Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[N:12]O)[CH2:3]1)[CH2:9]2.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>CCO.[Pd]>[NH2:12][CH:5]1[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2
Reactant: [H][H]
Reactant: ON=C1C2CC3CC1CC(O)(C3)C2
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: NC1C2CC3CC1CC(O)(C3)C2
Yield: 89.1 %

Procedure:
Pd/C (5%, 0.05 g) was added to a mixture of 5-hydroxy-adamantan-2-one oxime (1 g, 5.5 mmol) in EtOH in a Parr hydrogenation bottle. The hydrogenation reaction was performed in a Parr hydrogenation instrument with 55 Psi pressure of hydrogen at room temperature for 72 hours. The mixture was filtered through celite and concentrated under vacuum to dryness to give 4-amino-adamantan-1-ol (0.82 g, 89%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:20])=[CH:17][C:18]=1[Cl:19].[F:24][C:25]([F:36])([F:35])[C:26]([F:34])([F:33])[C:27]([F:32])([F:31])[C:28](O)=O>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([Cl:19])=[CH:17][C:16]2[N:20]=[C:28]([C:27]([F:31])([F:32])[C:26]([F:33])([F:34])[C:25]([F:36])([F:35])[F:24])[NH:21][C:15]=2[CH:14]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1N
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)c(C(F)(F)F)c1
Yield: 31 %

Procedure:
A solution of 4-[2,4-bis(trifluoromethyl)phenyl]-5-chlorobenzene-1,2-diamine (300 mg, 0.85 mmol) in heptafluorobutanoic acid (20 ml) was stirred overnight at 80° C. in an oil bath and then quenched with water (100 ml). The pH value of the solution was adjusted to 8 with sodium carbonate and extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 6-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a pink solid (137.7 mg, 31%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:16][C:13]1[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=Cc1ccncc1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCc1ccncc1)OCC
Yield: 43.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, 2,2-diethoxyethanamine (162.8 ml, 1120 mmol) was reacted with 4-pyridinecarboxaldehyde (120 g, 1120 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate and ethyl acetate:ethanol=15:1) to obtain the title compound (110 g, 44%).
Reaction SMILES: CN(O)[C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:11]=1)=[O:4].ClC1C=CC(C2N(C3C=CC([O:46]C)=CC=3)N=C(CCCO)C=2)=CC=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:11]=[C:7]([CH2:6][CH2:5][C:3]([OH:46])=[O:4])[CH:8]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(-n2nc(CCC(=O)N(C)O)cc2-c2ccc(Cl)cc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1

Procedure:
Known methods of synthesizing tepoxalin include the following. U.S. Pat. No. 4,826,868 describes reacting the alcohol, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanol with Jones reagent to form the acid, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid, which is reacted with dimethylformamide and oxalyl chloride in tetrahydrofuran (“THF”) which is then reacted with methylhydroxylamine hydrochloride and triethylamine in THF.
Reaction SMILES: Cl.C(OC([NH:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:18]=2[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[O:20])[CH2:12][CH2:11]1)=O)(C)(C)C>C(OCC)(=O)C>[NH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:18]=2[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[O:20])[CH2:12][CH2:11]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@@H](N)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4N-Hydrogen chloride solution in ethyl acetate (2 mL) was added to a solution of 2-[cis-4-(N-tert-butoxycarbonylamino)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (270 mg) in ethyl acetate (1 mL). The mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo. To the residue were added an aqueous saturated sodium bicarbonate solution and ethyl acetate. The appeared precipitates were collected by filtration and washed with ethyl acetate and water successively to give 2-(Cis-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (77 mg) as yellow powders. The filtrate was separated, and the aqueous layer was extracted with chloroform. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give a second crop (137.8 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:8]([C:5]1[CH:4]=[N:3][C:2]([C:17]#[C:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][CH:6]=1)[CH3:9]
Reactant: C#Cc1ccccc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cnc(C#Cc2ccccc2)nc1
Temperature: 47.5 °C
Yield: 105.6 %

Procedure:
2-Chloro-5-ethylpyrimdine (500 mg, 3.5 mmol), PdCl2(PPh3)2 (250 mg, 0.35 mmol), CuI (203 mg, 1.06 mmol), triethylamne (6.0 mL, 43 mmol), and n-Bu4NI (3.85 g, 10.4 mmol) were combined in dimethylformamide (DMF) (30 mL). The mixture was cooled in an ice bath and then phenylacetylene (1.5 mL, 14 mmol) was added. The reaction mixture was then heated to 45-50° C. and after 1.5 h, additional phenylacetylene (1.5 mL, 14 mmol) was added. After an additional 17 h the reaction was diluted with ethyl acetate, washed with brine (4.times.15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting black oil was purified by column chromatography eluting with hexane then 90:10 hexane:ethyl acetate to afford 5-ethyl-2-(phenylethynyl)pyrimdine (770 mg, >100%) as a black oil. MS (EI ionization) 208 (M+). This material was carried on to the salt formation without further purification.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+]>CO>[OH:8][CH:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCc2cc(C(=O)Cn3ccnc3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(O)Cn3ccnc3)ccc2N1

Procedure:
A solution of 3.0 g of 6-(imidazol-1-ylacetyl)-3,4-dihydrocarbostyril (the preparation of which is given in Example 3) in 120 ml of methanol was reacted with 1.2 g of sodium borohydride in the same manner as shown in Preparation 2, and the product similarly isolated to give 6-[1-hydroxy-2-(imidazol-1-yl)ethyl]-3,4-dihydrocarbostyril, m.p. 182°-184°
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(c2cc(Br)cc(C(C)(C)C)c2OC)CC1
Yield: 75 %

Procedure:
1-[5-Bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (750 mg), potassium carbonate (411 mg) and ethyl bromoacetate (0.27 ml) were stirred in dimethylformamide (4 ml) at room temperature for one day. The reaction mixture was diluted with ethyl acetate, the insoluble portion was filtered off and then the concentrated residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (715 mg) as a light red oil (75%).
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.Cl.[C:23]([C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>CC#N>[C:23]([C:27]1[CH:31]=[C:30]([CH2:32][NH:33][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:2]3([OH:1])[CH2:3][O:4][CH2:5]3)=[CH:11][CH:10]=2)=[O:21])[N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Nc1ccc(C2(O)COC2)cc1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C3(O)COC3)cc2)n(-c2cccc(Cl)c2)n1
Yield: 61.3 %

Procedure:
To a stirred solution of phenyl 4-(3-hydroxyoxetan-3-yl)phenylcarbamate (synthesis described for example A108) (97 mg, 0.34 mmol, 1.02 eq) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (100 mg, 0.33 mmol, 1.0 eq) in MeCN (8 mL) was added TEA (0.185 mL, 1.33 mmol, 4.0 eq) at RT and the mixture stirred at reflux overnight. The solvents were evaporated and the crude product was purified by CC (EtOAc/cyclohexane 3:2 as eluent) to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(3-hydroxyoxetan-3-yl)phenyl)urea (92 mg; 61%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](I)[C:41]=1[C:47]1[N:48]=[N:49][N:50]([CH3:52])[N:51]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:13][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[C:41]=2[C:47]2[N:48]=[N:49][N:50]([CH3:52])[N:51]=2)[CH:12]=1
Reactant: Cn1nnc(-c2c(F)cccc2I)n1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2c(F)cccc2-c2cncc(Cl)c2)n1
Temperature: 80 °C

Procedure:
A mixture of 5-chloropyridin-3-yl trifluoromethanesulfonate (6.00 g, 22.9 mmol), bis(pinacolato)diboron (6.12 g, 24.1 mmol), potassium acetate (6.75 g, 68.8 mmol), and [1,1′-bis-(diphenylphosphino)ferrocene]palladium(II) dichloride (0.60 g, 0.82 mmol) in 30 mL DMF was heated to 80° C. under N2 for 2 hours. The reaction mixture was cooled to room temperature, and 5-(2-fluoro-6-iodophenyl)-2-methyl-2H-tetrazole (4.88 g, 16.1 mmol), sodium bicarbonate (2M, 34.4 mL, 68.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.60 g, 0.82 mmol) were added. The reaction mixture was heated to 80° C. overnight, then cooled to room temperature and partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0–30% ethyl acetate in hexanes to provide 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]pyridine that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 290.11 for M+H+.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[CH2:36])[C@:20]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])([OH:27])[CH2:21][N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1>CO.[Pd]>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[C@:20]([OH:27])([C@H:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]=[N:9][NH:10][CH:11]=2)=[CH:14][CH:15]=1)[CH3:36])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: C=C(c1ccc(-c2cnnn2Cc2ccccc2)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CO
Product: C[C@@H](c1ccc(-c2c[nH]nn2)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(R)-3-(4-[1-Benzyl-1H-1,2,3-triazol-5-yl]phenyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2-ol (25.0 g, 0.05 moles) was dissolved in methanol (2400 ml) and hydrogenated at 100° C., 60 psi with 5% Pd/C for 20 hours. After catalyst removal by filtration the product solution was concentrated to a white foam (19.1 g, 0.05 moles). A sample was crystallised from ethanol/water and characterised by 1H NMR spectroscopy. It had an m.p. of 121° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[O:15][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of trans-tert-butyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (3.10 g, 14.1 mmol) and 4-methylbenzene-1-sulfonyl chloride (5.39 g, 28.3 mmol) in pyridine (20 mL) was stirred at room temperature for 18 hours. The pyridine was removed in vacuo, and the residue was dissolved in ethyl acetate (30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 2:1) to give trans-tert-butyl 4-fluoro-3-(tosyloxy)piperidine-1-carboxylate (3.95 g, 75%) as a solid.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.C([O-])(O)=O.[Na+].[Cl:19][CH2:20]S(OCl)(=O)=O>O>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([CH2:20][Cl:19])=[O:6]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=S(=O)(CCl)OCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)CCl
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of IClSO3H (5 g, 42.91 mmol) and ClCH2Br (5.55 g, 42.9 mmol) was refluxed for 3 hours, followed by pouring into ice. The ice water suspension was extracted with DCM (2×50 mL), and the combined DCM layers were washed with water (2×50 mL) to give a solution of ClCH2SO3Cl (solution A). A solution of Boc-β-Ala-OH (12, 4.73 g, 25 mmol), NaHCO3 (8.41 g, 100 mmol), and Bu4N+HSO4− (0.849 g, 2.5 mmol) in water (100 mL) was cooled to 0° C., followed by addition of solution A. The mixture was stirred vigorously for 2 hours, followed by separation of the layers. The DCM layer was washed with brine (2×100 mL), and dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (20% EtOAc in hexane, v/v) to yield 1.2 g (20%) of product (13): 13C NMR δ 28.218 (3×CH3 of Boc), 34.439 (CH2C(═O)O), 35.655 (NHCH2CH2), 68.565 (OCH2Cl), 79.547 (C(CH3)3), 155.811 (NHC(═O)O), 170.761 (C(═O)O).
Reaction SMILES: [F:1][C:2]([F:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][NH:4][C:5]1[C:6]([F:32])=[C:7]([CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([CH3:31])=[N:19][C:20]([NH:23]C(OC(C)(C)C)=O)=[CH:21][CH:22]=2)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1.Cl.O1CCOCC1>>[ClH:11].[NH2:23][C:20]1[N:19]=[C:18]([CH3:31])[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]([Cl:11])=[CH:9][CH:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:6]=2[F:32])=[CH:22][CH:21]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 181.3 %

Procedure:
To a flask charged with 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}-N-({6- [(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)}methyl)acetamide (770 mg, 1.37 mmol), as prepared in the preceding step, was added a solution of HCl in 1,4-dioxane (5 mL, 20 mmol, 4.0 M). After stirring at ambient temperature for 1.5 hours, some solid precipitated. A solution of MeOH (1 mL) in DCM (3 mL) was added to dissolve the solid, and the mixture was stirred for additional 4 hours. The solvents were removed, and the resulting residue was washed with DCM (5 mL×2), ether (8 mL×2), and dried in high vacuum to give the title compound (620 mg, 91% yield) as a pale brown solid. 1H-NMR (400 MHz, CD3OD) δ 7.81 (d, J=9.1 Hz, 1H), 7.54-7.51 (m, 2H), 7.45-7.42 (m, 3H), 6.94 (dd, J=8.9, 1.6 Hz, 1H), 6.80 (d, J=9.1 Hz, 1H), 6.65 (t, J=9.1 Hz, 1H), 4.25 (s, 2H), 3.81 (t, J=13.8 Hz, 2H), 3.70 (d, J=1.8 Hz, 2H), 2.50 (s, 3H). Mass spectrum (LCMS, ESI) calcd for C23H23ClF3N4O (M+H): 463.1. Found: 463.7.
Reaction SMILES: [CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].C([NH2:21])=O.C[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3]([NH2:21])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cc(F)cc2ccoc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1cc(F)cc2ccoc12
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A mixture of 0.156 gm (0.62 mMol) ethyl 2-methyl-2-(5-fluorobenzofur-7-yl)propionate, 0.095 gm (2.12 mMol) formamide, and 0.44 mL (0.44 mMol) sodium methoxide (1.0 M in methanol) in 3 mL dimethylformamide was heated at 100° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate and the organics washed sequentially with water and saturated aqueous sodium chloride. The organics were then concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 2:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.060 gm (25%) of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].[CH2:33](I)[CH3:34]>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:33][CH3:34])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cn[nH]c2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cnn(CC)c2cc1C
Yield: 68.3 %

Procedure:
Using the compound (1.68 g, 3.82 mmol) of Example 244, step B and ethyl iodide (0.50 ml, 6.25 mmol), and according to the method of Example 241, step C, the title compound (1.22 g, yield 68%) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH:14]=2)[CH:9]=[N:8]1)[CH:2]=[CH2:3]>[Pd].C(OCC)(=O)C>[CH2:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH:14]=2)[CH:9]=[N:8]1)[CH2:2][CH3:3]
Reactant: C=CCNCCn1ncc2ccc(-c3ccsc3)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCNCCn1ncc2ccc(-c3ccsc3)cc21
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A small scoop of palladium on carbon (10%, ˜10 mg, catalytic) was added to a solution of 1-(2-(N-allylamino)ethyl)-6-(3-thienyl)-1H-indazole (15 mg, 0.053 mmol) in ethyl acetate (1 mL). The resulting mixture was stirred under an atmosphere of hydrogen gas in a balloon for 1 h. Filtration through an SPE cartridge (Supelco, 6 mL, silica gel, 1000 mg, gradient from 0-10% 2M methanolic ammonia in ethyl acetate) gave the title product (12.2 mg, 81%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Si:15]([O:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC[C@@H]2NCCC[C@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 89 %

Procedure:
A solution of 77G (170 mg, 0.34 mmol) in 5% TFA/DCM (5 mL) was stirred at rt for 5 h and LC-MS showed completion. The mixture was concentrated and the residue was dissolved in EtOAc (30 mL), washed with saturated sodium bicarbonate solution (15 mL), brine (10 mL), dried (MgSO4) and evaporated to give desired product 77H (121 m, 89%) as a white solid: Rf (10% MeOH/DCM) 0.39; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 3.2 min (100%); MS (ES) m/z 344.1 [M+H]+; HRMS calcd for C20H33N3OSiCl 394.2081, Found 394.2080.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CC#N>[C:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: OCCC1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.6 %

Procedure:
Amine preparation: To a solution of 4-piperidine ethanol (540 mg) in MeCN (8 mL) was added triethylamine (0.70 mL) followed by tert-butyl dicarbonate (1.00 g). The mixture was stirred at room temperature for 22 h and partitioned between 0.5 M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated to give 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (897 mg). This was dissolved in THF (14 mL) and sodium hydride added (172 mg; 60% dispersion in mineral oil) at 0° C. After 30 min iodomethane (0.97 mL) was added and the mixture stirred for 22 h. The mixture was diluted with ethyl acetate and washed with water, brine and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(2-methoxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (724 mg). To a solution of 4-(2-methoxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (284 mg) in DCM (5 mL) was added 2M hydrogen chloride in diethyl ether (5.0 mL) and the mixture stirred for 21 h. The solvent was evaporated to give the desired amine as a white solid.