Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.1 g) and triethylamine (0.026 mL) in dichloromethane (3 mL) was added methanesulfonyl chloride (0.013 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.11 g). This material was dissolved in a solution of acetonitrile (2 mL) and methanol (2 mL). To the solution were added 3-benzylaminopropionamide (46 mg) and sodium iodide (24 mg), and the mixture was stirred at 60° C. for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give the title compound (78 mg).
Reaction SMILES: [NH2:1][C:2](=[C:8]1CNC(=O)[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[NH:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O[CH:23]([O:27]CC)[N:24]([CH3:26])[CH3:25])C.[C:30](OCC)(=O)C>>[CH3:26][N:24]1[C:23](=[O:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:11][C:10]=2[N:9]2[CH:30]=[N:1][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:25]1
Reactant: CCOC(=O)C(N)=C1CNC(=O)c2ccccc2N1
Reactant: CCOC(C)=O
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
4.1 g of ethyl α-amino-1,3,4,5-tetrahydro-5-oxo-2H-1,4-benzodiazepin-2-ylidene-acetate are dissolved in 25 ml of ethyl acetate, treated with 3.1 ml (18.1 mmol) of N,N-dimethylformamide diethyl acetal and heated to boiling under reflux for 0.5 hour. After cooling, the separated material is filtered off under suction and recrystallised from ethanol. After chromatography of the mother liquor, there is obtained a second portion of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of the same purity; melting point 166°-168° C.
Reaction SMILES: [C:1]1([C@H:7]([NH2:16])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[BH4-].[Na+].Cl>C(O)C>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:16][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(C[C@@H](N)c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C[C@@H](NCc2ccc(O)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
21.13 g (0.1 mole) of (R)-(-)-α-phenyl-β-p-tolylethylamine (optical purity: 100%) and 12.82 g (0.105 mole) of p-hydroxybenzaldehyde were dissolved in 750 ml of ethyl alcohol. The reaction solution thus obtained was stirred at room temperature for 3 hours, and then stirred under reflux for 1 hour. Thereafter, the reaction solution was admixed at room temperature with 1.89 g (0.05 mole) of sodium borohydride, stirred for 3 hours, and then stirred under reflux for 1 hour. The reaction mixture was admixed with 75 ml of a 10% hydrochloric acid, and then concentrated under reduced pressure to give a crude (R)-(+)-N-p-hydroxybenzyl-α-phenyl-β-p-tolylethylamine.HCl salt, which was thereafter neutralized with an aqueous sodium hydroxide solution. The resultant solution was concentrated under reduced pressure to obtain the crystals, which were then recrystallized from ethyl alcohol, so that 20.47 g of (R)-(+)-N-p-hydroxybenzyl-α-phenyl-β-p-tolylethylamine were obtained as colorless crystals. Yield: 64.5%. m.p. 129.5°-130° C.; α!D25 +21.2° (C 1.0, CHCl3) NMR-spectral data (δ ppm, CDCl3) 2.29 (s) 3H; 2.94 (d) 2H; 3.49 (d) 2H; 3.89 (t) 1H; 3.37 (s) 2H; 6.35-6.90 (m) 4H; 6.99 (s) 4H; 7.30 (s) 5H
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:14]([C:22]1([C:28](O)=[O:29])[S:27][CH2:26][CH2:25][CH2:24][S:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].S1CCCSC1C(O)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C(Br)CCCCCCC>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:28]([C:22]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:23][CH2:24][CH2:25][CH2:26][S:27]2)=[O:29])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CCCCCCCCC1(C(=O)O)SCCCS1
Reactant: COc1ccc2ncccc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)C1SCCCS1
Agent: [Na+]
Solvent: CCCCCCCCBr
Product: CCCCCCCCC1(C(=O)Nc2c(OC)ccc3ncccc23)SCCCS1

Procedure:
