Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([C:20]2[N:21]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:22]=[C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:24]=2)O)=[CH:13][CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([C:20]2[N:21]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:22]=[C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:24]=2)[F:7])=[CH:13][CH:12]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)Cc2ccc(Br)cc2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(F)Cc2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylaminosulfur trifluoride (7.01 mL, 53.5 mmol) was added to an ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxyethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.89 g, 10.7 mmol) in methylene chloride (100 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded 2-[2-(4-bromophenyl)-1-fluoroethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:12](#[N:16])[CH2:13][C:14]#[N:15]>>[NH2:16][C:12]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]=1[C:14]#[N:15]
Reactant: N#CCC#N
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Product: N#Cc1c(-c2ccccc2)c[nH]c1N

Procedure:
18.3 g of 2-amino-3-cyano-4-phenylpyrrole (compound a), readily obtained by condensation of 2-aminoacetophenone hydrochloride and malononitrile in the presence of an alkali, and 25.3 g of ethoxyethylidene diethyl malonate were dispersed in 300 ml of ethanol, and 22.0 ml of a solution of sodium methylate in methanol was added to the resulting dispersion, followed by heating under reflux for 5 hours. Thereafter, the reaction mixture was allowed to cool, and ethyl acetate was added thereto. After washing with water, the organic solvent was concentrated to precipitate crystals, which were then collected by filtration to obtain 11.6 g of compound b. Subsequently, 50 ml of fine oxocol 1600 and 2.0 g of titanium isopropoxide (Ti(O-i-Pr)4) were added to the compound b, and the resulting mixture was heated for 6 hours at an oil-bath temperature of 130° C. to 140° C. After being allowed to cool, the reaction mixture was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 14.7 g of coupler (III)-1 in the form of lemon yellow oily matter.
Reaction SMILES: [OH:1][C@H:2]([C:4]1[NH:5][C:6](=[O:19])[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:18][CH2:17]OC[CH2:14]3)[C:8]=2[N:9]=1)[CH3:3].C(O[C@@H](C)C(NC1N(C2CCOCC2)N=CC=1C(=O)N)=O)(=O)C>>[CH:13]1([N:10]2[C:8]3[N:9]=[C:4]([C@@H:2]([OH:1])[CH3:3])[NH:5][C:6](=[O:19])[C:7]=3[CH:12]=[N:11]2)[CH2:14][CH2:17][CH2:18]1
Reactant: C[C@H](O)c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: CC(=O)O[C@@H](C)C(=O)Nc1c(C(N)=O)cnn1C1CCOCC1
Product: C[C@H](O)c1nc2c(cnn2C2CCC2)c(=O)[nH]1

Procedure:
Compound C17 was prepared according to the general procedure for the synthesis of C4 in Example 1, except that C16 was used in place of C3. Additionally, in this case the crude product was purified via silica gel chromatography (Eluant: 50:1 chloroform:MeOH), to afford C17 as a solid. Yield 5.70 g, 24.3 mmol, 87%. LCMS m/z 235.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.64 (d, J=6.6 Hz, 3H), 1.91 (m, 2H), 2.44 (m, 2H), 2.75 (m, 2H), 4.26 (br s, 1H), 4.89 (q, J=6.6 Hz, 1H), 5.25 (m, 1H), 8.06 (s, 1H), 11.07 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.93, 22.42, 29.84, 50.92, 67.67, 104.42, 134.66, 151.71, 159.25, 161.48.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](C2C=CC=CC=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([S:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1Br
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2-[2-({4-[(E)-2-(2,4-Difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1-([2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole was prepared according to the method of Example 135 Step 2 using 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (Step 1) in place of (S)-1-(2-iodophenyl)ethanol and Intermediate 2 in place of Intermediate 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:10][NH:11]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>O1CCOCC1>[ClH:1].[F:24][C:22]([F:23])([F:25])[CH2:21][O:20][N:19]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:10][NH2:11]
Reactant: CC(C)(C)OC(=O)NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 150.3 %

