Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)=[O:8])[C@@H:4]([CH3:6])[OH:5].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.Cl>>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:2][C@@H:3]([C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH2:11][CH2:10]1)=[O:8])[C@@H:4]([CH3:6])[OH:5])=[O:33])=[CH:26]2
Reactant: C[C@@H](O)[C@@H](N)C(=O)N1CCN(C2CCN(C)CC2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: C[C@@H](O)[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(=O)N1CCN(C2CCN(C)CC2)CC1

Procedure:
Prepared from 1-(D-allo-threoninyl)-4-(1-methylpiperidin-4-yl)piperazine hydrochloride and 5-chloroindole-2-carboxylic acid using methods substantially equivalent to General Coupling Method 1. The HCl salt is prepared following Salt Formation Method 1. The final crude product is treated with aqueous 0.2 N HCl and purified via prep-HPLC (80:20 to 40:60 0.01% HCl in water:acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17]C.[OH-].[K+].CS(C)=O>O>[Cl:1][C:2]1[N:6]=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[OH:17])[N:3]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cnc(Cl)n2)c(O)c1
Temperature: 100 °C
Yield: 14.4 %

Procedure:
A mixture of 3-chloro-1H-1,2,4-triazole (2.76 g, 26.7 mmol), 1-chloro-2-methoxy-4-nitrobenzene (5.0 g, 26.7 mmol), potassium hydroxide flakes (1.496 g, 26.7 mmol), and DMSO (25 mL) was heated in a sealed reaction vessel 100° C. for 24 h. The reaction was allowed to cool to rt and additional portions of 3-chloro-1H-1,2,4-triazole (1.38 g, 0.5 equiv) and potassium hydroxide (0.75 g, 0.5 equiv) were added. The reaction vessel was resealed and heated to 110° C. for an additional 24 h. The resulting mixture was allowed to cool to rt and was poured into 500 mL of water. The aqueous mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-5% MeOH/chloroform, linear gradient over 144 min, flow 25 mL/min) to afford 2-(3-chloro-1H-1,2,4-triazol-1-yl)-5-nitrophenol (0.924 g, 3.84 mmol, 14.4% yield). LC-MS (M+H)+=241.0. 1H NMR (500 MHz, CDCl3) δ ppm 11.97 (br. s., 1H) 9.24 (s, 1H) 7.90-7.95 (m, 1H) 7.89 (d, J=2.44 Hz, 1H) 7.84 (dd, J=8.85, 2.44 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([OH:25])([C:21]([F:22])([F:23])[F:24])[CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[O:11])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSc1ccc(C(C)=O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CSc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 45.5 %

Procedure:
0.50 g (3.01 mmol) of 1-(4-(methylthio)phenyl)ethanone, 0.73 g of (3.01 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.46 g of toluene and 0.17 g (0.90 mmol) of tributylamine were fed and the mixture was stirred for 15 hours at 60° C. After leaving the reaction mixture for one night at room temperature, separation operation was performed by adding 30 ml of ethyl acetate and 10 ml of water, and the ethyl acetate phase was washed with diluted aqueous solution of hydrochloric acid. After removing the solvent by distilling under reduced pressure, the residue was purified by silica gel column chromatography to obtain 0.56 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl)butan-1-one (yield 45.2%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][CH:17](O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH:17]([CH3:16])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COc1ccc(C(C)O)cc1
Product: COc1ccc(C(C)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1

Procedure:
Similarly, 4,6-di-t-butyl-2-(α-methyl-4-methoxybenzyl) phenol was prepared from 2,4-di-t-butylphenol and α-methyl-4-methoxybenzyl alcohol. A yellow oil (b.p. 180° at 1.0 mm Hg) which crystallized was obtained. The product was recrystallized from methanol to give colorless needles melting at room temperature (Found: C, 81.0; H, 9.45 Calc. for C23H32O2 : C, 81.1; H, 9.47%). The pmr spectrum determined as above exhibited the following: δ1.35, 9H, S; δ1.37, 9H, S; δ1.63, 3H, D (J=7 Hz); δ3.78, 3H, S; δ4.17, Q, 1H (J=7 Hz); δ4.62, 1H, S; δ6.84, 2H, D (J=8 Hz); δ7.10-7.30, 4H, M.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(NCO)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCl)c1ccccc1C(F)(F)F
Yield: 100.6 %