5-Amino-6-methoxyquinoline, prepared as described in Example 60, was coupled with 2-octanyl-1,3-dithiane-2-carboxylic acid, prepared by treatment of 1,3-dithiane-2-carboxylic acid with sodium hexamethyldisilazide and octanyl bromide, according to the procedure described in Example 48 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[CH:9][CH:10]=1)[C:5]([O:7][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of Example 104B (5 g, 15.1 mmol), potassium carbonate (3.1 g, 22.7 mmol), and DMF (150 mL) was treated with benzyl bromide (1.8 mL, 15.1 mmol), stirred for 5 hours, and concentrated. The residue was partitioned between water (1 L) and dichloromethane (750 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered, concentrated, and purified by passing through a plug of silica gel (150 g) with 25% dichloromethane in hexane to provide the desired product. MS (ESI(−)) m/e 418, 420 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.05 (br s, 1H), 7.65 (d, 1H), 7.45 (m, 2H), 7.39 (m, 3H), 7.21 (d, 1H), 5.28 (s, 2H), 2.30 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][NH2:14])=[CH:5][NH:6]2.[F:15][C:16]([F:28])([F:27])[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(O)(=O)C.C(O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][NH:14][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:17][C:16]([F:15])([F:27])[F:28])[CH:20]=1)=[CH:5][NH:6]2
Reactant: NCCc1c[nH]c2c(F)ccc(F)c12
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1ccc(F)c2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Combine 2-(4,7-difluoro-1H-indol-3-yl)ethylamine (483 mg, 2.46 mmol) and ethanol (45 mL) and stir. After 10 minutes treat with 3-(2,2,2-trifluoroethoxy)benzaldehyde (502 mg, 2.46 mmol) and anhydrous sodium sulfate (3.5 g) and stir under nitrogen and heat at 70° C. After 2 h., cool the reaction vacuum filter to remove the sodium sulfate and treat with sodium borohydride (279 mg, 7.38 mmol) in a 500 mL round bottom flask equipped with magnetic stirring. Allow the solution to stir for 2 hours at room temperature and then carefully treat with three drops of glacial acetic acid to quench the excess hydride. Remove the solvent in vacuo and re-dissolve the crude material in methanol. Purify by a 10 g SCX column by washing thoroughly with methanol, eluting with 2N ammonia in methanol, and concentrating in vacuo to give the title compound as a straw colored oil. Prepare the hydrochloride salt by dissolving the free base (800 mg, 2.08 mmol) in methanol (15 mL) and treating with a solution of ammonium chloride (111 mg, 2.08 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes before concentrating in vacuo to give a white solid. Recrystallize from ethyl acetate to obtain the hydrochloride salt of the title compound: mp 208.5–210.0° C.; 1H NMR (400 MHz, dmso-d6): 11.79 (br s, 1H), 9.21 (br s, 2H), 7.39 (t, 1H, J=7.8 Hz), 7.32 (d, 1H, J=2.0 Hz) 7.30 (s, 1H), 7.18 (d, 1H, J=8.0 Hz), 7.11 (dd, 1H, J=2.6, 8.2 Hz), 6.85–6.91 (m, 1H), 6.67–6.73 (m, 1H), 4.77 (q, 2H, J=8.8 Hz), 4.16 (s, 4H), 3.12–3.16 (m, 4H); MS (APCI): m/e 385.1 (M+1); CHN (for C19H17F5N2O.HCl) calcd: C, 54.23, H 4.31, N, 6.66; found: C, 54.20, H 4.30, N 6.66.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:3]=1[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:27])C=1.S(=O)(O)[O-].[Na+].[OH2:35]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)(=[O:27])=[O:35])[C:3]=1[C:4]#[N:5]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(Sc2cccc(F)c2C#N)c1
Agent: O=S([O-])O
Agent: [Na+]
Product: COc1cccc(S(=O)(=O)c2cccc(F)c2C#N)c1

Procedure:
