Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:11])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 2-[4-chloro-3-(trifluoromethyl)phenyl]propanoic acid (47 mg, 0.184 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (40 mg, 0.184 mmol) in DMF (1 mL) was added Hunig's base (59 mg, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (77 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, and then was partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine and dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (24 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.48-7.42 (m, 4H), 7.16-7.11 (m, 2H), 4.11 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 2.77 (m, 2H), 1.96 (m, 1H), 1.80 (m, 1H), 1.55 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C22H18ClF4N3O [M+H]+ 452.1, found 452.1.
Reaction SMILES: [Cl-].[Sc+3:2].[Cl-].[Cl-].[CH3:5][N:6]([CH:8]([Li])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]>O1CCCC1>[CH3:5][N:6]([CH:8]([Sc:2]([CH:8]([N:6]([CH3:7])[CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:8]([N:6]([CH3:7])[CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: [Sc+3]
Reactant: [Li]C(c1ccccc1)N(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)C(c1ccccc1)[Sc](C(c1ccccc1)N(C)C)C(c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
1.0 g (6.6 mmol) of anhydrous scandium chloride and 10 mL of tetrahydrofuran (THF) were placed in a 100 mL glass vessel to prepare a suspension liquid, which was stirred at room temperature for 1 hour. 2.8 g (20 mmol) of the above-obtained dimethylaminobenzyllithium dissolved in 20 mL of THF was added dropwise thereto, followed by stirring for 12 hours. After completing the reaction, THF was removed, and the target compound was extracted with toluene and then purified by recrystallization to provide 2.4 g of tris(dimethylaminobenzyl)scandium (Sc (CH2C6H4N(CH3)2-o)3) as pale yellow crystals (yield: 80%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@H:27]([C:37]3[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[OH:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(I)cc1
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-tert-butyl-4-iodobenzene.
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH:16][C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)C>[CH2:23]([C:17]1([OH:16])[CH2:22][CH2:21][N:20]([CH:2]([CH3:15])[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)=[O:4])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(Cl)C(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C(=O)c1ccc2c(c1)CC(=O)N2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
5-(2-Chloropropionyl)-2(1H,3H)-indolone (2.5 g, 11.2 mmol), 4-hydroxy-4-benzylpiperadine (2.1 g, 11.2 mmol), and triethylamine (1.56 ml, 11.2 mmol) were combined in ethanol and refluxed overnight. The mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over calcium sulfate, and concentrated. The crude product was flash chromatographed on silica gel eluting first unreacted 5-(2-chloropropionyl)-2(1H,3H)-indolone with 1:1 ethyl acetate:hexane. Continued elution with ethyl acetate gave 3.6 g of product as a light brown foam. Recrystallization from ethyl acetate/hexane gave 1.23 g of purified title product. Less pure fractions from the column and mother liquors from the recrystallization were rechromatographed as above with 1:1 and then 3:1 ethyl acetate:hexane. Product fractions were triturated with ether/hexane to give 0.2 g more product for a total yield of 1.43 g, 34%; m.p. 188°-192° C.; NMR 8.22 (s, 1H), 8.08 (d, J=8 Hz, 2H), 7.99 (s, 1H), 7.31-7.13 (m, 5H), 6.89 (d, J=8 Hz, 1H), 4.03 (q, J=6.8 Hz, 1H), 3.57 (s, 2H), 2.72 (s, 2H), 2.72-2.58 (m, 3H), 2.46 (distorted t, 1H), 1.75-1.40 m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.23-1.19 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:13][CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cccc(-c2cnc[nH]2)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(-c2cncn2COCC[Si](C)(C)C)c1
Yield: 57.8 %

Procedure:
Reaction of 5-(3-methoxy-phenyl)-1H-imidazole (500 mg, 2.87 mmol), NaH (60%, 112 mg, 2.79 mmol), and SEMCl (598 uL, 3.35 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (505 mg, 60%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.93 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=9.0 Hz), 3.87 (s, 3H), 5.30 (s, 2H), 6.80-6.83 (m, 1H), 7.26-7.39 (m, 3H), 7.40 (s, 1H), 7.63 (s, 1H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=S.Cl.[Cl:7][CH:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[S]>C(O)C.O>[ClH:7].[NH2:5][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH3:16])[NH:1][N:2]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(N)=S
Agent: Cl
Agent: [S]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(N)n[nH]c1C
Temperature: 0 °C
Yield: 55.9 %

Procedure:
A stirred mixture of 9.1 g (0.1 mole) of 3-thiosemicarbazide and 1 mL of concentrated hydrochloride acid in 150 mL of absolute ethanol was cooled to 0° C. in an ice bath and 16.5 g (0.1 mole) of ethyl 2-chloroacetoacetate was added dropwise. The thiosemicarbazide dissolved as the reaction mixture was allowed to slowly come to ambient temperature, it then became yellow and a new precipitate formed. The reaction mixture was heated at reflux for 3 hr. All the material had not dissolved so the reaction mixture was diluted with water and made acidic with 3N hydrochloric acid to dissolve all the solids but sulfur. After filtering, the filtrate was concentrated in vacuo leaving an orange-red oil which slowly crystallized when acetone was added to give 11.5 g of orange powder, mp 186°-188° C., with decomposition.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[F:9][C:10]([F:26])([F:25])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:9])([F:25])[F:26])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1)[CH3:2]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCN(CC)CCN
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 100.5 %

Procedure:
N,N-diethylethylene diamine (2.50 kg, 21.12 moles) was added to a solution of 4-(4-trifluoromethylphenyl)benzaldehyde (3.54 kg, 14.08 moles) in toluene (21 L) and rinsed in with toluene (14 L) with stirring. The resultant solution was stirred at 17-21° C. for ca. 96 hours. The solution was then transferred to a hydrogenation vessel containing 5% palladium on alumina (0.213 kg, 0.11 moles Pd) and rinsed in with toluene (37 L). The mixture was hydrogenated at 19−27° C., 50 psig hydrogen for 1 hour until no further hydrogen was consumed. The catalyst was removed by filtration through celite (0.5 kg) and the celite bed was washed with toluene (14 L). The combined filtrate and wash were washed with process water (3×14 L) then the toluene removed by distillation at 20-80° C. in vacuo to give the title compound as a pale yellow oil (4.96 kg, 97.3%). 1H NMR (CDCl3) δ 1.01 (6H, t), 2.52 (4H, q), 2.58 (2H, t), 2.70 (2H, t),3.86 (2H, s), 7.42 (2H, d), 7.43 (2H, d), 7.68 (4H, s).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([CH:15]([C:29]2[N:34]=[C:33]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:31][CH:30]=2)[CH:16](C2C=CC=CN=2)[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.[C:43](O)([C:45](F)(F)F)=O>C(Cl)Cl>[NH2:35][C:33]1[N:34]=[C:29]([CH:15]([C:13]2[N:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=2)[CH:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[CH:13]=[N:14][CH:9]=[CH:43][CH:45]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(c2cccc(NC(=O)OC(C)(C)C)n2)C(c2cccnc2)c2ccccn2)n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(C(c2cccc(N)n2)C(c2cccnc2)c2cccnc2)n1
Reaction time: 1 h

Procedure:
To the solution of tert-butyl 6-(1-{6-[(tert-butoxycarbonyl)amino]pyridin-2-yl}-2-pyridin-2-yl-2-pyridin-3-ylethyl)pyridin-2-ylcarbamate (0.12 g, 0.211 mmol) in CH2Cl2 (2 mL) was added CF3COOH (2 mL) and stirred for 1 h. The mixture was concentrated and the residue was dissolved in MeOH (3 mL). Potassium carbonate (200 mg) was added and stirred for 0.5 h. The mixture was filtered and the filtrate concentrated. The residue was purified by silica gel chromatography (10% MeOH in CH2Cl2) to give the title compound. 1H-NMR (500 MHz, DMSO-d6) δ 8.60 (s, 2H), 8.32 (d, 2H, J=4.6), 7.92 (d, 2H, J=7.8), 7.41 (s, 2H), 7.28(dd, 2H, J=7.7, 4.7), 7.15 (broad, 4H), 6.60 (d, 2H, J=7.4), 6.46 (s,2H), 5.25 (d, 1H, J=10.3), 4.98 (broad, 1H). LRMS m/z (M+H) Calcd: 369.4, found: 369.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CC(C)CN
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCC(C)C
Yield: 82 %

Procedure:
The compound prepared in Example 3 was reacted with isobutylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 82%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: BrCCCCCCBr
Reactant: COc1ccccc1CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1CCCCOCCCCCCBr
Yield: 288.4 %

Procedure:
NaH (46% dispersion in oil; 1.36 g) was added portionwise to a solution of 2-methoxybenzenbutanol (5.0 g) and 1,6-dibromohexane (1.38 g) in THF (50 ml). The suspension was refluxed for 20 h and was treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (2×50 ml) and the dried extract was evaporated to leave a yellow oil. The oil was purified on a column of silica (Merck 5385, 600 ml) [A] to give the title compound as a colorless oil (5.6 g). T.l.c. [B] Rf 0.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:36])[CH:19](Br)[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:36])[CH:19]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: COC(=O)C(Br)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A mixture of 2, 4 difluorophenol (0.28 g, 2.18 mmol) and cesium carbonate (0.39 g, 1.19 mmol) in acetonitrilie (20 ml) stirred for 30 mins. A solution of bromo-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.75 g, 1.98 mmol) in acetonitrile (5 ml) was added drop wise at room temperature and stirred further for 2 hrs. Reaction mixture was diluted with ethyl acetate (50 ml), washed with water, 1N NaOH (cold, 50 ml), and brine (50 ml) dried over anhydrous sodium sulfate, filtered and concentrated to provide (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.35 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]2[C:56]([CH3:58])([CH3:57])[O:55][B:54]([OH:59])[C:53]=2[CH:60]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:48][C:49]1[CH:50]=[CH:51][C:52]2[C:56]([CH3:57])([CH3:58])[O:55][B:54]([OH:59])[C:53]=2[CH:60]=1)=[O:6]
Reactant: CC(C)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1(C)OB(O)c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
To a solution of 2-chloro-4-isopropyl-benzoic acid (63 mg, 0.33 mmol) in DMF (4 mL) was added HATU (90 mg, 0.23 mmol) and DIEA (43 mg, 0.33 mmol). After 1 hour 6-amino-3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride salt (50 mg, 0.22 mmol) was added. After 12 hours the reaction was concentrated down under reduced pressure onto celite. The crude material was subjected to flash chromatography (Isco Companion, 4 g SiO2 cartridge, SiO2 solid load, neat DCM to 10% MeOH gradient) to give 2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-isopropyl-benzamide as a white powder. Amount obtained: 6.3 mg (8%). Data: LCMS (M/Z): 358 (M+H); 1H NMR (DMSO-d6) δ: 1.23 (d, J=6.8 Hz, 6 H) 1.44 (s, 6 H) 2.97 (dt, J=13.8, 6.9 Hz, 1 H) 7.29-7.41 (m, 2H) 7.43 (d, J=1.4 Hz, 1 H) 7.49 (d, J=7.8 Hz, 1 H) 7.68 (dd, J=8.3, 1.9 Hz, 1 H) 8.05 (dd, J=1.7, 0.5 Hz, 1 H) 9.08 (br. s, 1 H) 10.45 (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=CC=CC=1.O=CCCC[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:29]([O:28][C:27]([NH:26][CH2:7][CH2:2][CH2:1][N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)CCCN1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCN1CCN(CCCNC(=O)OC(C)(C)C)CC1
Reaction time: 20 h
Yield: 78.2 %

Procedure:
To a solution of methyl 4-(4-benzylpiperazin-1-yl)butanoate (500 mg, 2.68 mmoles) in dichloromethane (5 mL) was added tert-butyl 4-oxobutyl-carbamate (505 mg, 2.68 mmoles) and sodium triacetoxyborohydride (900 mg, 1.5 eq) and stirred 20 h. To the reaction mixture water was added followed by 1M aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate. The organics were evaporated to afford methyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propyl}-piperazin-1-yl)butanoate (0.72 g, 75%). MS (ESI+) for m/z 358 (M+H)+.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1.Cl>CO.O1CCCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][C:9]=1[O:19][CH3:20]
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)NC(=O)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1CC(O)CO)NC(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 117 %

