Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:23]
Reactant: N#CC1(c2ccc(N)cc2)CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#CC1(c2ccc(N)c(Br)c2)CCCCC1

Procedure:
The title compound was prepared from 1-(4-amino-phenyl)-cyclohexane carbonitrile (as prepared in the previous step) by bromination with NBS according to the procedure in Example 4, step (b), replacing CH3CN with CH2Cl2. 1H-NMR (CDCl3; 400 MHz): δ 7.49 (d, 1H, J=2.0 Hz), 7.23 (dd, 1H, J=8.4, 2.0 Hz), 6.76 (d, 1H, J=8.4 Hz), 2.16-2.08 (m, 2H), 1.90-1.73 (m, 8H).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].[BH4-].[Na+].[Cl:27][C:28]([F:33])([F:32])[C:29](O)=O>>[Cl:27][C:28]([F:33])([F:32])[CH2:29][N:4]1[C:5]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[O:23][CH2:24][C@H:3]1[CH2:1][CH3:2]
Reactant: O=C(O)C(F)(F)Cl
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: [BH4-]
Agent: [Na+]
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC(F)(F)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (22 mg, 0.06 mmol) and NaBH4 pellets (large excess, >10 equiv) in 4 mL chlorodifluoroacetic acid (0.02 M) stirred at rt for 12 h, to afford 17 mg (61%) of (3R)-4-(2-chloro-2,2-difluoroethyl)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. 1H NMR (500 MHz, CDCl3) 7.44 (d, 1H, J=9.3), 7.32 (d, J=1H, 9.3), 7.21 (s, 1H), 5.50 (m, 1H), 4.39 (dd, 1H, J=10.7, 1.5), 4.09 (m, 1H), 3.99 (dd, 1H, J=10.7, 2.4), 3.92 (m, 1H), 3.33 (m, 1H), 1.6 (m, 2H), 1.39 (d, 3H, J=6.3), 1.38 (d, 3H, J=6.3), 0.99 (t, 3H, J=7.3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=3[C:11]=2[CH2:10][CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:12]2[C:11]3[CH2:10][CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])[C:16]=3[CH2:15][CH2:14][C:13]=2[CH:17]=1
Reactant: CC(=O)Cl
Reactant: NCCCC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5.09 g (0.015 mol) of 4-(4-aminobutyryl) -8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in 50 mI of methylene chloride are added 5 ml (0.036 mol) of triethylamine and then at 0° 1.33 ml (0.019 mol) of acetyl chloride dissolved in 15 ml of methylene chloride, and the mixture is stirred at room temperature for 1 hour. Then, the mixture is extracted with methylene chloride/ water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Crystallization from methylene chloride/ether, chromatography on silica gel with ethyl acetate/methanol (9:1) and renewed crystallization from methylene chloride/ether gives N-[4-[8-chloro-2,3,5,6-tetrahydrobenzo[f]quinolin-4(1H)-yl]-4-oxobutyl]acetamide as white crystals with melting point 142-143°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13]Br>C(O)(=O)C.O>[Br:13][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:12]
Reactant: BrBr
Reactant: O=C1CCCc2cc(O)ccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2c1ccc(O)c2Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
To a solution of 4.3 g of 6-hydroxy-1-teralone in 0 ml of acetic acid and 6 ml of water with stirring under ice cooling is added dropwise a solution of 5.1 g of bromine in acetic acid for 8 minutes. After addition, the mixture is stirred unde ice cooling for 5 minutes and at room temperature for 30 minutes. To the reaction mixture is added 170 ml of ice-cold water. The insoluble substance is collected by filtration, dried and recrystallized from a mixture of hexane, ethyl acetate and ethanol to give 4.8 g of 5-bromo-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone, melting at 183°-186° C.
Reaction SMILES: [CH3:1][C:2]1[S:3](=[C:11]=[O:12])[C:4]([O:8][CH2:9][CH3:10])=[C:5]([OH:7])[N:6]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[S:3](=[C:11]=[O:12])[C:4]([O:8][CH2:9][CH3:10])=[C:5]([OH:7])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC1=C(O)N=C(C)S1=C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1=C(O)N=C(CBr)S1=C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
2-Methyl-5-ethoxy-carbonyl-4-hydroxy-thiazole (45 g, 0.24 mol) was dissolved in 1 L of carbon tetrachloride. The solution was cooled down to 0° C. N-Bromo succinimide (43 g, 0.24 mol) was added portion-wise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was then passed through a short pad of celite. Removal of solvent gave crude product as solid, which was washed with ethyl acetate/hexane (1/3) three times (1×40 ml; 2×20 ml) to give 30 g of the title compound (yield: 50%; LC: Retention Time=1.66 min; MS: M+1=267).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1OC(=O)c1ccccc1

Procedure:
To a cooled solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (8.0 parts) in dry pyridine (42 parts) was added benzoyl chloride (4.75 parts) at such a rate that the temperature did not exceed 10° C. After one hour the mixture was poured into a slight excess of dilute hydrochloric acid. The product was extracted with ether and the ethereal solution washed, dried with sodium sulphate and evaporated to give an oil which solidified on scratching. The solid was recrystallised from a mixture of benzene and light petroleum to give 2-benzoyloxy-2,3-dihydro-3, 3-dimethylbenzofuran-5-yl methanesulphonate (5.1 parts), melting point 102°-104° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[N:8]2.[C-:16]#[N:17].[K+]>CN(C)C=O>[F:15][C:4]1[C:3]([CH2:2][C:16]#[N:17])=[C:12]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2
Reactant: [C-]#N
Reactant: COc1cnc2ccc(F)c(CBr)c2n1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc2ccc(F)c(CC#N)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A mixture of 8-bromomethyl-7-fluoro-2-(methyloxy)quinoxaline (5.89 g, 20 mmol) and potassium cyanide (3.2 g, 49 mmol) in dimethylformamide (125 ml) was heated at 50° C. for approx. 40 h. More potassium cyanide (0.8 g) was added and heating continued at 60° C. for ˜8 h. The mixture was then evaporated and the residue was dissolved in dichloromethane and washed with water. The aqueous phase was extracted twice with dichloromethane and the combined organic fractions were dried and evaporated. Chromatography on silica (300 g), eluting with 0-25% ethyl acetate/hexane gave product (2.47 g, 57%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]1=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]1=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(N)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid tert-butyl ester (2.6 g, 8.26 mmol) in dichloromethane (50 mL) was added triethylamine (918 mg, 9.09 mmol) and DMAP (20 mg) followed by dropwise addition of benzoyl chloride (1.27 g, 9.1 mmol). The reaction mixture was stirred at room temperature for 12 hours and then partitioned between EtOAc and sat. aqueous NH4Cl. The organic layer was washed with water (30 ml), brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (10-25% ethyl acetate/petrol ether) to afford the title compound as a colourless oil (2.07 g, 60%); 1H NMR (400 MHz, CDCl3) δ 1.48 (9H, s), 3.35 (1H, dd), 3.55 (1H, dd), 5.5 (1H, m), 6.26 (1H, t), 6.90 (1H, d), 7.15 (2H, m), 7.28 (3H, m), 7.52 (3H, m), 7.95 (2H, m), 8.52 (1H, d), 9.22 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1
Reactant: CNOC
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.63 g of 4-methyl-3-sulfamoyl-benzoic acid, 1.92 g of N,O-dimethylhydroxylaminehydrochloride, and 5.02 mL of triethylamine in methylene chloride (120 mL) is treated with 8.32 g of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate. The reaction mixture is stirred overnight at room temperature, washed sequentially with saturated aqueous sodium bicarbonate, water and a saturated sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo. The crude material is purified by silica gel chromatography (1:2 hexanes/ethyl acetate) to give N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide as a white powder. MS (m/z): 257 (M−1); Rf 0.25 (1:2 hexanes/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(#N)C.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([C:4]1[NH:5][CH:6]=[C:2]([CH3:1])[N:3]=1)=[O:22]
