated to reflux for 1 h. It was allowed to cool and concentrated. The residue was dissolved in a mixture of EtOAc and water. The phases were separated. The aqueous phase was acidified and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness, to afford 57 mg of title compound (yield: 66%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH:23]=[CH2:24])[C:11]1=[O:25])=[O:4].B1C2CCCC1CCC2.[OH-:41].[Na+].OO>C1COCC1.CCO>[CH:16]1([CH:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:31])[CH3:29])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[C:11](=[O:25])[C@H:12]([CH2:22][CH2:23][CH2:24][OH:41])[CH2:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC[C@@H]1CCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@H](CCCO)CCC2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (less polar diastereomer from previous step) (60 mg, 0.14 mmol, 1.0 equiv) in anhydrous THF (2.0 ml) was added 9-BBN (0.5 M in THF, 0.68 ml, 0.34 mmol, 2.5 equiv) at 0° C. and the resulting solution was stirred at room temperature for 2 hours. The solution was then cooled at 0° C. and to the solution was added EtOH, 1.0 M aq. NaOH solution and aqueous H2O2 solution. The reaction mixture was heated to reflux for 90 minutes and then cooled at room temperature. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC (0.1% NH4OH) to give 20 mg of the desired product (yield 33%). MS: 446 [M+H+]. 1H-NMR (400 MHZ, CD3OD): 6.81 (s, 1H), 4.00 (br, 1H), 3.53 (t, 2H), 2.27 (br, 1H), 1.97 (m, 3H), 1.82˜1.64 (m, 7H), 1.58 (m, 2H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H).