Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][CH2:16][C@@H:17]([OH:19])[CH3:18])([CH3:14])([CH3:13])[CH3:12].O.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28](F)[CH:29]=1)[C:25]#[N:26]>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:19][C@@H:17]([CH3:18])[CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:29]=1)[C:25]#[N:26]
Reactant: C[C@H](O)COC(C)(C)C
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COC(C)(C)C)Oc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a stirred suspension of sodium bis(trimethylsilyl)amide (74.25 mmol; 14.33 g) in DMF (150 mL) at 23° C. was added (S)-tert-butoxy-2-propanol (74.25 mmoles, 9.82 g) over 15 minutes. A slight exotherm was observed (cold water cooling bath applied). A solution of 3-bromo-5-fluorobenzonitrile (49.50 mmol, 10.0 g) in DMF (40 mL) was added over 15 minutes with cold water bath still present. An exotherm (3° C.) was observed and the mixture turned from yellow to brown. DMF (10 mL) was added and the mixture stirred at ambient temperature for 1 hour. The reaction was quenched by addition of aqueous HCl (2M, 100 mL), maintaining temperature below 25° C. The mixture was diluted with water (200 mL) and extracted with 2:1 EtOAc/MTBE (3×200 mL). The organic layers were combined, washed with water (3×200 mL) and dried over MgSO4, and the solvent removed in vacuo affording the title compound as an orange oil (17.4 g). Further drying in vacuo at 23° C. gave the title product (15.5 g, ˜100%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([S:22]([N:19]3[CH2:18][CH2:17][CH:16]([OH:15])[CH2:21][CH2:20]3)(=[O:24])=[O:23])=[CH:33][CH:32]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 114 mg of 4-(4-hydroxypiperidin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-hydroxypiperidin-1-ylsulfonyl)benzamide. MS (Q1) 472.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@:13]3([CH3:35])[CH2:17][CH2:16][CH2:15][N:14]3C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.N1CCCCC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C@:13]3([CH3:35])[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@]1(c2ncc(-c3ccc(Br)cc3)[nH]2)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C[C@@]1(c2ncc(-c3ccc(Br)cc3)[nH]2)CCCN1
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To (S)-(9H-fluoren-9-yl)methyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (intermediate LS32; 329 mg; 0.62 mmol) in 3 mL DMF was added 1.5 mL piperidine. The reaction mixture was concentrated via a nitrogen stream overnight. The resultant residue was washed with hexane and passed through an MCX cartridge (Oasis; 6 g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 193 mg of (S)-5-(4-bromophenyl)-2-(2-methylpyrrolidin-2-yl)-1H-imidazole which was dissolved in 6 mL dichloromethane and combined with di-t-butyldicarbonate (413 mg; 1.89 mmol), DMAP (15 mg; 0.13 mmol) and TEA (0.17 mL; 1.30 mmol). After 48 h, the reaction mixture was concentrated and purified via chromatography on a Biotage system providing (S)-tert-butyl 5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-imidazole-1-carboxylate (intermediate LS33; 150 mg; 48%) as an off white solid. LC (Cond'n 5): RT=3.75 min; MS: Anal. Calcd. for [M+H]+ C24H32BrN3O4: 506.2. found 506.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N:14]2[CH2:15][CH:16]([CH2:17][OH:18])[O:19][CH:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CC(C)NCC(O)CO)cc1OC
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)N2CC(CO)OC2c2ccccc2)cc1OC

Procedure:
A mixture of 3-[3-(3,4-dimethoxyphenyl)-2-propylamino]-1,2-propanediol (14.3 g, 0.053 m), benzaldehyde (12.7 g, 0.12 m) and benzoic acid (0.3 g) in toluene (45 ml) is refluxed for 3 hours, collecting the water formed in a Dean-Stark trap. After washing with saturated NaHCO3 solution and with H2O (2x), the solvent is distilled under reduced pressure. Excess benzaldehyde is distilled at 100° C. at 0.1 mm. The residue, (II) (16.88 g, 89%) is used without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:24]1(=[O:34])[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:20][C@H:19]3[N:2]([CH3:1])[CH2:3][CH2:4][C@:5]45[C:6]=2[C:11]=1[O:12][C@H:13]4[C:14](=[O:15])[CH2:16][CH2:17][C@@:18]35[O:21][C:24](=[O:34])[C:25]1[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:27]([OH:29])=[O:28]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OC(=O)c5ccccc5C(=O)O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 24 h
Yield: 35 %

Procedure:
A solution comprised of oxycodone free base, 1-1, (63 mg, 0.2 mmol), phthalic anhydride (1.185 g, 8.0 mmol) and DMAP (24 mg, 0.2 mmol) in 10 mL of pyridine was stirred in an oil bath at 50–55° C. for 24 h and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with a 5%–20% methanol in dichloromethane gradient. The fraction containing 2-1 was collected and concentrated under reduced pressure. HPLC indicated that the fraction was 60% pure. The concentrated fraction was subjected to another silica gel flash chromatography using a gradient of 0–20% methanol in dichloromethane as eluent to yield a fraction containing 32 mg (35% yield) of 96% pure (HPLC) 2-1, which was further purified by HPLC. The 1H and 13C NMR spectra verified the structure of 2-1 as a hydrogen phthalate ester of the 14-hydroxyl group of oxycodone. (The absence of an 1H resonance in the region of 5.5–6 ppm for a C7 vinylic proton, and the presence of a 13C resonance at 207.5 ppm for the C6 carbonyl group excluded the presence of an enol ester linkage in 2-1.)
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: O=c1c(I)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2n[nH]c3ccccc23)oc2ccccc12
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 mg) prepared in Example 1, indazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 mg) were added and the mixture was reacted at 80° C. for 30 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and the purified product was recrystallized from benzene/hexane to give the titled compound (113.6 mg; yield=88.5%) as crystals. Melting point: 237°-238° C. 1H-NMR(CDCl3, δ ppm): 6.94 (s, H3), 8.26 (dd, H5), 7.58-7.68 (m, H6), 7.75 (t, H7), 7.58-7.68 (m, H8), 8.30 (s, H3'), 7.82 (m, H4'), 7.35-7.53 (m, H5'), 7.35-7.53 (m, H6'), 8.26 (m, H7') .
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].O[N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:3][C:2]([C:1]([O:6][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])=[O:5])=[CH2:4]
Reactant: C=C(C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: C=C(C)C(=O)ON1C(=O)CCC1=O
Reaction time: 3 h
Yield: 71.7 %

Procedure:
In 20 ml of acetonitrile were dissolved methacrylic acid (1.72 g, 20 m mols) and N-hydroxysuccinimide (2.19 g, 19 m mols), and under ice-cooling, N,N'-dicyclohexylcarbodiimide (4.33 g, 21 m mols) was added. The reaction was conducted in the dark, at 0° C. for one hour and at room temperature for 3 hours. The precipitate was separated by filtration and the filtrate was distilled under reduced pressure. To the residue was added petroleum ether and, after cooling, the crystals were collected by filtration. By the above procedure there was obtained 2.5 g of methacrylic acid N-hydroxysuccinimide ester as crystals melting at 100°-102° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13])#[N:2].[NH2:14][OH:15]>CCO>[NH2:2][C:1](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13]
Reactant: NO
Reactant: COC(=O)c1ccc(C#N)c(F)c1
Solvent: CCO
Product: COC(=O)c1ccc(C(N)=NO)c(F)c1
Temperature: 74 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-cyano-3-fluorobenzoate obtained in Step 1 (834.5 mg; 4.66 mmol) in EtOH (9 mL) was added hydroxylamine (50% in water, 1.37 mL; 23.29 mmol). The solution was stirred at 74° C. for 4 h. The solvents were evaporated and the residue was taken in EtOAc (20 mL), washed with brine (3×15 mL), dried over MgSO4 and evaporated, affording the title compound as a yellow solid. 1H NMR: (DMSO-d6, 300 MHz) δ 9.89 (s, 1H), 7.92 (t, J=7.91 Hz, 1H), 7.69 (dd, J=1.70 Hz, J=8.10 Hz, 1H), 7.64 (dd, J=1.51 Hz, J=12.81 Hz, 1H), 5.97 (s, 2H), 3.92 (s, 3H). HPLC (Method A) Rt 2.90 min (Purity: 90.3%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Yield: 82.3 %

Procedure:
In a similar manner to that described in Reference example 37(b), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-(4-chlorophenoxy)propionate (5.99 g), which is the product of Reference example 38(a), a solution of hydrogen bromide in acetic acid (25%, 60 ml) and potassium carbonate (4.68 g) and the reaction mixture was treated to afford the desired compound (3.85 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]4)=[CH:40][CH:39]=3)=[CH:22][CH:23]=1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(-n2ncc3cc(OCc4ccccc4)ccc32)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(-n2ncc3cc(OCc4ccccc4)ccc32)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 988 was prepared according to the procedure described in Scheme IV from 5-benzyloxy-1-(4-aminophenyl)indazole and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C32H30N4O3: 519.23; found: 519.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.O.[C:15]([OH:19])(=[O:18])[CH:16]=[O:17]>CCOC(C)=O>[OH:17][CH:16]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[C:15]([OH:19])=[O:18]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)CCC(C(O)C(=O)O)C2=O
Temperature: 120 °C
Yield: 29.8 %

Procedure:
A mixture of 6-methoxy-1-tetralone (20 g, 114 mmol) and glyoxylic acid monohydrate (10.5 g, 114 mmol) was heated at 120° C. in a melt for 5 min. After slight cooling, EtOAc (100 mL) was carefully added. The solid which precipitated was collected to afford 8.5 g (30%) of hydroxyl-(6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetic acid; Mp 212-214° C., MS m/z 251 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([Cl:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[N:56][C:55]([Cl:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Cl)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 200 mg, 0.56 mmol) and triphenylphosphine (192 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyrazine (145 mg, 1.12 mmol) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (137 mg, 52%) as a light yellow foam: [α]23589=−27.35° (c=0.49, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 470.0703. found 470.0705.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[CH3:18].[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:18])=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:25])[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1[nH]c2ccc(O)cc2c1-c1ccccc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3ccccc3Cl)c2c1

Procedure:
The above compound was prepared from 3-(2-chlorophenyl)-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester analogously to Example 10.
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)S[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2].OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[S:20](=[O:23])(=[O:21])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Temperature: 80 °C
Yield: 71 %

Procedure:
1 ml of acetic acid was added to 1.22 g (4.22 mmol) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman, 1.43 g (12.66 mmol) of a 30% hydrogen peroxide aqueous solution was further added, and the mixture was heated at 80° C. for 2 hours. To the reaction mixture was added 10 ml of a 2% sodium hydrogensulfite, and a precipitated solid was recovered by filtration to give 0.96 g (yield 71%) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman-1,1-dioxide.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28](O)=[O:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Product: O=C(Cc1c(Cl)cccc1Cl)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2,6-dichlorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (d, J=7.9 Hz, 1H), 8.02-8.08 (m, 1H), 7.96-8.00 (m, 1H), 7.89-7.95 (m, 1H), 7.49-7.51 (m, 2H), 7.30-7.45 (m, 1H), 4.04 (s, 2H), 3.81-3.84 (m, 4H), 3.08-3.12 (m, 4H); MS (ESI+) M/Z 433 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([CH:30]([OH:33])[CH2:31][F:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][F:32])[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Yield: 49.2 %

Procedure:
To a solution of N-[(1-methylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (51 mg, 0.11 mmol) in DMSO(1 mL) was added Dess-Martin periodinane (110 mg). After 30 min at room temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried and concentrated to a white solid. Trituration with diethyl ether and collection of the solid afforded the title compound as a white powder (25 mg, 49% yield). TLC(MeOH:CH2Cl2, 5:95): Rf=0.48.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([NH:22][OH:23])([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N+:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[O-:23])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=Cc1ccc(OCc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared by refluxing a benzene solution of 4-(4-fluorobenzyloxy)benzaldehyde and N-tert-butylhydroxylamine for 21 hours with p-toluenesulfonic acid as a catalyst. The title compound was obtained as a solid in 98.5% yield, m.p. 180.3° C. (Rf=0.16 on a silica gel plate using hexanes: EtOAc, 1:1, v/v, as an eluant).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2>>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=3)[NH:22][C:21]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Reactant: O=C1Cc2cc(F)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.25 g of 3-(3-cyclopentyl-4-methoxybenzylidene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:17][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH3:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2ccccc2c1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc2ccccc2c1OP(=O)(Cl)Cl
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.176 mL, 1 equiv) and 2-methylnaphthalen-1-ol (Aldrich, 0.3 g, 1 equiv) were stirred in anhydrous diethyl ether (10 mL). Anhydrous triethylamine was added (0.264 mL, 1 equiv) at −78° C. and stirred for 30 min. The dichloridate was very unstable at room temperature. The progress of the reaction was monitored by 31P NMR. This crude mixture was considered to be a 100% conversion to dichloridate and was used directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 619.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>C(O)C>[C:7]1([CH2:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3][CH2:2][NH:1][CH2:22][CH2:21][C:20]([O:24][CH2:25][CH3:26])=[O:23])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCCCN(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCNCCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
Reaction under an argon flow. A mixture of 1-amino-3-dibenzylaminopropane (0.195 mol) in ethanol (225 ml) was stirred at room temperature. Ethyl propenoate (0.2 mol) was poured into the mixture and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane/CH3OH 50/45/5). The desired fractions were collected and the solvent was evaporated, yielding 27 g of N-[3-[bis(phenylmethyl)amino]propyl]-β-alanine, ethyl ester (intermediate 52).