Procedure:
To 4.9 g of tert-butyl N-[2-(3,5-dichloropyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)ethyl]carbamate in 5 ml of 1,4-dioxane, 25 ml of a 1,4-dioxane solution (4 mol/L) of hydrogen chloride was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was washed with 20 ml of hexane to obtain 3.1 g of the desired product as pale brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][NH:11][CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][N:11]([CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:44]([O:46][CH2:47][CH:48]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=2[C:55]2[C:60]1=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:45])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
The product from Example 26B (1.28 g, 2.6 mmol) in tetrahydrofuran (11 mL) was treated with triethylamine (0.39 mL, 2.8 mmol) and 9-fluorenylmethyl chloroformate (0.72 g, 2.8 mmol) at ambient temperature. After stirring for 1 hour, the mixture was concentrated and the residue was dissolved in ethyl acetate (10 mL), wash with 10% NaHCO3 (2×10 mL), 10% citric acid (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with chloroform (1.68 g, 90%). 1H NMR (CDCl3) δ 7.82-6.94 (m, 18H), 4.93 (br s, 1H), 4.66-4.43 (m, 2H), 4.20 (t, 1H), 3.87-3.35 (m, 4H), 3.00-2.20 (m, 7H), 1.38-1.23 (m, 18H); MS (ESI+) m/z 706 (M+H)+.
Reaction SMILES: [CH:1]1[C:23]2=[C:24]3[C:4]4[C:5]([CH:17]=[CH:18][C:19]3=[C:20](S([O-])(=O)=O)[CH:21]=[C:22]2[OH:25])=[C:6](S([O-])(=O)=O)[CH:7]=[C:8](S([O-])(=O)=O)[C:3]=4[CH:2]=1.[Na+:30].[Na+].[Na+].[OH:33][S:34](O)(=[O:36])=[O:35]>O>[OH:25][C:22]1[CH:21]=[CH:20][C:19]2[C:24]3=[C:4]4[C:5]([CH:6]=[CH:7][CH:8]=[C:3]4[C:2]([S:34]([O-:36])(=[O:35])=[O:33])=[CH:1][C:23]=13)=[CH:17][CH:18]=2.[Na+:30]
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])c1cc2c(O)ccc3ccc4cccc1c4c32
Temperature: 150 °C

Procedure:
Referring to Scheme 4, a 50-mL round bottom flask equipped with a magnetic stirring bar was charged with HPTS (9.5 mmols, 5 g) and 30% H2SO4 (35 mL). The mixture was heated at 150° C. for 20 min and then allowed to cool at ambient temp for 10 min. The solution was poured into 100 g of crushed ice and diluted to 200 mL with water. The mixture was extracted with isopropyl acetate (200 mL×4) and concentrated in vacuo. The residue was mixed with silica gel (3 g) and crushed into a fine powder and dry loaded onto a Biotage 40 M cartridge. The residue was purified via gradient elution using 5% MeOH: (5% NEt3:CH2Cl2) to 15% MeOH: (5% NEt3:CH2Cl2) to give the triethylamine salt of 1 (0.281 g). The salt was treated with 1 M HCl and extracted with isopropyl acetate and the isopropyl acetate layer dried over MgSO4 and concentrated in vacuo to give 1 as a brown/green foam. Synthesis of 1 was reported previously by E. Tietze and O. Bayer 1939 Ann 540:189-210. TLC (MeOH: CH2Cl2:NEt3, 2:7:1) Rf=0.23. 1H NMR (500 MHz, CD3OD) δ7.94 (t, J=7.6 Hz, 1H), 7.97 (d, J=9.4 Hz, 1H), 8.02 (d, J=9.2 Hz, 1H), 8.11 (t, J=7.7 Hz, 2H), 8.25 (s, 1H), 8.39 (d, J=9.1 Hz, 1H), 8.98 (d, J=9.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[N:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH:18]([C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]2[C:34]([CH:30]2[CH2:31][CH2:32][CH2:33][O:29]2)=[O:35])[N:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: COc1cc2nc(N3CCN[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCNC(C(=O)NC(C)(C)C)C3C(=O)C3CCCO3)nc(N)c2cc1OC

