Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].C(Cl)Cl.CS(C)=O.C(N(CC)CC)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]=[O:13]
Reactant: OCCc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=CCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
In an amount of 515.8 mg of 2-naphthaleneethanol was added with 30 ml of methylene chloride and dissolved therein, added with 6.3 ml of dimethyl sulfoxide, 2.5 ml of triethylamine, and 1.4 g of sulfur trioxide/pyridine complex, stirred at room temperature for 2 hours, then added with 50 ml of water, and extracted with 50 ml of ethyl acetate, and the organic layer was successively washed with 30 ml of saturated aqueous ammonium chloride, and 30 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to obtain 511 mg of 2-(naphthalen-2-yl)acetaldehyde.
Reaction SMILES: I[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C([O-])([O-])=O.[Cs+].[Cs+].[F:52][C:53]1[CH:54]=[C:55]([OH:59])[CH:56]=[CH:57][CH:58]=1>CN1C(=O)CCC1.O>[F:52][C:53]1[CH:54]=[C:55]([CH:56]=[CH:57][CH:58]=1)[O:59][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(I)cnc32)cc1
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Oc4cccc(F)c4)cnc32)cc1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
A solution of tert-butyl 4-(5-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.100 g, 0.182 mmol, see Example 13), Cu(I)Cl (0.00901 g, 0.0910 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (0.00950 mL, 0.0455 mmol), Cs2CO3 (0.119 g, 0.364 mmol) and 3-fluorophenol (0.165 mL, 1.82 mmol) in NMP (2 mL) was stirred at 106° C. for 20 hours. The reaction was then cooled to room temperature, and H2O (5 mL) was added. The reaction mixture was then extracted with ethyl acetate (15 mL), washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 2.5:1) to give tert-butyl 4-(5-(3-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.020 g, 21%) as a solid. MS APCI (+) m/z 534.4 detected.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C@H:28]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:13][CH2:14][C:15](=O)[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[Si:36]([O:35][C@H:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@@H:12]1[NH:11][C@H:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[CH2:14][CH2:13]1)([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccc(CC(=O)CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of the title compound from Step G above (9.00 g, 0.625 mmol) in ethanol (200 ml) was added 3.0 g of 10% Pd/C under argon. The reaction mixture was stirred at 50° C. under a H2 balloon overnight. After filtration and removal of the solvent, 6.0 g (90%) of the title compound was obtained which was directly used for the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ7.89 (d, J=7.9 Hz, 2H), 7.24-7.19 (m, 7H), 4.40 (d, J=7.0 Hz, 1H), 3.82 (s, 3H), 3.26-3.09 (m, 2H), 2.75 (d, J=7.0 Hz, 2H), 1.71-1.63 (m, 2H), 1.33-1.25 (m, 2H), 0.75 (s, 9H), 0.00 (s, 6H). MS: m/z (ESI) 440 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH:14]([CH3:16])[CH3:15])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O.CO>[CH2:1]([O:8][C@@H:9]([CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](OCc1ccccc1)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
To a 50 mL flask containing methyl(S)-2-benzyloxy-3-methylbutanoate (309 mg, 1.39 mmol, 1.0 eq.) (prepared as in Example 24) was added methanol (9 mL). All starting material dissolved. Then a solution of potassium hydroxide in water (1 N, 4.2 mL, 4.2 mmol, 3.0 eq.) was added at ice-water bath temperature. The resulting mixture was stirred at room temperature for 3 days. The reaction was monitored by LC-MS, and almost no SM remained. The reaction mixture was diluted with water (15 mL) and most of methanol was removed under reduced pressure. The aqueous layer was extracted by ether (2×10 mL), and neutralized by hydrochloric acid (1 N, 4.2 mL, 4.2 mmol, 3.0 eq.) to reach pH 3 at 0° C. The cloudy aqueous layer was extracted by ether (5×20 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure to afford crude product (S)-2-benzyloxy-3-methylbutanoic acid (260 mg, 1.25 mmol, 90%). 1H NMR (300 MHz, CDCl3): consistent with proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:6][N:5]=[C:4]2[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=[CH:24][C:3]=12.C(N(C(C)C)CC)(C)C.C(O)C.O.[OH-].[Li+]>[Pd].O1CCOCC1.O>[CH3:14][C:9]([CH3:15])([CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:2]=[C:3]2[CH:24]=[N:23][N:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]2=[N:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1Cl
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)O)C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1
Reaction time: 1.33 h
Yield: 67.2 %

