Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10]/[N:11]=[CH:12]/[C:13]1[CH:18]=[C:17]([C:19](=[O:25])[NH:20][O:21][CH2:22][CH2:23][OH:24])[C:16]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:15]([F:35])[C:14]=1[F:36])(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:7][CH2:8][CH2:9][O:10]/[N:11]=[CH:12]/[C:13]1[C:14]([F:36])=[C:15]([F:35])[C:16]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:17]([CH:18]=1)[C:19]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.4 %

Procedure:
To a solution of {2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzylideneaminooxy]-ethyl}-carbamic acid tert-butyl ester (55 mg, 0.31 mmol) prepared in Step B in ethyl acetate (5 ml) was added 1 N HCl solution in ethyl acetate (1 ml), and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was neutralized with saturated solution of sodium bicarbonate (50 ml), and extracted with ethyl acetate (3×100 ml). The extract was washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and after washing with diethyl ether (10 ml), the residue was recrystallized from methanol to give (E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (17.31 mg, 37% yield) as a pale yellow solid.
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: CC(=O)OC(C)=O
Solvent: CS(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: [S:1]1[C:5]([C@H:6]([O:31][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:49]=[CH:50][CH:51]=[CH:52][C:2]1=2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[S:1]1[C:5]([C@H:6]([OH:31])/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:49]=[CH:50][CH:51]=[CH:52][C:2]1=2
Reactant: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,5S)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-methylene-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (19a, limiting reagent) is dissolved in THF (0.3 M) under a nitrogen atmosphere. A solution consisting of TBAF in THF (1.2 molar equivalents, 1 M) is added and the reaction mixture is stirred at room temperature. Upon completion, as judged by TLC, water is added and most of the THF is removed under reduced pressure. The remaining aqueous solution is extracted with ethyl acetate and is washed with water and brine. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate (+0.4% acetic acid) to afford the title intermediate.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[OH:26][CH2:25][CH:24]([NH:23][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH2:27][OH:28]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Reactant: NC(CO)CO
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(CO)CO)s1
Yield: 86 %

Procedure:
As described for example 95, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (60 mg, 0.19 mmol) was converted, using 2-amino-1,3-propanediol instead of isopropylamine, to the title compound (61 mg, 86%) which was obtained as a colourless oil. MS: m/e=380.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])O[C:3]1([O:13]C)[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:15][C:2]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:13]
Reactant: COC1(c2ccc(SC)cc2)OC1(C)C
Reactant: C1COCCN1
Product: CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1

Procedure:
151.4 g (0.675 mol) of 3,3-dimethyl-2-methoxy-2-[4-(methylthio)-phenyl]-oxirane (melting point 62°-64° C.) are dissolved in 235.2 g (2.70 mols) of morpholine and the solution is warmed to reflux temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a solution of 4-bromo-N-isobutyl-benzenesulfonamide (0.25 g, 856 μmol) in anhydrous dimethylacetamide (5 mL) was added NaH (60% dispersion in mineral oil, 37.7 mg, 942 μmol) and the mixture was stirred at room temperature for 15 minutes. 4-Fluorobenzyl bromide (117 μL, 942 μmol) was added and reaction heated at 90° C. for 2 hours. The reaction was left to cool to room temperature, water added and then extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give 4-bromo-N-(4-fluoro-benzyl)-N-isobutyl-benzenesulfonamide (267 mg, 78%) 1H NMR (300 MHz, CDCl3): δ 7.65-7.66 (m, 4 H), 7.23 (m, 2 H), 6.99 (t, 2 H), 4.27 (s, 2 H), 2.89 (d, 2 H), 1.64 (dt, 1 H), 0.74 (d, 6 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(Cc2ccccc2)nc1C
Reaction time: 8 h
Yield: 71 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (5.1 g) synthesized in Example 1(3) was dissolved in dimethylformamide (50 mL), potassium carbonate (5.3 g) and benzylbromide (4.6 mL) were added to at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (5.9 g, 71%) as an oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:19]2[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=2)[C:13](=[O:23])[CH2:12]1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:10][CH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:18]=2)[C:13](=[O:23])[CH2:12]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1CC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1CC(=O)c2cc(NC(=O)c3ccccc3)ccc21
Reaction time: 2 h
Yield: 87.7 %

Procedure:
As presented in the following reaction formula, a solution of benzoyl chloride (PhCOCl; 6.7 g, 0.043 mol) in dichloromethane (DCM; 20 mL) was added at 0° C. to a mixture of 3-methyl-6-nitro-2,3-dihydro-1-H-inden-1-one (7 g, 0.043 mol) and triethylamine (9.6 g, 0.095 mol) in dichloromethane (DCM; 100 mL), and the reaction mixture was stirred for 2 hours. After the completion of reaction, the mixture was washed with water (50 mL), saturated sodium hydrogen carbonate (50 mL) and saturated brine (50 mL) and then concentrated to give a crude product. The crude product was purified by silica gel (50 g) column chromatography (product of Merck Co., Ltd.) using an eluent of pentane (PE):ethyl acetate (10:1 (by volume)) to give the desired product N-(1-methyl-3-oxo-indan-5-yl)benzamide (10 g, yield: 87%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][O:32][CH:33]1[CH2:36][NH:35][CH2:34]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH:33]([O:32][CH3:31])[CH2:34]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC1CNC1
Product: COC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methoxy-azetidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-methoxy-azetidine following General Procedure B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:9](I)([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:10][C:3]=12.N1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)N1c2nccc(Br)c2CC1(I)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccnc1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c(-c2cccnc2)cc2c(Br)ccnc21
Yield: 50 %

