Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:31])([F:30])/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[F:12][C:11]([F:14])([F:13])[O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][CH:23]([C:22]([F:21])([F:31])[F:30])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Nc1ccc(OC(F)(F)F)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 90 °C
Yield: 103.9 %

Procedure:
The 2-amino-5-(trifluoromethoxy)benzaldehyde from Step 3 (5.3 g, 26 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol), and ethyl 4,4,4-trifluorocrotonate (7.7 mL, 50 mmol) were mixed in anhydrous dimethylformamide (50 mL) and heated at 90° C. for 6 hours. The reaction was allowed to cool to room temperature and was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with more ethyl acetate (100 mL). The ethyl acetate extracts were combined and washed with brine (200 mL), dried over MgSO4, and concentrated in vacuo yielding an oil (9.6 g). The oil was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1). Fractions containing the desired product were combined, concentrated in vacuo, and the residue recrystallized from ethyl acetate-hexanes to afford the ethyl 1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (4.05 g, 32%): mp. 123–125° C. 1H NMR (CDCl3, 300 MHz) 7.65 (s, 1H), 7.02 (m, 2H), 6.60 (m, 1H), 5.10 (m, 1H), 4.60 (brs, 1H), 4.28 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). ESHRMS m/z 356.0698 (M−H, Calc'd 356.0721). Anal. Calc'd for C14H11NO3F6: C, 47.34; H, 3.12; N, 3.94. Found: C, 47.37; H, 3.04; N, 3.93.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16].[CH:30](=[O:32])[CH3:31]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:30]([OH:32])[CH3:31])[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: CC=O
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)CN(C(=O)OC(C)(C)C)CCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (1.3 mL, 9.092 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (10 mL) was treated with a solution of n-butyllithium in hexanes (3.4 mL, 8.524 mmol, 2.5 M). After stirring at −78° C. for 30 minutes, the mixture was treated with a solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (1.394 g, 5.683 mmol) in anhydrous tetrahydrofuran (10 mL). After stirring at −78° C. for 20 minutes, the mixture was treated with acetaldehyde (0.96 mL, 17.05 mmol). After stirring at room temperature for 1 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 40 mL). The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (1.476 g, 90%) as a yellow oil and as a 2:1 mixture of diastereoisomers.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[OH:26][C@H:27]1[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[C:36]([O:40][C:41]([NH:43][CH:44]([C@H:48]([CH3:56])[CH2:49][CH:50]([CH3:55])[CH2:51][CH2:52][CH:53]=[CH2:54])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C@@H:44]([C@H:48]([CH3:56])[CH2:49][CH:50]([CH3:55])[CH2:51][CH2:52][CH:53]=[CH2:54])[C:45]([N:30]1[CH2:31][C@H:27]([OH:26])[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 31.7 g, 83 mmol) was added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (16.68 g, 92 mmol), (3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (25 g, 83 mmol) and NEt3 (34.9 mL, 250 mmol) in DCM (250 mL) and stirred at RT for 16 h. The reaction was washed with 1N HCl (3×) and then brine. The organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified via silica gel chromatography using 20-60% Acetone in hexanes to give the desired product (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.8 g, 30% yield), MS: MS m/z 427.2 (M++1) and the undesired product (2S,4R)-methyl 1-((2R,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (12 g, 34% yield), MS: MS m/z 427.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH2:9]([OH:12])[CH:10]=[CH2:11].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:10][CH:9]=[O:12]
Reactant: C=CCO
Reactant: Clc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=CCCc1ccccc1Cl
Temperature: 30 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
2-Chloro-iodobenzene (700 mg), allyl alcohol (256 mg, 1.5 eq.), palladium acetate (13 mg, 0.02 eq), sodium bicarbonate (616 mg, 2.5 eq), and tetrabutylammonium chloride (816 mg, 1 eq) were mixed together in anhydrous DMF (12 mL). The mixture was stirred at 30° C. for 24 h, then diluted with water. The crude mixture was extracted into EtOAc 3×, and the organic layer was washed with water twice, then brine, and then dried over sodium sulfate, and concentrated. The residue was purified by chromatography (gradient: 88:12 hexanes:EtOAc to 1:1 hexanes:EtOAc) delivering the product (200 mg, 40% yield). 1H-NMR (300 MHz, CDCl3) δ 9.80 (s, 1H), 7.38-7.30 (m, 1H), 7.28-7.10 (m, 3H), 3.10-3.02 (m, 2H), 2.84-2.68 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:22]([O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 50 °C