Procedure:
A solution of (S)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-3-(1,1-dimethylethylamino)carbonyl piperazine (133.2 mg, 0.3429 mmol) was treated with 2-furoyl chloride in dry 1.0 mL THF (14 h). The reaction mixture was concentrated in vacuo and submitted to PCTLC (SiO2, 2 mm, 0-10% CH3OH/CH2 Cl2) providing the desired amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20](=O)[CH3:21])[CH2:16][CH2:15]1.Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:20]([CH:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]3)([CH3:21])[O:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCO)cc1OC
Reactant: CC(=O)C1CCNCC1
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C)(C1CCNCC1)OCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.5 %

Procedure:
A mixture of 200 g of 3,4-dimethoxybenzeneethanol and 163,7 g of 1-(4-piperidinyl)ethanone in 800 ml of ethanol saturated with anhydrous hydrochloric acid was stirred for 15 h at ambient temperature. The mixture was concentrated under vacuum, and the concentrate was diluted with 500 ml of ethanol after which the hydrochloride precipitated. After filtration the hydrochloride was dissolved in water and sodium hydroxide until the pH was 12. The base was extracted with dichloromethane, and the organic phase was washed with water, dried and evaporated to yield 251 g (86,5%) of crude 4-(3,4-dihydro-6,7-dimethoxy-1-methyl-1H-2-benzopyran-1-yl)piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][O:13][CH2:12][C:11](=O)[N:10]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:14][O:13][CH2:12][CH2:11][N:10]([C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)COCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1ccccc1)N1CCOC[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
To a solution of (S)-6-(4-bromophenyl)-4-((R)-1-phenylethyl)-1,4-oxazepan-3-one (1.09 g, 2.91 mmol) in tetrahydrofuran (14.0 ml) was added 1.0M-borane-tetrahydrofuran complex in tetrahydrofuran (6.40 ml, 6.40 mmol) at 0° C. The mixture was stirred at room temperature for 5 hours. After the reaction mixture was cooled to 0° C., methanol (15 ml) and 6.0N-sodium hydroxide (10 ml) was added carefully. The resulting mixture was refluxed for 2 hours and cooled to room temperature. The organic solvent was removed under reduced pressure. The residue was partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant; hexane/ethyl acetate=7/3) to afford (S)-6-(4-bromophenyl)-4-((R)-1-phenylethyl)-[1,4]oxazepane as white solid (1.00 g, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].[Sn].Cl.[OH-].[Na+]>O1CCCC1>[NH2:27][C:26]1[C:17]([NH:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 27.5 °C
Reaction time: 5 h

Procedure:
Methyl 2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate [MBN] (400 kg) obtained in Reference Example 4(3) and tetrahydrofuran [THF] (1080 kg) were mixed, and the MBN solution was stirred. Tin (400 kg) and 35% hydrochloric acid (1322 kg) were mixed, the mixture was stirred at 25 to 30° C. for about 5 hours, warmed to about 80° C. over about 3 hours, and stirred at about 80° C. for about 8 hours. The resulting stannous chloride solution was added dropwise to the MBN solution at 15 to 25° C. over 5 to 8 hours to carry out reduction reaction at 15 to 25° C. for 2 to 5 hours. After completion of the reaction, the pH of solution was adjusted to 12 with 24% sodium hydroxide (about 2000 L) and flaky sodium hydroxide (about 177 kg). The organic layer was separated, and washed twice with an aqueous sodium bicarbonate solution (950 L) and three times with an aqueous saturated sodium chloride solution (840 L). The organic layer was filtered through a 3μ filter, and the solvent was distilled off. The residue was dissolved in ethyl acetate (540 kg), and concentrated again to give concentrate of methyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]animo]benzoate [MBA].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:32]([CH3:31])=[CH:33][CH:34]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.1 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 170 μl (1.25 mmol) of 4-methylbenzoyl chloride, and after purification, 350 mg (70%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4, N-dimethylbenzamide are obtained in the form of a white solid with a melting point of 198° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32]([NH2:34])=O)([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl.CCN(C(C)C)C(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32]#[N:34])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC#N)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl) propanamide (80 mg, 0.166 mmol) in anhydrous CH2Cl2 (5 mL) and DIEA (0.5 mL) was added TFAA (72 mg, 0.332 mmol) at 0° C. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl) propanenitrile (40 mg, yield 54%). 1H NMR (CDCl3): 1.98-2.18 (m, 1H), 2.11-2.40 (m, 4H), 2.51-2.60 (m, 1H), 2.92 (m, 1H), 5.53 (m, 1H), 6.80-6.90 (m, 2H), 6.94 (m, 2H), 7.01 (m, 2H), 7.19 (m, 2H), 7.21 (m, 2H). LC-MS Method 3 tR=1.22 min, m/z=488.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH:36](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.CCOC(C)=O>[CH2:27]([C@H:26]1[C@@H:22]([N:21]2[C:3]3=[C:4]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=5)(=[O:12])=[O:13])[C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[CH:36]2)[CH2:23][C@@H:24]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:32])[CH2:25]1)[CH3:28]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 65 °C
Yield: 79.7 %