Procedure:
To 15.50 g of N-hydroxymethyl-2-(trifluoromethyl)benzamide in 200 ml of dichloromethane, 16.83 g of thionyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the precipitated solid was washed with 50 ml of hexane to obtain 16.90 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1[C:18]2[N:17]([CH2:19][CH:20]([OH:29])[CH2:21][NH:22][CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:15]1[C:16]2[N:17]([CH2:19][CH:20]([OH:29])[CH2:21][N:22]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[S:2]([CH3:1])(=[O:4])=[O:3])[C:18]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccco1)CC(O)Cn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Methanesulfonyl chloride (0.650 mL, 8.4 mmol) was added dropwise to a cold stirring solution of 1-(9H-carbazol-9-yl)-3-((furan-2-ylmethyl)amino)propan-2-ol (2.7 g, 8.4 mmol) and triethylamine (1.3 mL, 9.2 mmol) in anhydrous methylene chloride (55 mL), which was kept at 0-5° C. with an external ice bath. The solution was stirred at 0° C. for 2 hours and then diluted with methylene chloride and successively washed with 0.25N aqueous hydrochloric acid twice, water, and saturated aqueous sodium chloride. The organics were dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-10% ethyl acetate in methylene chloride) to give the desired product as a white solid (1.5 g, 45%). 1H NMR (d6-DMSO, 300 MHz) δ 8.09-8.06 (d, 2H, J=8.1 Hz), 7.42-7.37 (m, 5H), 7.18-7.14 (m, 2H), 6.37-6.35 (dd, 1H, J=1.8, 3 Hz), 6.31-6.30 (d, 1H, J=3 Hz), 4.52-4.39 (dd, 2H, J=15.9, 24.6 Hz), 4.39-4.30 (dd, 1H, J=3.3, 14.4 Hz), 4.22-4.10 (m, 1H), 4.20-4.05 (br m, 1H), 3.40-3.33 (m, 1H) 3.26-3.17 (m, 1H), 2.90 (s, 3H). ESI (m/z): 398.9 (M+H). HPLC analysis: (C18, 10-90% acetonitrile in water+0.1% trifluoroacetic acid over 10 min: retention time, % area at 254 nm): 8.6 min, 97.9%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].C(OC(N1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=O)C>O1CCCC1>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][N:8]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[CH3:11]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(CCCN)OCC
Solvent: C1CCOC1
Product: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
A solution of 4-aminobutyraldehyde diethyl acetal (48.5 g, 0.3 mol) in tetrahydrofuran (60 ml) was added dropwise to a stirred slurry of N-(ethoxycarbonyl) phthalimide (65.93 g, 0.3 mol) in tetrahydrofuran (250 ml) at 0° C. After stirring at 0° C. for 0.16 h and at room temperature for 18 h the solvent was removed in vacuo and the residue distilled at 1 mmHg to remove the ethyl carbamate by-product. The residual brown oil was allowed to cool to afford the title compound (91 g, 93%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]1[C:15]2([C@H:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][NH:17][CH2:16]2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:23]([O:22][C:21]([NH:20][C@H:19]1[C:15]2([CH2:14][CH2:13][CH2:12]2)[CH2:16][N:17]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:18]1)=[O:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC12CCC2
Reaction time: 0.75 h