Procedure:
20.0 g (75% pure, 42.5 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were added to a suspension of 16.3 g (84.9 mmol) of cesium acetate in 80 ml of DMF. The resulting mixture was heated at 50° C. for 1.5 h. After cooling, the mixture was diluted with ethyl acetate, washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→about 10:1). This gave 11.7 g (76.4% of theory) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([CH3:11])=[CH2:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)=[O:2]>CO>[OH:2][CH2:1][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=1
Reactant: C=C(C)c1cc(C(F)(F)F)cc(-c2ccc(C(=O)OC)cc2)c1C=O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CO)cc1

Procedure:
A solution of methyl 2′-formyl-3′-(prop-1-en-2-yl)-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (122 mg, 0.35 mmol) in MeOH (10 mL) was hydrogenated using H-Cube (10 Bar H2) at 40° C. at a flow rate of 1 mL/min. The resulting solution was concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: C([N:8]1[C:12]([C:13]2([CH2:23][CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:22])[CH:19]=3)[CH2:14]2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1>C(O)C.[Ni]>[CH2:23]([C:13]1([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:22])[CH:19]=2)[CH2:14]1)[CH3:24]
Reactant: CCC1(c2cncn2Cc2ccccc2)Cc2ccc(F)cc2C1
Agent: [Ni]
Solvent: CCO
Product: CCC1(c2c[nH]cn2)Cc2ccc(F)cc2C1

Procedure:
10 ml of the crude product obtained in Example 3 was placed in a round-bottomed flask equipped with a thermometer and a stirring bar. 1.5 ml of Raney-Nickel in ethanol (Raney-Nickel prepared according to Vogel, Practical Organic Chemistry, 5th Edition, 1999, Longman, U.K. p. 450–451), was added under nitrogen atmosphere. The reaction mixture was stirred at reflux temperature for about 14 hours. After filtration and evaporation crude 4-(2-ethyl-5-fluoro-indan-2-yl)-1H-imidazole was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Br[CH:15]([CH3:19])[C:16]([OH:18])=[O:17].Cl>CS(C)=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(C(C)(C)C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled slurry of 9.3 g of sodium hydride-oil dispersion (57%) in 150 ml of dimethyl sulfoxide is added 15.0 g of p-tert-butylphenol in 50 ml of dimethyl sulfoxide and 18.9 g of 2-bromopropionic acid in 50 ml of dimethyl sulfoxide. The mixture is stirred at room temperature for 1/2 hr. and heated on a steam bath overnight. The mixture is diluted with 250 ml of water, acidified with 10 ml of conc. hydrochloric acid and extracted with ether. The ether extracts are dried (MgSO4) and the solvent removed under vacuum. Chromatography over silica gel with dichloromethane as eluent gives the product as white crystals, mp 86°-89° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH3:13]N(C)C=O.C(=O)(OC)OC.N1C2C(=CC=CC=2)C=C1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1
Reactant: CN(C)C=O
Reactant: N#CCc1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: COC(=O)OC
Product: Cn1cc(CC#N)c2ccccc21
Temperature: 126 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A 1 L, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with indole-3-acetonitrile (58.0 g, 90% pure=0.334 mol), tetrabutylammonium bromide (11.6 g, 36 mmol), N,N-dimethylformamide (348 mL) and dimethyl carbonate (92.8 mL, 1.10 mol) and the resulting mixture was heated to 126±1° C. The progress of the reaction was monitored by HPLC and after 3 h at this temperature, the presence of remaining starting indole could not be detected. After the reaction mixture was then cooled to zero to −5° C., water (696 mL) was added which resulted in the formation of a precipitate. The mixture was stirred at −5° C. for 1 hour, then the solid was collected by filtration, washed with water (150 mL) and dried under high vacuum at 45° C. for 24 h to give 1-methylindole-3-acetonitrile (52.0 g, 91.5%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH2:11])=[O:10].C(=O)([O-])O.[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:18][CH2:19][C:20]([N:6]1[CH2:5][C:4](=[O:7])[N:3]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1([CH3:12])[CH3:1])=[O:21]
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An ice cold solution of 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (1 g) in 20 ml of saturated solution of sodium hydrogen carbonate was added with an additional 2 g of sodium hydrogen carbonate and treated dropwise with chloroacetyl chloride (3 ml). After 30 minutes of stirring the precipitate was collected and crystallized from methanol, to give 3-(2-chloroacetyl)-2,2-dimethyl-5-oxo-1-imidazolidineacetamide (0.53 g) as a white powder m.p. 214°-216° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
4.9 g of 4-(3-phenylpropyloxy)benzaldehyde were dissolved in 30 ml of ethanol, and 0.39 g of sodium borohydride were added to the resultant solution, then the solution was stirred for 1 hour at room temperature. After completed the reaction, the solvent used was distillated under reduced pressure, and the residue obtained was dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. After washing the ethyl acetate layer with dilute hydrochloric acid, dilute alkaline aqueous solution and water in series, the organic layer was then dried with anhydrous magnesium sulfate, and the solvent used was distillated under reduced pressure, thereby affording 4.1 g of 4-(3-phenylpropyloxy)benzyl alcohol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]2[CH:4]1[CH:5]=[C:6]([CH2:10][CH3:11])[CH2:7]2.[C:20]([OH:30])(=[O:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22]>C(#N)C>[C:20]([OH:30])(=[O:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].[NH2:1][CH2:2][C@:3]1([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][C@@H:8]2[C@H:4]1[CH:5]=[C:6]([CH2:10][CH3:11])[CH2:7]2
Reactant: CCC1=CC2C(C1)CC2(CN)CC(=O)OC(C)(C)C
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC#N
Product: CCC1=C[C@@H]2[C@H](C1)C[C@]2(CN)CC(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 29.4 %