Procedure:
A solution of 4-bromo-2-iodo-1-(phenylsulfonyl)-2-(3-pyridinyl)-1H-pyrrolo[2,3-b]pyridine (0.44 mmol), 3-pyridinyl boronic acid (0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.013 mmol) in a 4:1 solution of 1,4-dioxane (4 mL):saturated sodium carbonate (1 mL) was stirred for 18 h at 100° C. in a sealed tube. After concentrated in vacuo, the residue was partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer was washed with brine (1×5 mL), dried over magnesium sulfate, and concentrated. Purification by flash chromatography (0-20% ethyl acetate/dichloromethane) provided the title compound as a yellow oil (50%). ESMS [M+H]+: 414.8.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:54][C:55]([C:57]1[C:65]2[N:64]=[C:63]([NH2:66])[NH:62][C:61]=2[CH:60]=[C:59]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:58]=1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH2:47]([O:54][C:55]([C:57]1[C:65]2[NH:64][C:63]([NH:66][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:62][C:61]=2[CH:60]=[C:59]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:58]=1)=[O:56])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Nc1nc2c(C(=O)OCc3ccccc3)cc(OCc3ccccc3)cc2[nH]1
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(OCc3ccccc3)cc(C(=O)OCc3ccccc3)c2[nH]1)c1cc2ccccc2cn1

Procedure:
600 mg (3.0 mmol) of isoquinoline-3-carboxylic acid and 1200 mg (3.1 mmol) of HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and reacted with 1.1 g (3.0 mmol) of 2-amino-6-benzyloxy-1H-benzoimidazole-4-carboxylic acid benzyl ester as described in general procedure A to produce 6-benzyloxy-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid benzyl ester. LCMS: 530 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7](=O)[CH2:8][CH2:9][CH3:10].[OH-].[K+].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[CH2:15]([N:22]1[CH:4]([CH2:3][CH2:2][CH3:1])[CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH3:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC(=O)CCC(=O)CCC
Reactant: NCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCC1CCC(CCC)N1Cc1ccccc1
Temperature: -15 °C