Procedure:
A mixture of methyl 3-(4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,2-dimethyl-3-phenylpropanoate (27 mg, 0.064 mmol), palladium (10% on carbon, 10 mg), diisopropylethylamine (0.017 mL, 0.096 mmol), and ethanol (3 mL) was stirred under hydrogen balloon for 80 min. The mixture was then filtered through a pad of silica gel and concentrated. The residue was mixed with lithium hydroxide monohydrate (30 mg, 0.7 mmol), water (1 mL), and dioxane (1 mL), and stirred at 110° C. overnight. After cooled, the mixture was partitioned between water and diethyl ether. The ether layer was extracted with water. Combined aqueous solutions were acidified with 10% citric acid aqueous solution and extracted with ethyl acetate. Combined extracts were washed with brine, dried (Na2SO4) and concentrated to give 2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)propanoic acid (16 mg, 0.043 mmol, 69% yield).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@H:10]([OH:11])[CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C@H:6]1[O:16][CH:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2]>ClCCl>[C:1]([NH:4][C@@H:5]1[C:10](=[O:11])[CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C@H:6]1[O:16][CH:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C[C@@H](OC(C)C)[C@H](NC(C)=O)[C@H](O)C1
Solvent: ClCCl
Product: COC(=O)C1=C[C@@H](OC(C)C)[C@H](NC(C)=O)C(=O)C1
Reaction time: 8 h

Procedure:
PCC/Al2O3 can be added to a room temperature solution of Example 13L in dichloromethane. After stirring overnight, the reaction mixture can be filtered and concentrated. The concentrate can be purified by flash chromatography using ethyl acetate to afford the desired product.
Reaction SMILES: C(O)C.[OH-].[Na+].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].Cl>O>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)COc1cccc(-c2ccco2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cccc(-c2ccco2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
10 mL of ethanol and 4.0 mL of 1N aqueous sodium hydroxide solution were added to 615 mg (2.50 mmol) of ethyl [3-(furan-2-yl)phenoxy]acetate, and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid was added to acidify the reaction mixture, and water was added thereto. The precipitated solids were collected by filtration, washed with water, and air-dried, thereby giving 448 mg of [3-(furan-2-yl)phenoxy]acetic acid (yield: 82%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH3:32][CH:33]([O:35][CH2:36][CH2:37][NH2:38])[CH3:34]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:38][CH2:37][CH2:36][O:35][CH:33]([CH3:34])[CH3:32])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CC(C)OCCN
Product: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-[(1-methylethyl)oxy]ethanamine employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.67 (1H, br), 8.16 (1H, br s), 7.27 (3H, m), 7.10 (2H, t, J=9 Hz), 4.93 (2H, s), 4.00 (2H, s), 3.54 (1H, m, J=6 Hz), 3.40 (2H, m), 3.31 (2H, m), 3.08 (3H, s), 2.78 (3H, s), 1.08 (6H, d, J=6 Hz); HRMS calcd for C25H29FN4O5+H+: 485.2200. Found: 485.2205.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccc(N)cc1F
Product: COc1ccc(Nc2ccccc2CC(=O)O)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-fluoro-4-methoxyaniline to yield 2-[(3-fluoro-4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]>>[OH:8][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10][C:9]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:17]
Reactant: O=C1Cc2ccccc2O1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)Cc2ccccc2O)CC1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 101.7 %