Procedure:
Acetonitrile (4.7 L, 8.6 v/w) was added to tert-butyl [6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate (627.0 g, net: 543.6 g, 2.05 mol, 85:15 diastereomeric mixture), and the mixture was stirred at 40° C. To the reaction solution, D-mandelic acid (116.3 g, 0.76 mmol, 0.37 eq.) was added, and the mixture was stirred at 40° C. for 1 hour and then allowed to cool slowly to 3° C. After stirring at 3° C. for 1 hour, the resulting crystal was collected by filtration. Then, the crystal was dried under reduced pressure under the condition of 40° C. to obtain tert-butyl [(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate D-mandelate as a white powder (251.2 g, yield: 29.4%, 97.6% ee, 99.6% de).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:18][CH:17]=1
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(6-chloro-pyridin-3-yl)-amine and hydrazine monohydrate.
Reaction SMILES: C[O:2][C:3]1[C:16]2=NC3C(C=[C:15]2[C:14]2[CH:13]=[C:12]4[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]4)=[N:6][C:5]=2[CH:4]=1)=CC=CC=3.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:2][C:3]1[CH:16]=[C:15]2[C:14]3[C:13](=[C:12]4[C:7](=[N:6][C:5]=3[C:14]3[CH:15]=[CH:16][CH:3]=[CH:4][C:5]=3[N:6]2[CH3:7])[CH:8]=[CH:9][CH:10]=[CH:11]4)[CH:4]=1
Reactant: COc1cc2nc3ccccc3cc2c2cc3ccccc3nc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN1c2ccccc2-c2nc3ccccc3c3cc(O)cc1c23
Temperature: 80 °C

Procedure:
(Method K) (Demethylation) The appropriate 6-methoxyquinoacridine was suspended in benzene and anhydrous aluminium chloride added (3 eq). The mixture was heated to 80° C., giving a red oily suspension and bright green haze on the solvent, until complete reaction was seen by tlc (0.2 mL sample, 0.5 mL methanol quench, 0.2 mL sat. aq. NaHCO3 neutralisation, neat EtOAC eluent) then allowed to cool to room temperature. Methanol was added slowly with ice cooling of the suspension and the stirring continued until all red oil was gone. The solvent was evaporated under reduced pressure, and the residue treated with sat. aq. sodium hydrogen carbonate. The organics were separated form the crude filtrate by soxhlet extraction with ethyl acetate. Filtration of the precipitate on cooling gave the desired compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][CH:17]=C)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=CC=2)C=C[CH:20]=1.C(OCC)(=O)C>CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:10]2[S:15][CH:16]([CH3:17])[CH2:20][C:11]=2[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2ncccc2c1
Reactant: C=CCSc1ccccc1S(=O)(=O)NC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Temperature: 220 °C