Procedure:
A mixture of N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.160 g, 0.309 mmol), trimethyl orthoformate (3.42 mL, 30.9 mmol) and toluene-4-sulfonic acid hydrate (0.006 g, 0.031 mmol) in MeOH (3.1 mL) was heated at about 65° C. for about 1 h then heated at about 60° C. for about 14 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (5 mL), water (5 mL), and brine (5 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide as a yellow solid (0.130 g, 76%): LC/MS (Table 1, Method n) Rt=0.76 min; MS m/z 528 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][N:32]([S:38]([NH:41][C:42]1[S:43][C:44]([F:47])=[CH:45][N:46]=1)(=[O:40])=[O:39])[CH2:33]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[F:47][C:44]1[S:43][C:42]([NH:41][S:38]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[C:19]3[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=3[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)[CH2:33]2)(=[O:39])=[O:40])=[N:46][CH:45]=1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)CC1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.020 g, 0.028 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.078 g, 0.350 mmol), 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.150 g, 0.280 mmol), and potassium phosphate (0.237 g, 1.119 mmol) in 2 mL dioxane 1 mL water, was heated to 110° C. 2 hours. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with 1N citric acid. The organic layer was then concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave N-(5-fluorothiazol-2-yl)-5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.044 g, 0.080 mmol). [M+H]+=553.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.72 (d, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.03-7.14 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.58-6.64 (m, 1H), 5.92 (br. s., 1H), 4.53 (d, J=17.3 Hz, 1H), 4.19 (d, J=17.6 Hz, 1H), 3.71-3.84 (m, 2H), 3.13-3.46 (m, 4H), 2.86-2.99 (m, 1H), 2.75-2.86 (m, 1H), 2.53-2.60 (s, 3H), 1.94-2.19 (m, 2H)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.CN(CCN(C)C)C.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccccc1
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CO
Product: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a mixture of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (90 mg, 0.32 mmol) containing [Cu(OH).TMEDA]2Cl2 (14.95 mg, 0.032 mmol) in dry methanol (5 mL) was added phenylboronic acid (81.0 mg, 0.64 mmol) under an air atmosphere and the resulting mixture stirred at room temperature overnight. After this time, the resulting mixture was diluted with water and extracted with ethyl acetate. The organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=9:1 to 3:2) afforded the title compound (48 mg, 42%) which was obtained as a white solid. MS: m/e 356.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[CH2:10]([NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCCCCCN
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCCCCNc1ccc(C#N)cc1
Yield: 91.9 %

Procedure:
According to the general procedure B, 4-Chlorobenzonitrile (69 mg, 0.50 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 70° C. for 8 h to give the title compound as a solid (79 mg, 78%). On the other hand, the reaction of 4-chlorobenzonitrile (69 mg, 0.50 mmol) with n-hexylamine (61 mg, 0.60) using K3PO4 and DME also occurred in 92% yield to afford the title compound (93 mg) at 100° C. for 13 h. 1H-NMR (300 MHz, CDCl3): δ 7.39 (d, 2H, J=8.4 Hz), 6.54 (d, 2H, J=8.7 Hz), 4.34 (bs, 1H, —NH—), 3.13 (t, 2H, J=6.9 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 151.43, 133.47, 120.60, 111.56, 97.69, 43.03, 31.37, 28.89, 26.55, 22.43, 13.88. GC/MS(EI): m/z 202 (M+).