Procedure:
109 mg of 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 4 ml of methanol-tetrahydrofuran (1:1). While cooling on ice, 1 ml of 2 N hydrochloric acid was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, so as to obtain 110 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one. This compound was directly used in the following reaction without further purification.
Reaction SMILES: O[CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].C(N(S(F)(F)[F:19])CC)C.O.[OH-].[Na+]>C(Cl)Cl>[F:19][CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3]
Reactant: CC(O)c1nc2ccccc2[nH]1
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(F)c1nc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
A solution of 3.24 g (0.02 mole) of 1-hydroxyethylbenzimidazole in 50 ml of methylene chloride was added to a solution of 2.44 ml (0.02 mole) of diethylaminosulfur trifluoride in 50 ml of methylene chloride cooled to -78° C. and under a nitrogen atmosphere. The reaction mixture was allowed to warm slowly to room temperature where it was stirred for 4 hours. The mixture was poured into water, the pH adjusted to 8 with aqueous sodium hydroxide solution and the organic layer separated and dried. Removal of the solvent gave 1.25 g of a brown oil which was chromatographed on 100 g of silica gel using 5% methanol chloroform as the eluent, 845 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=4[F:27])=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:30](Cl)Cl>>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:27])=[C:11]3[C:10]([CH3:30])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Reactant: ClCCl
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Yield: 94 %

Procedure:
Prepared according to the procedure of Example 1, Step D, substituting 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7.4 g, 18 mmol) for 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine, and substituting EtOAc for DCM during the workup. The product was obtained as a gum (7.2 g, 94%) and used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=5 Hz, 1H), 7.30 (d, J=9 Hz, 2H), 7.00 (m, 1H), 6.82 (d, J=9 Hz, 2H), 6.54 (m, 1H), 6.48 (m, 1H), 6.16 (d, J=5 Hz, 1H), 5.55 (s, 2H), 3.83 (br s, 2H), 3.75 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C1(C)C=CC=CC=1.I[C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([O:51][CH3:52])[CH:45]=1>COCCOCCOC>[CH3:52][O:51][C:46]1[CH:45]=[C:44]([CH:49]=[C:48]([CH3:50])[CH:47]=1)[O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16]
Reactant: COc1cc(C)cc(I)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: COc1cc(C)cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
(1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (prepared according to Kuchkova et al., Synthesis, 1045-1048, 1997) (0.24 g, 1.0 mmol), Cu(I)I (0.019 g, 0.10 mmol)) and 3,4,7,8-tetramethyl-[1,10]phenanthroline (0.047 g, 0.20 mmol)) were added to an oven dried sealed tube, sealed with a rubber septum, and flushed with a stream of nitrogen for 15 min. Anhydrous toluene (5 mL), anhydrous diglyme (1 mL) and 1-iodo-3-methoxy-5-methylbenzene (2) (0.273 g, 1.10 mmol) were added via a syringe with vigorous stirring under a stream of nitrogen at room temperature. The rubber septum was replaced with the Teflon cap and the sealed tube was heated at 120° C. in an oil bath for 18 h. The reaction was allowed to cool to room temperature, and then quenched with ethyl acetate. The resulting suspension was filtered through a celite pad. The filtrate and the washings were concentrated to dryness. The crude product was purified by flash chromatography (Hexanes/EtOAc, 9:1) to yield (1S,2R,4aS,8aS)-1-(3-methoxy-5-methylphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (4) (0.33 g, 92% yield) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:11]2)=[N:4][C:5]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]2)=[N:6][CH:7]=1
Reactant: OCC1CCNCC1
Reactant: Clc1ncc(Br)c(OC2CN(c3ccc4ccccc4n3)C2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: OCC1CCN(c2ncc(Br)c(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Temperature: 150 °C
Yield: 16 %

Procedure:
To a mixture of 2-(3-((5-bromo-2-chloropyrimidin-4-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.11; 0.1 g, 0.25 mmol) and piperidin-4-yl-methanol (0.028 g, 0.25 mmol) was added DMSO (2 mL) and triethylamine (0.05 g, 0.50 mmol). The solution was heated to 150° C. under microwave for 3 hours. The mixture was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) to give the title product (0.02 g, 0.04 mmol, 17% yield) as white solid. ESI-MS (M+1): 471 calc. for C22H24BrN5O2 470.