Procedure:
A mixture of 89.9 g of N-t-butyl-2-(2-propenylthio)benzenesulfonamide and quinoline (90 ml) were heated at 220° C. for 2 hours under an inert atmosphere. The mixture was cooled, was poured into ice-water (500 ml) and was extracted with several portions of a 1:1 mixture of chlorobutane and tetrahydrofuran. The combined extracts were washed with 6N hydrochloric acid and brine. The organic mixture was dried over magnesium sulfate and was concentrated. The residue was distilled in a kugelrohr apparatus at 170°-200° C. (1 torr), giving after trituration with chlorobutane and hexane a yellow solid. Chromatography of the mixture on silica gel eluting with 20% ethyl acetate in hexane afforded after recrystallization from hexanechlorobutane the title compound as a white solid, m.p. 97°-98° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([O:14][CH3:15])[N:3]=1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])[CH3:17]>C(Cl)Cl>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:28][C:29]([NH:1][C:2]1[N:3]=[C:4]([O:14][CH3:15])[N:5]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[N:7]=1)=[O:30])(=[O:26])=[O:27])[CH3:17]
Reactant: COc1nc(N)nc(OCC(F)(F)F)n1
Reactant: CCOc1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.8 %

Procedure:
To 1.9 g of 2-amino-4-(2,2,2-trifluoroethoxy)-6-methoxy-1,3,5-triazine suspended in 50 mL of dry methylene chloride was added 2.4 g of 2-ethoxybenzenesulfonyl isocyanate. The mixture was stirred at ambient temperature for three days, filtered, and the filtrate stripped to an oil which crystallized. The solid was triturated with n-butyl chloride and collected to give 2.94 g of white solid with m.p. 180°-181° (dec).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][CH:15]([CH3:18])[CH2:16]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+]>O1CCCC1>[CH2:7]([O:14][CH:15]([CH3:18])[CH2:16][CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCC1
Reactant: CC(CCl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CC1CCCC1=O)OCc1ccccc1

Procedure:
5,7-dihydroxyoctanoic acid delta-lactone was prepared in several steps from cyclopentanone and 2-benzyloxy-1-chloropropane. Thus, alkylation of cyclopentanone was effected by treatment with sodium hydride in tetrahydrofuran (THF) solution to generate the alpha-anion, followed by the dropwise addition of a THF solution of 2-benzyloxy-1-chloropropane. Reaction workup yielded 2-(2-benzyloxy-1-propyl) cyclopentanone. This ketone was treated with peroxy trifluoroacetic acid under Baeyer-Villiger conditions to give the 7-benzyl ether of 5,7-dihydroxyoctanoic acid gamma-lactone. The benzyl group was removed by catalytic hydrogenation, yielding 5,7-dihydroxyoctanoic acid delta-lactone.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[O:10][CH:11]=[C:12]([C:14]#[N:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:37]2[C@H:38]([CH3:61])[C@H:39]3[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:40]3[C:41]=2[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=2)=[O:43])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:8][CH:5]([S:4][C:37]3[C@H:38]([CH3:61])[C@@H:39]4[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:40]4[C:41]=3[C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=3)=[O:43])[CH2:6]2)[O:10][CH:11]=1)#[N:15]
Reactant: CC(=O)SC1CN(c2nc(C#N)co2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C#N)co4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 3-acetylthio-1-(4-cyano-1,3-oxazol-2-yl)azetidine (156 mg, 0.70 mmol) (obtained as described in Reference Example 23) in dimethylformamide (8 ml) was added hydrazine acetate (77 mg, 0.84 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (416 mg, 0.70 mmol) in acetonitrile (8 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.49 ml, 2.80 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-cyano-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (309 m yield 84%) as a pale yellow solid.