Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:9]1[CH:30]=[CH:29][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.C1(C)C=CC=CC=1>CC(N(C)C)=O>[O:7]([C:9]1[CH:30]=[CH:29][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Oc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccc(C#Cc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Temperature: 23 °C
Yield: 96.3 %

Procedure:
A 100 mL flask equipped with nitrogen inlet, overhead stirring assembly, Dean-Stark trap, and reflux condenser was charged with phenol (0.35 g, 0.0038 mol), 4-fluoro-4'-phenylethynylbenzophenone (0.10 g, 0.0038 mol) potassium carbonate (0.39 g, 0.003 mol), 25 mL of toluene, and 50 mL of DMAc. The mixture was heated to reflux and water was removed by azeotropic distillation, followed by the removal of toluene over a 20 hour period. The reaction was cooled to 23° C., and the mixture was poured into 1 L of acidic (HCl) water. The precipitate was collected by filtration to afford 1.37 g (96%) of 4-phenoxy-4'-phenylethynylbenzophenone as a white powder: mp 165.5° C. IR (KBr): 2216 cm-1 (ethynyl), 1650 cm-1 (carbonyl): 1H-NMR (CDCl3): 7.8-6.8 pp, (m H aromatic). Anal Calcd. for C27H18O2 : %C=86.61, %H=4.85. Found: %C=86.46, %H=4.68. The structure of this compound is given below: ##STR10## The DSC thermogram of this compound is presented in FIG. 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 98.4 %

Procedure:
2,4-Dibenzyloxybenzaldehyde (20 g) was dissolved in methanol (700 ml) and then thereto was added sodium borohydride (3.6 g) and this was left to stand at room temperature (20° C.) for 1.5 hours. To the reaction mixture was added water (1.5 l) and the resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 2,4-dibenzyloxybenzyl alcohol (19.8 g, yield 98%). Melting point; 84°-85° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([F:13])[C:5]=1[N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>CO.C(OCC)(=O)C>[F:13][C:6]1[CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]([F:3])[C:5]=1[N:14]1[CH2:15][CH2:16][S:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(N2CCSCC2)c(F)c1
Yield: 70 %

Procedure:
Sodium borohydride (285 mg, 7.5 mmol) was added to a stirring solution of NiCl2.6H2O (1.16 g, 5.0 mmol) and 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine, obtain in Preparation 3, in methanol (30 mL). The reaction mixture was diluted with ethyl acetate (50 mL) after 0.5 h and the organic portion was washed with water (30 mL×2) followed by brine (30 mL) and dried over sodium sulfate. Evaporation of the volatiles yielded the title compound as light brown solid (400 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a homogeneous solution of 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 eq), triphenyl phosphine (1.5 eq), and phthalimide (1.5 eq) in THF (0.2 M) cooled to 0° C., ditertbutylazodicarboxylate (1.5 eq) in THF was added to the solution. The mixture was stirred at 0° C. for 2 hours. The reaction was concentrated in vacuo. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (99%). LC/MS (m/z): MH+=378.2, Rt=1.10.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2C=CC=CC=2O)=[O:23])[C:11]1=[O:40].C(N1C=CN=C1)(N1C=CN=C1)=O.CN.O1CCCC1>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([C@H:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][CH3:25])=[O:23])[C:11]1=[O:40]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(C)nc1C
Agent: CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NC)c1ccc(C)nc1C
Reaction time: 8 h

Procedure:
2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)acetamide (intermediate 2) (0.400 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.192 g, 1.18 mmol) in dry dichloromethane (10 mL) were stirred at room temperature under N2 for 7 hrs. The mixture was treated with a 2M solution of methylamine in tetrahydrofuran (1.849 mL, 3.70 mmol) and left to stand overnight at room temperature. The solvents were blown down under N2 and the residue was purified on a Redisep silica column (35 g) eluted with 0-10% methanol in ethyl acetate followed by further purification on a Kromasil KR100-10-C18 reverse-phase column eluted with aqueous acetonitrile (20-45% MeCN) containing 0.1% formic acid. This gave the title compound as a white lyophilisate (30%) after freeze-drying from 1,4-dioxane.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14][C:15](OC(C)(C)C)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:42]([NH:49][C@H:50](C(O)=O)[CH:51]([CH3:53])[CH3:52])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14][C:15](=[O:16])[C@H:50]([CH:51]([CH3:53])[CH3:52])[NH:49][C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
A 500 mL round bottom flask was charged with 46.52 g (99 mmol) N-tert-Butyloxycarbonyl-L-leucinyl-L-phenylalanine benzyl ester, 340 mL anhydrous m ethylene chloride (CH2Cl2), and 51 mL trifluoroacetic acid (TFA). The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours, and then concentrated in vacuo. The residue was azeotroped twice with toluene, and carried on. The same 500 mL round bottom flask containing the crude TFA salt was placed under a nitrogen atmosphere and charged with 21.5 g (99 mmol) Boc-L-valine, 13.4 g (99 mmol) HOBT, and 270 mL anhydrous THF The solution was cooled in an ice/acetone bath and 21.4 a (104 mmol) DCC was added in one portion. The mixture was stirred in the cold for 1 hour, and then warmed to room temperature and stirred overnight. The precipitated DCU was filtered off, and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed once with water, once with a 10% solution off citric acid, once with saturated NaHCO3, and once with brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The resultant solid was precipitated from ethanol with H2O to provide 41.96 g (75%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:15][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred suspension of 6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 990 mg, 5.15 mmol) in DMF (3.0 mL) is added K2CO3 (855 mg, 1.2 equiv.) followed by MeI (0.64 mL, 2.0 equiv.). The resulting solution is stirred overnight at room temperature. Water (20 mL) is then added and the reaction mixture is extracted with ethyl acetate (20 mL×2) and washed with saline (20 mL). The organic layers are collected and dried over MgSO4. Solvent is removed to yield the title compound as a yellow solid (956 mg, 90%). 1H NMR (300 MHz, DMSO) δ 8.16-7.26 (m, 3H), 3.30 (s, 3H), 3.00 (t, 2H), 2.61 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1-c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.1 %