Procedure:
N-Methylpiperazine (1.52 g) was added to 2-coumaranone (2.01 g) and stirred for 3.5 hours at 85° C., thereby yielding the entitled compound (3.57 g) as pale brown solid.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:16]=[C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:11][CH:10]=2)[O:15][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(SC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.45 g (18.0 mmol) 3-(4-Trifluoromethylsulfanyl-phenyl)-acrylamide, 2.80 g (22.2 mmol) 1,3-dichloroacetone and 50.0 ml toluene were kept at reflux temperature for 40 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 1:1). All fractions containing the product were concentrated to a volume of 10 ml and the crystallized material isolated by filtration, washed with cold heptane and dried. Yield 2.02 g (35%) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=3[C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:35]=4[CH3:44])[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[C@H:10]2[CH3:45])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:17]=3[C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:35]=4[CH3:44])[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[C@H:10]2[CH3:45])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(Cl)cc(Cl)c2)[C@@H]1C

Procedure:
Methyl 2″-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (EXAMPLE 26) (50 mg, 0.076 mmol), aqueous potassium hydroxide (600 μL, 3M, 1.8 mmol) and ethanol (4 mL) were stirred at 20° C. for 6 hours. The reaction mixture was acidified by HCl (aq., 1N) and then basified by sodium bicarbonate. Volatiles were removed under reduced pressure. The resulting mixture was worked up with ethyl acetate, washed with brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford an oil. The oil was purified by preparative TLC (eluted with EtOAc/hexanes) to afford 2″-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=643.11; found=644.14 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 8.01 (d, J=5.5 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.65-7.61 (m, 1.5H), 7.44-7.37 (m, 3H), 7.34-7.31 (m, 1H), 7.29 (d, J=8.0 Hz, 0.5H), 7.29 (d, J=8.0 Hz, 0.5H), 7.27-7.24 (m, 0.5H), 7.14 (dd, J=7.0, 2.5 Hz, 1H), 7.09-7.03 (m, 1.5H), 7.00 (dd, J=8.25, 2.0 Hz, 1H), 5.42 (d, J=8.5 Hz, 0.55H), 5.17 (d, J=8.0 Hz, 0.45H), 4.92 (d, J=16.0 Hz, 0.55H), 4.86 (d, J=16.0 Hz, 0.45H), 4.18 (d, J=15.5 Hz, 0.55H), 3.96 (d, J=15.5 Hz, 0.45H), 3.86 (s, 3H), 3.75-3.66 (m, 1H), 2.38, 2.34 (s, 3H), 0.56 (d, J=6.5 Hz; 1.35H), 0.44 (d, J=6.5 Hz, 1.65H).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:18][C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:34])[F:35])=[CH:21][CH:22]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A6) (370 mg, 1.2 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (397 mg, 1 equiv), sodium triacetoxyborohydride (400 mg, 1.5 equiv), DCM (10 ml) and acetic acid (0.076 ml, 1 equiv) was combined and stirred at room temperature until LCMS confirmed disappearance of the amine starting material (approx. 18 hours). Aqueous sodium carbonate was added and then extracted with DCM. The organics were dried over sodium sulfate and concentrated to give a solid (420 mg) that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[NH:4][C:3]1=S.O=S(Cl)[Cl:17]>>[Cl:17][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=S)[nH]c2cc([N+](=O)[O-])ccc21
Product: Cn1c(Cl)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
The compound 1-Methyl-5-nitro-1,3-dihydro-benzoimidazole-2-thione (5.8 g, 27.9 mmol) was heated to reflux with SOCl2 (30 ml) overnight. The reaction mixture was cooled to room temperature and poured into 300 ml of ice water and extracted with CH2Cl2. The organic layers was washed with 10% NaHCO3 water solution, brine, dried over Na2SO4 and concentrated to give the title compound as a yellow solid. MS (ESI) m/z=212 [M+H].
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].[C:5]1([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]([OH:15])[CH2:13]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:1][N:2]([CH2:13][CH:12]([OH:15])[CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH3:4]
Reactant: CCNC
Reactant: OC(CBr)C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCN(C)CC(O)C(c1ccccc1)c1ccccc1