Procedure:
Benzyl chloroformate (0.224 mL, 1.569 mmol) was added dropwise to a stirred solution of (S)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.2368 g, 1.046 mmol) in dichloromethane (7 mL) and a solution of sodium carbonate (69.1 mg, 0.652 mmol) in Water (1.05 mL) @ 0° C. Stirring of the biphasic reaction was continued @ 0° C. for 45 minutes. +/−MS analysis after 16 hrs indicated that essentially no starting material remained (m/e 361.3, M+H for desired product). A small amount of water was added and the layers were separated. The CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to yield 0.433 g of the desired product as a viscous yellow oil. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 12 g column), eluting with 100 mL ea of 95:5, 90:10, and 200 mL of 80:20 hexane:EtOAc yielded 0.324 g of the title compound as a viscous colorless oil that slowly solidifies upon standing under vacuum to a white solid. +/−MS: m/e 361.3 (M+H), 305.2 (M+H-56 isobutylene), 261.2 (M+H-Boc). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.45-7.32 (m, 5H), 5.15 (s, 2H), 4.53 (br. s., 1H), 4.14-4.01 (m, 1H), 3.70-3.50 (m, 2H), 3.47-3.24 (m, 2H), 2.19-2.09 (m, 1H), 2.05-1.83 (m, 5H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:6]2[N:13]([CH3:14])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>CC(O)=O.C(Cl)Cl.[Fe]>[CH3:14][N:13]1[C:6]2[C:5]([O:4][C:3]3[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:2]=3[F:1])=[N:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12]1
Reactant: Cn1ccc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-5H-pyrrolo[3,2]-4 pyrimidine (29) (253.6 mg, 0.879 mmol) in AcOH (3 mL) at 90° C. was added iron powder (245 mg, 4.4 mmol). The mixture was stirred vigorously for 10 min and filtered. The filtrate was concentrated under reduced pressure to produce a solid, which was dissolved in DCM. The resultant solution was washed with cold NaHCO3 solution and water, dried over Na2SO4 and concentrated to provide a residue which was purified by column chromatography (eluent MeOH—CH2Cl2 1:20) to afford the title compound 30 as a brown solid (120.6 mg, 53% yield). LRMS (M+1) 240.1 (100%).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[C:30]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][NH:29][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCC(c2ccccc2)c2ccccc2)nc1
Yield: 67.6 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 536 mg, 2.00 mmol), 2,2-diphenylethylamine (473 mg, 2.40 mmol), Ti(iPrO)4 (1.14 g, 4.00 mmol), TiCl4 (1.0 M/DCM, 4.00 ml, 4.00 mmol), and NaBH3CN (251 mg, 4.00 mmol) gives the title compound (608 mg) as a white solid. Mass spectrum (ion spray): m/z=450 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.14 (d, 1H), 7.33-7.18 (m, 11H), 6.98-6.90 (m, 3H), 5.85 (br. s, 2H), 4.33-4.23 (m, 2H), 3.41-3.31 (m, 2H), 2.95 (m, 1H), 2.81 (m, 1H), 2.46 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[CH:22]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:24]3)[CH:15]1[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:25])=[O:3])=[CH:14][CH:13]=1)[CH2:23]2
Reactant: CCOC(=O)CCCOc1ccc(C2C3CC4CC(C3)CC2C4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1ccc(C2C3CC4CC(C3)CC2C4)cc1
Reaction time: 24 h

Procedure:
A solution of 7.2 g of 4-[4-(2-adamantyl)-phenoxy]butyric acid ethyl ester in 150 ml of ethanol is mixed with 150 ml of sodium hydroxide solution and the mixture is left to stand for 24 hours at 30° C. The reaction solution is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 100 ml of 2 N Hydrochloric acid and twice 100 ml of ether. The organic phases are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Recrystallisation of the evaporation residue from ethanol gives 4-[4-(2-adamantyl)-phenoxy]-butyric acid of melting point 163°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:13]/[C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 98.4 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (5.0 g, 27 mmol) in 42 mL of ethanol was added methyl 4-aminobenzoate (4.07 g, 27 mmol), and the reaction mixture was stirred over weekend. The yellow precipitates were filtered, and 8.47 g of (E)-methyl 4-(4-chloro-3-nitrobenzylidenamino)benzoate a yellow solid was obtained. (Yield=98%). (E)-methyl 4-(4-chloro-3-nitrobenzylideneamino)benzoate (8.47 g, 26.6 mmol) and yttrium(III) trifluoromethanesulfonate (800 mg, 1.33 mmol) was dissolved in dry tetrahydrofuran (100 mL), and then cooled below 0° C. Isobutyl aldehyde (2.30 g, 31.9 mmol) was added below 0° C. The reaction mixture was stirred at room temperature overnight. Thin layer chromatography showed most of starting material was consumed. 50 mL of ethyl acetate and 50 mL of water were added to the mixture, and the separated organic layer was washed with brine again. The organic layer was dried over sodium sulfate and purified on silica gel to afford 4.9 g of methyl 2-(4-chloro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. (Yield=47%). MS (ESI+APCI) M+1=373.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].Br[CH2:27][CH3:28]>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH2:27][CH3:28])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CCBr
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Product: CCCN(CCC)C1Cc2cc(OCC)c(OS(=O)(=O)C(F)(F)F)cc2C1