Procedure:
To a solution of 4-(2-bromophenyl)-1H-imidazole (880 mg, 3.94 mmol) in 10 mL DMF, were added TEA (0.605 mL, 4.34 mmol) and trityl chloride (1.21 g, 4.34 mmol). The mixture was stirred at rt for 14 h, then diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 1.34 g of Intermediate 217.1 as an off-white solid. LCMS (50 to 100% B, 4 min gradient, A 95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=0.77 min, 465.2 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+]=[N-].[H][H]>C(O)C.[Pt](=O)=O>[NH2:1][CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Yield: 92.3 %

Procedure:
(3R,4S)-3-Azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine (1.35 g) was dissolved in ethanol (30 mL) and platinum (IV) oxide (190 mg) was added. The mixture was then stirred at room temperature for 2 hours under a stream of hydrogen gas (blown by a balloon). The catalyst in the reaction mixture was filtered through a Celite pad, and the catalyst and the Celite pad were washed with ethanol. The filtrate and the washings were then combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: methanol=10:1) to give (3S,4S)-3-aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown oil (1.13 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 30.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2 CO3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31 %) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1C=C[CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=O.[O-:16][CH2:17][CH3:18].[Na+].[Na].[O:21]1[CH:25]=[CH:24][N:23]=[C:22]1[SH:26]>C(O)C>[C:11]1(=[O:12])[N:10]([CH2:8][CH2:7][CH2:13][S:26][C:22]2[O:21][CH:25]=[CH:24][N:23]=2)[C:17](=[O:16])[C:18]2=[CH:2][CH:3]=[CH:4][CH:5]=[C:6]12
Reactant: Sc1ncco1
Reactant: CC[O-]
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCSc1ncco1

Procedure:
3-Bromopropylphthalimide (13.4 g.) was added to a stirred solution of sodium ethoxide (from 1.15 g. sodium and oxazole-2-thiol(5.1 g.) in ethanol (100 ml.). The resultant solution was heated under reflux for 2.5 hours and concentrated under reduced pressure. The residue was triturated with water (100 ml.) to afford 2-(3-phthalimidopropylthio)oxazole (14 g.) m.p. 101°. Recrystallisation from ethanol gave the pure oxazole, m.p. 102°-3°.
Reaction SMILES: CN(C)C=O.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[Na+].[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>O>[C:7]1([C:6](=[O:13])[CH2:18][CH2:17][C:19](=[O:20])[CH3:21])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CC(C)=O
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCC(=O)c1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To 1200 ml of dimethylformamide (DMF) containing 3 moles of benzaldehyde and heated at 35° C., a mixed solution of 0.3 mole of sodium cyanide and 2400 ml of DMF was added dropwise in 30 minutes, and the reaction was carried out for further 30 minutes with stirring. To the reaction solution, a mixed solution of 2.25 moles of methyl vinyl ketone and 2400 ml of DMF was added dropwise in 30 minutes, and the reaction was carried out for further 1 hour. After the reaction, water was poured into the reaction solution, followed by extraction with chloroform. The obtained chloroform solution was washed with dilute sulfuric acid, saturated aqueous solution of sodium bicarbonate, and water in this order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The resulting residue was distilled under reduced pressure to give a fraction of pale yellow liquid of 1-phenyl-1,4-pentanedione having a boiling point of 124°-127° C./0.15 mmHg (yield 40% ).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccsc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a stirred solution of methyl (2-bromothiophen-3-yl)acetate (120 mg, 0.51 mmol) and 4-iodo-3-nitrobenzoyl chloride (150 mg, 0.48 mmol) in anhydrous CH2Cl2 (10 mL) was added AlCl3 (260 mg, 1.95 mmol) in four portions in 10-minute intervals at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 2 as a light yellow solid (158 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=2.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.70 (dd, J=2.0, 8.2 Hz, 1H), 7.48 (s, 1H), 3.74 (s, 3H), and 3.68 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 183.8, 170.0, 153.2, 142.9, 141.9, 138.3, 136.5, 135.8, 133.1, 125.7, 124.5, 91.8, 52.6, and 35.0.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:33])=O>O1CCCC1>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:33])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a cooled (-10°) and stirred solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-hydroxyacetate (102 g., 0.250 mole) in tetrahydrofuran (2000 ml.) were added in succession pyridine (27.1 ml., 0.287 mole) and thionyl chloride (25.2 ml., 0.287 mole); the thionyl chloride addition was done over ca 15 minutes. The mixture was stirred for 30 minutes at -10° and filtered. Concentration of the filtrate left a yellow oil which was partially purified by absorption on a pad of silica gel (800 ml.) and elution with chloroform (ca 3000 ml.). Concentration of the eluates gave an oil (92.9 g., 100%) which was found to contain a minimum of 90% of the title ester as a mixture of epimers.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 100 °C
Yield: 48.3 %