Reactant: Cc1c[nH]cn1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c[nH]c(C(=O)c2cccc(F)c2)n1
Temperature: 140 °C
Yield: 67.7 %

Procedure:
To a 350 mL pressure vessel was added 4-methylimidazole (17.85 g, 217 mmol, 1 eq.) and a stirbar. Acetonitrile (53 mL, 1022 mmol, 4.7 eq.) was added. Triethylamine (88 mL, 631 mmol, 2.9 eq.) was added and the mixture was stirred until it became homogeneous. 3-Fluorobenzoylchloride (100 g, 631 mmol, 2.9 eq.) was added. Upon addition of the acyl chloride, the mixture became warm and viscous. The vessel was sealed and heated at 140° C. for 2 hours with stirring. During heating, the mixture turned black in color. The vessel was removed from the heat, allowed to cool, and its contents were diluted with acetone (250 mL). The mixture was stirred and transferred to a 2 L round-bottomed flask containing 7% aqueous HCl (1000 mL). Charcoal was added to the flask and the mixture was refluxed at 85° C. for 1 hour. The mixture was allowed to cool slightly and then was filtered through a Celite pad followed by a rinse with 1N HCl (˜200 mL). The filtrate was made alkaline with NH4OH whereupon a solid precipitate formed. The solid was filtered and washed with copious amounts of dilute NH4OH to remove triethylamine hydrochloride salts. The solid was collected and placed under high vacuum, yielding ketone 3 as an off-white solid (30.0 g, 80%). LC/MSD (HP Series 1100 MSD) Expected MW: 204.07, Observed M+H: 205.0, Retention time: 1.48. Analytical HPLC: >95% purity, retention time: 3.00 (8 minute run) 1H NMR, DMSO-d6, Varian 400 MHz δ 13.10 (br s, 1H), 8.28 (m, 2H), 7.60 (m, 1H), 7.52 (m, 1H), 7.30-7.06 (d, 1H), 2.29 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[C:24]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:1][CH:2]([CH2:3][N:34]1[CH2:35][CH2:36][N:31]([CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:33]1)[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 91.4 %

Procedure:
Using the procedure of Example 28 of Step C, 3.08 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide of step B of Example 28, and 5.2 g of 1-(diphenylmethyl)piperazine were reacted to obtain after chromatography over silica (eluant: chloroform/ethyl acetate 7:3), 5.12 g of 2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1H-indol-4-yl)benzamide, and then 3.22 g of its neutral oxalate from 4.36 g of base melting at 170° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (3-hydroxy)-2-(S)-(t-butoxycarbonylamino)propionate (58 g, 196 mmol), dry methylene chloride (150 ml), p-toluenesulfonyl chloride (43.35 g, 227.4 mmol), 4-(dimethylamino)pyridine (2.4 g, 19.6 mmol) and pyridine (30 ml, 371 mmol) were combined and stirred at room temperature overnight. The reaction solution was concentrated in vacuo to a pale yellow oil. The oil was stored in vacuo overnight, then the white solid that formed was isolated to give 75.33 g of crude product. The product was triturated in petroleum ether (approximately 200 ml) to yield methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate: n.m.r.: (CDCl3, 90 MHz): δ7.72, 7.31 (2x dd, 4, aromatic protons), 5.26 (m, 1, nitrogen proton), 4.48 (m, 1, C-2 proton), 4.32 (m, 2, C-3 protons), 3.68 (s, 3, methyl protons of methyl ester), 2.44 (s, 3, methyl protons of toluene moiety), 1.40 (s, 9, protons of t-butyl moiety); i.r. (CHCl3): 3435, 3019, 1753, 1711, 1502, 1369, 1351, 1250, 1215, 1190, 1177 cm-1 ; m.s.: 279, 210, 172, 91, 41;
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN1C(=O)N=C(P(=O)(OCC)OCC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g, 0.025 moles) in DMF (15 mL), under N2, is added K2CO3 (17.5 g, 0.127 moles) and 1-iodobutane (2.9 mL, 0.025 moles). This mixture is stirred at room temperature for 16 hours and then the mixture is filtered and the solid washed with ethyl acetate. The filtrate is concentrated in vacuo, to afford a yellow oil which is redissolved in ethyl acetate and washed with water and brine and then dried over MgSO4. Evaporation of solvents under high vacuum affords the required product as a viscous yellow oil which solidifies on standing.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:22](=[O:63])[CH2:23][CH2:24][C:25](=[O:62])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:33](=[O:53])[CH2:34][CH2:35][C:36](=[O:52])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:72](Cl)(=[O:74])[CH3:73]>C(Cl)Cl>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:22](=[O:63])[CH2:23][CH2:24][C:25](=[O:62])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:33](=[O:53])[CH2:34][CH2:35][C:36](=[O:52])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:72](=[O:74])[CH3:73])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)OC(C)(C)C)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
NEt3 (0.16 mL, 1.15 mmol) was added to (11) (0.87 g, 0.98 mmol) in CH2Cl2 (40 mL) and the solution was cooled to 0° C. Acetyl chloride (0.074M in CH2Cl2, 14 mL, 1.04 mmol) was added by syringe over 4 minutes and stirring was continued (0° C. to room temperature) for 24 hours. The aqueous phase was extracted with CH2Cl2 (4×50 mL) and the organic phase was washed with 40 mL portions of cold 0.25M citric acid, 5% NaHCO3 and H2O. Solvent removal and flash column chromatography with 60% acetone/hexane gave 0.79 g (87%) of (12) as an oil: 300 MHz NMR δ 1.23-1.69 (m+s, 27 H), 2.09 (s, 3 H), 2.44-2.53 (m, 4 H), 2.76-2.84 (m, 6 H), 3.03-3.24 (m, 6 H), 3.57-3.68 (m, 6 H), 4.7 (br s, 1 H), 4.81 (s, 2 H), 4.85 and 4.86 (2 s, 4 H), 6.35 (br s, 1 H), 7.38 (s, 15 H). Anal. calcd. for C51H74N6O10 : C, 65.78; H, 8.01; N, 9.03. Found: C, 65.89; H, 8.04; N, 8.95.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33](O)[CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:27][C:26]=1[NH:42][C:43](=[O:59])[CH2:44][CH:45]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[O:52][C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]([O:2][C:1](=[O:3])[C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:34][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)=[CH:27][C:26]=1[NH:42][C:43](=[O:59])[CH2:44][CH:45]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[O:52][C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C(Cc1ccc(C(=O)O)cc1)OCc1ccccc1
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)c2ccc(CC(=O)OCc3ccccc3)cc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Preparation 25, but using benzyl 4-carboxyphenylacetate [prepared as described in step (iv) above] and N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained as a foam-like material.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 941.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (240 mg, 0.32 mmol) was reacted with (S)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (3.5 g, 9.7 mmol) to afford the desired product (1.4 g, 32%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=N)[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.C(O)(=[O:34])C.Cl>O>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:34])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
3.1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one [prepared as described in Example 1(a)] were added to a mixture of 45 ml of acetic acid, 15 ml of concentrated hydrochloric acid and 8 ml of water, and the mixture was reacted for 12 hours at 85°-90° C. It was then processed and purified in a similar manner to Example 1(a), giving 2.5 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione, whose melting point and nuclear magnetic resonance spectrum were consistent with those of the product of Example 1(b).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:12][C:13]3[NH:17][CH:16]=[C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]=3[CH3:23])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:35][O:34][C:32]1[CH:31]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[CH:33]=1)[CH2:29][O:21][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[C:14]([CH3:23])=[C:13]([CH:12]=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[NH:17][CH:16]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(O)ccc21
Reactant: COc1cc(CCl)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COC(=O)CCc2c[nH]c(C=C3C(=O)Nc4cc(O)ccc43)c2C)cc(OC)c1
Yield: 28.1 %

Procedure:
3-[5-(6-Hydroxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid (100 mg), 56 mg 3,5-dimethoxy-benzylchloride and 207 mg potassium carbonate in 2 mL anhydrous dimethylformamide were heated at 90° C. overnight. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 39 mg of the title compound as a brown solid.