Procedure:
Using procedure 38, 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 1.9 g, 5 mmol) was treated with bromoethane (2.2 g, 20 mmol). Chromatographic purification yielded pure product 73 as a oil which was converted into the HCl salt and crystallized from EtOAc/hexane to give a white solid (mp 181-182 ° C.)
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([C@H:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Product: C[C@@H](N[C@@H]1CCCNC1)c1cccc2ccccc12
Reaction time: 40 h
Yield: 96.6 %

Procedure:
To a solution containing 24.2 g of benzyl(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10% wet), and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 40 hours. Palladium carbon was removed, and the solvent was evaporated, the residue washed with ethyl acetate-chloroform (10:1), and collected by filtration to obtain 15.3 g of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-piperidine (the following Reference example Table, Reference example 3.001(a)). MS·APCI (m/z): 255 [M+H]+ (7) By using 14.5 g of benzyl(S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (5) to obtain 4.74 g of benzyl(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS·APCI (m/z): 389 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=3)[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.37 g of 2-butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone in 115 ml of acetone is added 1.58 g of 4-bromobenzyl bromide and 2.18 g of anhydrous potassium carbonate. The resulting suspension is heated to reflux for 16 hours. The reaction mixture is then allowed to cool to room temperature, filtered and the filtrate is concentrated in vacuo. The residue is purified by HPLC eluting with ethyl acetate/hexanes (1:3) to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A mixture 4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (9.6 g, 16.1 mmol) in 4 M HCl in dioxane (60 mL), and water (15 mL) was heated at 100° C. for 20 h. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the desired product. 1H NMR (400 MHz, CDCl3) δ 11.1 (s, 1 H), 8.22-8.14 (m, 2 H), 8.00-7.97 (m, 1 H), 7.72-7.65 (m, 3 H), 7.33 (d, J=7.2 Hz, 1 H), 3.04 (s, 3 H); Mass spectrum m/z: 553.40 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:21][CH2:20]3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)c(Cl)c3)CC2)cn1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
Add 3-chloro-4-fluorobenzeneboronic acid (71 mg, 0.41 mmol) to a mixture of 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (104 mg, 0.34 mmol), potassium carbonate (113 mg, 0.82 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (0.002 g, 0.002 mmol) in N,N-dimethylacetamide (2 mL) and water (1 mL). Purge with nitrogen and heat overnight at 110° C. Cool to room temperature, add water (10 mL), extract with DCM (3×20 mL), combine and purify using high pH reverse phase HPLC to give title compound (76 mg, 57.7%). MS (ES): m/z=387 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1>CS(C)=O>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:25]4[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC(=O)NC1CCNC1
Solvent: CS(C)=O
Product: CC(=O)NC1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and N-pyrrolidin-3-yl-acetamide with DMSO as a solvent. 1H NMR (400 MHz, DMSO-d6): δ 8.73-8.76 (m, 1H), 8.17-8.18 (m, 1H), 7.72-7.75 (m, 1H), 7.49-7.56 (m, 2H), 6.96-6.99 (m, 1H), 4.34-4.35 (m, 1H), 3.71-3.76 (m, 1H), 3.59-3.63 (m, 2H), 3.38-3.40 (m, 1H), 3.22-3.25 (m, 2H), 2.15-2.20 (m, 1H), 2.01-2.07 (m, 2H), 1.73-1.94 (m, 9H), 1.29-1.32 (m, 2H). m/z: 465.2 [M+H]+
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([OH:17])=[O:16].[CH3:18]O>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)cc1F

Procedure:
Sulfuric acid (3.35 mL) was added to a stirred solution of 2,4-difluorophenylacetic acid ([CAS 81228-09-3], 3.5 g, 20.33 mmol) in MeOH (70 mL) at RT. The mixture was stirred at reflux for 18 h. The methanol was removed in vacuo. The residue was diluted with EtOAc and washed successively with H2O, sat. aq. NaHCO3 and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield I-24 (3.34 g, 88%) as a light yellow oil.