Procedure:
Chlorosulfonic acid (10 ml, 0.15 mol) is added dropwise slowly to acetanilide (4 g, 0.029 mol). The mixture is then heated to 100° C. for one hour. The oil that forms is cooled and carefully poured onto ice. The resulting precipitate is collected by filtration affording the desired product (3.4 g, 0.014 mol, 48% yield). The sulfonyl chloride is used directly without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C.CN(C=O)C>C(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
para-Toluenesulfonyl chloride (13.8 g, 72.2 mmol) was added to a suspension of 4-piperidone (10.1 g, 65.7 mmol) and triethylamine (7.30 g, 72.2 mmol) in CH2Cl2(100 ml). After stirring at room temperature for 2 hours DMF (50 ml) was added to the reaction mixture and the stirring was continued overnight. The reaction mixture was concentrated in vacuo and saturated aqueous sodium bicarbonate was added to the residue. The resulting precipitate which formed was collected by suction filtration. The precipitate was washed with water followed by hexane and then dried under high vacuum to afford a white solid (9.4 g) which was used without further purification. 1H NMR (300 MHz, CDCl3) 7.69 (d, 2H, J=8.1 Hz), 7.34 (d, 2H, J=8.1 Hz) 3.39 (m, 4H), 2.55 (m, 4H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[CH3:12][NH2:13]>C1COCC1>[F:11][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][C:6]=1[CH2:7][NH:13][CH3:12])[C:1]#[N:2]
Reactant: CN
Reactant: N#Cc1ccc(CBr)c(F)c1
Solvent: C1CCOC1
Product: CNCc1ccc(C#N)cc1F
Reaction time: 0.08 h
Yield: 89 %

Procedure:
A solution of 4-cyano-2-fluoro-benzylbromide (15 g, 0.07 mol) in dry THF (50 mL) was added to the 40% aqueous solution of methyl amine (400 mL) at 5-10° C. and allowed to stir for 5 min. The mixture was extracted with DCM and the organic layer was dried over Na2SO4 and concentrated under vacuum, affording the title compound as a brown liquid (10 g, 89%). 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (m, 1H), 7.68-7.61 (m, 2H), 3.71 (s, 2H), 2.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:19][O+](C)C>>[F:14][B-:15]([F:18])([F:17])[F:16].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N+:5]([CH3:19])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: Cc1cc(Cl)c2cc(Cl)ccc2[n+]1C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
The starting material may be prepared as follows. Powered 4,6-dichloro-2-methylquinoline (254 mg.) was added to a stirred solution of trimethyloxonium tetrafluoroborate (177 mg.) in acetontrile (1 ml.), and stirring was continued overnight. The solvent was evaporated and the residue was triturated with ether to give 4,6-dichloro-1,2-dimethylquinolinium tetrafluoroborate (296 mg.). N.m.r. in solvent A:-3.07(s, 3H); 4.44(s, 3H9; 7.9-8.8(complex, 4H).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[C:4]1([CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([CH3:3])[CH3:1]
Reactant: C=CC
Reactant: Cc1ccccc1
Product: CC(C)Cc1ccccc1
Temperature: 163 °C
Reaction time: 6 h

Procedure:
In a 300 ml autoclave equipped with a magnetic stirrer, Solid Base A (4.07 g) and toluene (79.5 g) were charged under nitrogen and then liquid propylene (70 ml) was injected under pressure. The mixture was stirred at 163° C. for 6 hours to obtain isobutylbenzene (hereinafter referred to as "IBB").
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C@@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@H:13]2[CH3:12])[N:3]=1
Reactant: C[C@@H]1COCCN1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Temperature: 80 °C
Yield: 31.2 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (2.18 g, 11.53 mmol), (R)-3-methylmorpholine (1.40 g, 13.84 mmol) and DIPEA (2.57 mL, 14.99 mmol) in IMS (50 mL) were heated at 80° C. for 8 h. The reaction mixture was concentrated in vacuo to a reduced volume and the residue partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as an off-white solid (914 mg, 31%). LCMS (method H): RT 2.53 min [M+H]+ 254.3