Procedure:
Dissolve 11.92 g decane-4,7-dione from the Step B above in 4.62 g acetic acid and 100 mL methanol. Add 1.16 g potassium hydroxide pellets. Stir to dissolve the potassium hydroxide. Cool the reaction mixture in an ice acetone bath at −15° C. Add 7.50 g benzylamine followed immediately with 5.4 g sodium cyanoborohydride in several portions. Let the reaction mixture warm up to room temperature over two days. Add 45 mL 4 N HCl drop-wise and stir for 30 minutes. Evaporate the reaction mixture under reduced pressure to remove most of the solvents. Dilute the residue with water, filter off some white solid, and extract the aqueous layer with ether. This ether solution contained 2,5-dipropylpyrrole. Cool the aqueous layer with an ice bath and add solid sodium hydroxide in small portions with stir until pH ˜13. Dissolve the white solid above in this mixture. Extract with ether several times. Wash the combined ether solution with saturated brine, dry over anhydrous Na2SO4 and evaporate to give the crude 1-benzyl-2,5-dipropylpyrrolidine. The cis and trans isomers were separated on silica gel (5˜10% EtOAc in hexanes with 1% Et3N). The fast eluting isomer was trans-1-benzyl-2,5-dipropylpyrrolidine. 1H NMR (CDCl3, 500 MHz) δ 7.38 (d, J=7.6 Hz, 2H), 7.29˜7.33 (m, 2H), 7.21˜7.24 (m, 1H), 3.83 (d, J=13.9 Hz, 1H), 3.66 (d, J=14.0 Hz, 1H), 2.86 (br s, 2H), 1.85˜1.94 (m, 2H), 1.45˜1.60 (m, 4H), 1.27˜1.37 (m, 2H), 1.09˜1.20 (m, 4H), 0.875 (t, J=7.2 Hz, 6H). The slower-eluting isomer was cis-1-benzyl-2,5-dipropylpyrrolidine. 1H NMR (CDCl3, 500 MHz) 7.29˜7.35 (m, 4H), 7.24˜7.26 (m, 1H), 3.77 (s, 2H), 2.53˜2.58 (m, 2H), 1.77˜1.84 (m, 2H), 1.52˜1.58 (m, 2H), 1.27˜1.44 (m, 4H), 1.13˜1.25 (m, 4H), 0.865 (t, J=7.2 Hz, 6H).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][N:43]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[CH:47]=[CH:46][C:45]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:27])([CH3:28])[N:5]([C:3](=[O:4])[CH:2]([F:29])[F:1])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:44][N:43]=1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (634 mg, 1.53 mmol) in a mixture of toluene (12 ml) and ethanol (9 ml) is added 2-(5-Bromo-pyridin-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.53 mmol), aqueous sodium bicarbonate solution (2M, 6 mmol, 3 ml), and 1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (57 mg, 0.08 mmol). The stirred reaction mixture is heated at 80° C. under a blanket of nitrogen for 1 hour. The reaction is concentrated to ⅓ its volume and partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase is washed with saturated brine (25 ml) and concentrated on to silica gel (3 g). Purification by column chromatography (40 g silica gel, ethyl acetate/heptane 0-100%) affords the title compound (500 mg): 1H NMR (400 MHz, CDCl3) 1.25 (s, 5H) 1.48 (s, 4H), 1.64 (s, 3H), 1.70 (s, 3H), 1.85-1.98 (m, 2H), 1.99-2.1 (1H), 2.3-2.48 (m, 1H), 3.5-3.74 (m, 2H), 4.54-5.1 (m, 4H), 5.23-5.33 (m, 1H), 6.13 (t, 1H), 7.23-7.31 (m, 1H) 7.5-7.57 (m, 2H), 7.57-7.67 (m, 2H), 7.78-7.87 (m, 1H), 8.77 (s, 1H). m/z M+H 534.2.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:32]1([NH:37][C:38]([NH2:40])=[NH:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:40]=[C:38]([NH:37][CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[N:39]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)NC1CCCC1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (5.97 g, 14.7 mmol) in dimethylformamide (80 mL) was added N-cyclopentyl guanidine hydrochloride (4.33 g, 26.5 mmol; Prepared by modification of a procedure from Bannard, R. A. B. et al., Can. J. Chem. 1958, 36, 1541–1549), followed by potassium carbonate (2.03 g, 14.7 mmol). The resulting solution was heated at reflux for 6 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (4:6 ethyl acetate:hexane) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine (5.02 g, 73%) as a yellow solid. 1H NMR (CDCl3): δ 7.95 (d, 1H), 7.72 (d, 1H), 7.54 (dd, 2H), 7.25 (t, 1H), 6.94 (dd, 2H), 6.28 (d, 1H), 6.00–5.97 (m, 2H), 5.03 (d, 1H), 4.33–4.31 (m, 1H), 3.96 (m, 1H), 3.83 (s, 3H), 2.10–2.01 (m, 4H), 1.77–1.50 (m, 12H); MS m/z 469 (M+1); Anal. Calcd for C28H32N6O: C, 71.77; H, 6.88; N17.93. Found: C, 71.41; H, 7.02; N, 17.89.
Reaction SMILES: C([N:4](CC)[CH:5]([CH3:7])[CH3:6])(C)C.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O>C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:4][CH:5]2[CH2:7][CH2:6]2)=[O:19])=[N:15][CH:16]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (0.69 mL, 0.0040 mol) was added to a mixture of 5-bromopyridine-2-carboxylic acid (400 mg, 0.002 mol), cyclopropylamine (0.16 mL, 0.0024 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.1 g, 0.0024 mol) in N,N-dimethylformamide (9.4 mL, 0.12 mol) at 0° C. and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine successively, dried over sodium sulfate, filtered and concentrated. The product was purified by CombiFlash eluting with CH2Cl2/EtOAc (max.EtOAc 20%). LC-MS: 241.1/243.1 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[O:21]1[CH2:26][CH2:25][CH:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:27]([CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[O:28])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCOCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A solution of 1-(4-chlorophenyl)ethanone (2.0 g, 12.9 mmol) in anhydrous THF was cooled in a dry ice acetone bath and treated with sodium hexamethyldisilazid (14.2 mL, 1M in THF, 14.2 mmol). The resulting solution was stirred for 1 h at −78° C. and a solution of tetrahydro-pyran-4-carbonyl chloride (1.92 g, 12.9 mmol) in THF was slowly added. The resulting solution was stirred for 30 min at −78° C., allowed to warm up to room temperature and stirred for 5 h. The reaction was quenched by adding 6N HCl and extracted with EtOAc (×3). The organic fractions were combined and washed with sat. NaCl, dried over Na2SO4 and evaporated under vacuum. The resulting residue was purified by silica column chromatography to give 2 g (58%) of 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione. 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione 1 g (3.75 mmol) was taken in absolute ethanol (20 mL) and TEA (1.4 mL, 10 mmol) was added slowly. This solution was stirred for 20 min and added drop-wise to a solution of (2-methoxyphenyl)hydrazine hydrochloride (0.7 g, 4.0 mmol) in ethanol (20 mL). This solution was heated to 60° C. and stirred for 5 h. Ethanol was removed under vacuum and the residue was taken in EtOAc and washed with water, and sat. NaCl. The solution was dried over Na2SO4 and evaporated. The residue was purified by silica column chromatography to give 5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole.