Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH2:32][CH3:33])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CCC(=O)CBr
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Product: CCc1csc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)n1

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-bromobutan-2-one using the same procedure as reported for 2.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].Cl.[CH3:14]O>>[CH3:14][O:1][C@H:2]1[O:10][CH:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Product: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
In a manner similar to that described in Example 3, 300 parts by weight of D-glucose obtained from used paper was added to 1,100 parts by weight of a methanol solution containing hydrochloric acid at a concentration of 0.25 wt % and was then refluxed for 72 hours, whereby 160 parts by weight of methyl-D-glucopyranoside was obtained. The measurement results are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH:41]([NH:44][CH3:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH:41]([N:44]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:30])([F:31])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH3:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-Methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: C(=O)(O)O.[C:5]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[C:7]=1[OH:8])[OH:6].[CH2:14]([C@H:16]1[O:18][CH2:17]1)Cl.N1C=CC=CC=1>C(OCC)(=O)C>[OH:6][C:5]1[C:7]2[O:8][C@@H:16]([CH2:17][OH:18])[CH2:14][O:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Oc1cccc(O)c1O
Reactant: ClC[C@@H]1CO1
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: OC[C@H]1COc2cccc(O)c2O1
Yield: 10.1 %

Procedure:
A mixture of pyrogallol carbonate (8.2 g), (S)-epichlorohydrin (5.0 g) and dry pyridine (0.2 ml) in dry ethyl acetate (50 ml) was heated under reflux for 2 hours. The solvent was removed in vacuo, water (30 ml) was added, and the mixture heated under reflux for 30 minutes. A solution of potassium hydroxide (10 g) in water (20 ml) was added dropwise and the mixture heated under reflux under nitrogen for a further 30 minutes. The cooled mixture was diluted with water (100 ml), acidified with hydrochloric acid (5 M) then extracted with ethyl acetate (3×200 ml). The combined extracts were washed with water (2×100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by chromatography over silica eluting with a 1:1 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) followed by neat ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give (S)-8-hydroxy-1,4-benzodioxan-2-ylmethanol (0.8 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:5]4[C:4]/3=[CH:9][CH:8]=[CH:7][N:6]=4)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: O=C1Cc2cccnc2N1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2[nH]ncc2c1
Yield: 95.3 %