To a solution of 2 g (7.7 mmol) of 2-fluoro-6-[(3-methoxyphenyl)thio]benzonitrile (Example 13) was added 2.93 g (17 mmol) of m-chloroperbenzoic acid. The resultant mixture was stirred for 24 h. Additional 0.29 g of m-chloroperbenzoic acid was added and the resultant mixture was stirred for 15 min. Excess sodium bisulfite was added, followed by water. The H2O solution was extracted with EtOAc. After drying over MgSO4 and solvent removal, the resultant crude product was purified by flash column chromatography on silica gel with methylene chloride as the fluent. This resulted in 1.15 g of 2-fluoro-6-[(3-methoxyphenyl)sulfonyl]benzonitrile as a solid: mp 113°-117° C.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:22]([O:26][C:27](=[O:41])[CH:28]=[CH:29][C:30]1[CH:39]=[C:38]2[C:33]([O:34][CH2:35][C:36](=[O:40])[NH:37]2)=[N:32][CH:31]=1)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[C:22]([O:26][C:27](=[O:41])[CH2:28][C@H:29]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C:30]1[CH:39]=[C:38]2[C:33]([O:34][CH2:35][C:36](=[O:40])[NH:37]2)=[N:32][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)NC(=O)CO2
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)c1cnc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-α-(R)-methylbenzylamine (0.82 g, 3.87 mmol) in THF (25 mL) at 0° C. was treated with n-BuLi (1.6 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of acrylate 20-5 (0.485 g, 1.76 mmol) in THF (5 mL) was added. After stirring for 15 min at −78° C., satd aq NH4Cl soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (40% ethyl acetate/hexanes) to give the β-aminoester 20-6 as a yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1.[O:26]1CCC[CH2:27]1>CN1CCCN(C)C1=O.[Au]>[CH3:13][O:14][C:15](=[O:25])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)[CH2:11][C@H:10]1[CH2:9][CH2:8][CH2:27][O:26]1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1ccc(SC)cc1
Agent: [Au]
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C[C@H]1CCCO1)c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of diisopropylamine (1.21 mL, 8.62 mmol) in dry tetrahydrofuran (30 mL) was cooled to −78° C. under argon and was then treated with a 2.5M solution of n-butyllithium in hexanes (3.3 mL, 8.25 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (4-methylsulfanyl-phenyl)-acetic acid methyl ester (1.47 g, 7.5 mmol) in dry tetrahydrofuran (10 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.34 mL). The reaction mixture turned gold in color and was allowed to stir at −78° C. for 1 h. The reaction mixture was then treated with a solution of trifluoromethanesulfonic acid (R)-tetrahydro-furan-2-yl methyl ester (2.30 g, 9.8 mmol) in dry tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (30 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 9/1 hexanes/ethyl acetate) afforded 2-(4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (0.810 g, 39%) as a pale yellow oil: [α]23589=−10.87° (c=0.46, chloroform); EI-HRMS m/e calcd for C15H20O3S (M+) 280.1133, found 280.1130.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI/CI): predicted mass O21H26N6O2, 394.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using butyryl chloride (59 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]butanamide (0.045 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1(=O)O[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[CH2:16]1.C(N(CC)CC)C>C(#N)C>[O:20]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH2:2][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[NH:14]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: COC(=O)c1cccc(C#N)c1CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2ccccc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of methyl 2-bromomethyl-3-cyanobenzoate (14.1 g, 55.5 mmol) and homophthalic anhydride (22.5 g, 138.8 mmol) in acetonitrile (150 ml) was stirred at room temperature, and a solution of triethylamine (23.2 ml) in acetonitrile (100 ml) was added dropwise to the mixture over the period of 1 h. After the completion of addition, the resultant suspension was refluxed for 4 hours. The reaction mixture was then cooled down to room temperature and filtered. The filtered solid was washed thoroughly with acetonitrile (100 ml) and ethanol (2×100 ml) and dried under vacuum at 50° C. Compound 17a was obtained in 81% yield (13.1 g). 1H NMR (DMSO-d6): δ 12.21 (s, 1H); 8.20 (m, 2H); 7.83 (d, J=7.5 Hz, 1H); 7.71 (m, 2H); 7.47 (m, 2H); 4.07 (s, 2H); 3.89 (s, 3H).
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH3:16])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].C[Al+]C.[O:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]1=[O:28].[Cl-].[NH4+]>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH2:1]([C:7]1[N:8]([CH3:16])[C:9]2[C:14]([C:15]=1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]([OH:28])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCc1cc2ccccc2n1C
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCc1c(C(=O)CCCC(=O)O)c2ccccc2n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hexyl-1-methyl-1H-indole in methylene chloride at 0° C. was added dimethyl aluminum chloride solution in hexane. The reaction mixture was stirred for 30 minutes. To this solution dihydro-pyran-2,6-dione was added at 0° C. and the reaction mixture was stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[OH:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=[NH:12])[O:9]CC.O1CCCC1>C1(C)C=CC=CC=1>[C:13]1([CH:7]2[O:6][C:1](=[O:2])[NH:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=N)C(O)c1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2ccccc2)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 16 hours at room temperature was used following cold perfusion with phosgene, ethyl 1-hydroxy-1-phenylmethanecarboximidate hydrochloride (22 g., 0.102 mole) in 450 ml. of tetrahydrofuran was converted to toluene recrystallized 5-phenyloxazolidine-2,4-dione (10.5 g., m.p. 103°-105° C.).
Reaction SMILES: C(C1C=CC=CC=1OC)(C)C.[Br:12][C:13]1[CH:14]=[C:15]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[C:17]([Br:20])[C:18]=1[SH:19].[I:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[Br:12][C:13]1[CH:14]=[C:15]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[C:17]([Br:20])[C:18]=1[S:19][C:31]1[CH:30]=[CH:29][C:28]([O:33][CH3:34])=[C:27]([I:26])[CH:32]=1
Reactant: COC(=O)Cc1cc(Br)c(S)c(Br)c1
Reactant: COc1ccccc1I
Agent: COc1ccccc1C(C)C
Product: COC(=O)Cc1cc(Br)c(Sc2ccc(OC)c(I)c2)c(Br)c1
Yield: 83.2 %

Procedure:
Following the procedures of Example 1, but substituting 2-iodoanisole for 2-isopropylanisole, methyl 3,5-dibromo-4-mercaptophenylacetate (1 g) was reacted with 2-iodoanisole (0.7 g) to yield the thioether, methyl 3,5-dibromo-4-(3-iodo-4-methoxyphenylthio)phenylacetate (1.4 g) which in turn was oxidized to methyl 3,5-dibromo-4-(3-iodo-4-methoxyphenylsulfonyl)phenylacetate, MP: 127°-129° C. The acetate was saponified to the acid, 3,5-dibromo-4-(3-iodo-4-methoxyphenylsulfonyl)phenylacetic acid, MP: 158°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:15])([F:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].O.C(Cl)(=O)C([Cl:22])=O>C(O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:15])([F:14])[C:9]([Cl:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C(F)(F)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=C(Cl)C(F)(F)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Ethyl 4-chlorophenyl-2,2-difluoroacetate (250 mg) and potassium hydroxide (300 mg) were mixed in 27 ml of ethanol and 2.4 ml of water and the reaction mixture was refluxed for four hours. The mixture was then acidified and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and the solvent was removed in vacuo to give a product which was dissolved in 410 mg of oxalyl chloride with catalytic amount of N,N-dimethylformamide. The mixture was stirred for two hours and excess oxalyl chloride was removed in vacuo to give 4-chlorophenyl-2,2-difluoroethanoyl chloride which was used as is for the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[H][H]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: COC(=O)C=Cc1ccc(OCc2ccccc2)cc1CCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)(C)C
Yield: 36.7 %

Procedure:
To a solution of 3-[4-benzyloxy-2-(2-tert-butoxycarbonylamino-ethyl)-phenyl]-acrylic acid methyl ester (4.15 g, 10.1 mmol) in THF (100 mL) and MeOH (10 mL) was added 5% Pd—C (200 mg) in THF (10 mL). The resulting suspension was treated with hydrogen under balloon pressure for 18 h. The mixture was filtered through a pad of Celite and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexanes, 6/4) to afford the title compound (1.20 g, 34%). 1H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.57 (t, 2H, J=7.8 Hz), 2.77 (t, 2H, J=7.3 Hz), 2.88 (t, 2H, J=7.8 Hz), 3.33 (br s, 2H), 3.68 (s, 3H), 6.65 (br s, 1H), 6.67 (d, 1H, J=8.3 Hz), 7.02 (d, 1H, J=8.3 Hz). MS (ES+) m/z 324.1 [M+H]+.