Procedure:
Excess N methyl-N-ethylamine was added to a solution of 1,1 -diphenyl-3-bromo-propan-2-ol (2 g.) in ethanol. After 60 hours the solution was evaporated and the residue was evaporated and the residue dissolved in dilute hydrochloric acid and ether. Basification of the acid extract and subsequent isolation through ether in the usual manner gave 3-(N-methyl-N-ethylamino)-1,1 -diphenyl-propan-2-ol isolated as the hydrochloride (1 25 g., 60%), m.p. 159° - 161°.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])/[CH:34]=[CH:35]/[C:36]([O:38]C)=[O:37])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].O1CCOCC1>[OH-].[Na+]>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(OCCNC(=O)/C=C/C(=O)OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)/C=C/C(=O)O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 39.6 %

Procedure:
0.2 g (0.4 mmol) of (S,E)-N-(a-ethylbenzyl)-3-[2-(3-methoxycarbonylpropenoyl) aminoethoxy]-2-phenylquinoline-4-carboxamide (compound of Example 18) were dissolved in 25 ml of 10% NaOH and 5 ml of 1,4-dioxane and warmed to 60° C. for 15 minutes. After cooling, the reaction mixture was extracted with CH2Cl2 and washed with 10% citric acid and sat. sol. NaCl. The organic layer was dried over Na2SO4, evaporated in vacuo to dryness and triturated with i-Pr2O to yield 83 mg of the title compound.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].C=O.N1C2C=CC=C[C:21]=2N=N1.O>C(O)C.O1CCCC1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][CH3:21]
Reactant: c1ccc2[nH]nnc2c1
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Agent: C=O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CNc1cccc2cc(C3=NCCS3)[nH]c12
Yield: 31.3 %

Procedure:
2-(4,5-Dihydro-1,3-thiazol-2-yl)-1H-indole-7-amine (1.08 g), aqueous formaldehyde solution (37%, 372 μL) and benzotriazole (595 mg) were dissolved in ethanol (15 mL) and tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give a yellow oil (360 mg, yield 31%). M+1=232.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([NH2:12])[S:8][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1COCC1.CN(C1C=CN=CC=1)C>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:9]2[S:8][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)cc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)cc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-amine (100 mg, 392 mmol) in THF (5 ml) with triethylamine (0.049 ml, 0.9 eq.) and DMAP (5 mg, 0.1 eq) was stirred together at 0° C. under an argon atmosphere. To this was slowly added 4-fluorobenzoyl chloride (0.038 ml, 314 mmol, 0.8 eq.) and the mixture stirred to 20° C. over 2 h. The mixture was then evaporated to dryness and chromatographed over silica gel eluting with a gradient of heptane/EtOAc (6:1 to 2:1). The product fractions were pooled and evaporated to afford the title compound (74 mg, 50% yield) as a yellow solid MS: m/e=378.3 (M+H+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)#[N:14].C1(CBr)CC1>C1COCC1>[C:13]([C:15]1([CH2:1][CH:2]2[CH2:4][CH2:3]2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: [Li]CCCC
Agent: BrCC1CC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium in hexanes (1.6M, 11.2 mL, 17.9 mmol) was added dropwise to diisopropylamine (2.5 mL, 17.8 mmol) in THF (20 mL) cooled in an ice bath. After stirring for 0.5 h, the solution was cooled in a dry-ice bath and a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (I-1) (2.50 g, 11.9 mmol) in THF (20 mL) was added dropwise. The solution was stirred in a dry-ice bath for 1 h then cyclopropylmethyl bromide (1.27 mL, 13.1 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 h then quenched with water. The mixture was extracted with DCM (3×). The combined organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Biotage chromatography (5-10% ethyl acetate-hexanes) afforded tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) as a colourless oil. 1H NMR (500 MHz, CDCl3): δ 4.12 (br s, 2H), 3.05 (br s, 2H), 2.02 (m, 2H), 1.52 (d, J=7.0, 2H), 1.46 (s, 9H), 0.89 (m, 1H), 0.58 (m, 2H), 0.19 (m, 2H).