Procedure:
The title compound (50 mg, 95%) was synthesized as an orange solid according to the method described for Example A67 using 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and 1H-indazole-5-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H, NH), 11.20 (s, 1H, NH), 8.21 (s, 2H), 8.09 (d, J=5.2 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 6.91 (dd, J=8.0 Hz, 5.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:8](OS(C)(=O)=O)[CH2:9][S:10][C@H:5]12)=[O:2].[SH:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:17])=[C:8]([S:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: SCc1ccncc1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 1.9 h
Yield: 88.4 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-methanesulfonyloxy-3-cephem-4-carboxylate (14.66 g, 30 m mol) in DMF (103 ml) was added 4-(mercaptomethyl)pyridine (4.13 g, 33 m mol) at −20° C., followed by dropwise addition of N,N-diisopropylethylamine (3.88 g, 30 m mol). The mixture was stirred at the same temperature for 1.9 hours and poured into ice water (500 ml). The resulting precipitates were collected by filtration and washed with water. The powder was dissolved in THF, and ethyl acetate and water were added respective. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give diphenylmethyl 7β-formamido-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (13.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:3]=12.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[C:10]([C:11]#[N:12])[C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1c[nH]c2nccc(Cl)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (2.5 g, 14.08 mmol) in tetrahydrofuran (200 mL) was cooled to 0° C. and treated with sodium hydride (0.5 g, 21.1 mmol). The mixture was stirred at 0° C. for 30 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (2.8 g, 16.9 mmol) was added. After stirring at room temperature for 2 hours, the mixture was treated with brine and extracted with ethyl acetate (three times) and the organic layers were dried over sodium sulfate. Filtration, concentration and purification by flash chromatography (Combi Flash Rf) (silica gel, 40% ethyl acetate in hexane) afforded the title compound. MS (ESI+) m/z 308 (M+H)+.
Reaction SMILES: [I:1]I.[CH3:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([O:13][C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:6]=2[O:5]1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:1][C:12]1[C:6]2[O:5][CH:4]([CH3:3])[CH2:8][C:7]=2[CH:9]=[C:10]([O:13][C:14]([F:15])([F:17])[F:16])[CH:11]=1
Reactant: CC1Cc2cc(OC(F)(F)F)ccc2O1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc(OC(F)(F)F)cc(I)c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Iodine (2.8 g, 11 mmol) was added in few portions to a stirred mixture of 2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran (Description 21; 2.8 g, 12.8 mmol), silver(I) trifluoroacetate (3.5 g, 15.8 mmol) in chloroform (60 ml). The mixture was stirred at room temperature for 1 hour, filtered through a pad of Celite™ and concentrated. The residue was treated with iso-hexane (150 ml), washed with aqueous sodium sulphite. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-4%) to give the title compound (3.76 g, 85%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:13]I.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH3:13])[CH:7]=1
Reactant: CI
Reactant: Cc1c(Br)c[nH]c(=O)c1C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(Br)cn(C)c(=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 5-bromo-3,4-dimethyl-1H-pyridin-2-one (402.0 mg, 2.0 mmol) in anhydrous THF (20 mL) was added NaH (96.0 mg, 2.4 mmol). The resulting mixture was stirred at 0° C. for 30 min. Methyl iodide (568.0 mg, 4.0 mmol) was added and the reaction was stirred at 32° C. for 3 h. Then, saturated aqueous NH4Cl (100 mL) was added and the mixture extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA=10:1 to 2:1) to give the title compound (350.0 mg, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.38 (s, 1H), 3.52 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H). LCMS (M+H)+ 216.
Reaction SMILES: C([Sn:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])CCC.[Sn](Cl)(Cl)(Cl)[Cl:43]>CCCCCCC>[CH2:6]([Sn:5]([Cl:43])([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCC[Sn](CCCC)(CCCCCCCCCCCC)CCCCCCCCCCCC
Reactant: Cl[Sn](Cl)(Cl)Cl
Solvent: CCCCCCC
Product: CCCCCCCCCCCC[Sn](Cl)(CCCCCCCCCCCC)CCCCCCCCCCCC
Yield: 97.1 %

Procedure:
A 500 ml four-necked flask was charged with 95.0 g of n-butyl tri-n-dodecyltin, 36.4 g of tin tetrachloride and 150 ml of n-heptane, and they were reacted at 40° to 50° C. for 1 hour. After the reaction, the reaction mixture was washed three times with 100 ml of 10% aqueous solution of hydrochloric acid to remove mono-n-butyltin trichloride. The organic layer was dried with anhydrous magnesium sulfate, and concentrated to afford 89.3 g of tri-n-dodecyltin chloride having a purity of 97.2% as an oily substance (m.p. 30° to 32° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:6]=1)(=[O:16])=[O:15]
Reactant: Nc1ccc(CCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCCCOS(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
9.25 g (0.056 mole) 4-aminobenzenebutanol is dissolved in 100 ml pyridine and the solution is cooled to ca. -10° C. 17.33 ml (25.65 g) (0.244 mole) methanesulfonyl chloride is added dropwise with vigorous stirring at a rate such that the methanesulfonyl chloride is added, the reaction mixture is left in the freezer for two days. The reaction mixture is poured onto 300 ml ice water and extracted with 3×200 ml methylene chloride. The combined organic layers are washed with 1 liter cold 5% HCl in 3 portions. The organic layer is dried over sodium sulfate, filtered, and stripped. The residue is crystallized from ethyl acetate/ether to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=O)=[O:20])=[CH:13]2>>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][N:6]([CH3:7])[C:23]([CH:22]([NH:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)=[O:20])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:25]
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CNCCCN(C)C
Product: CN(C)CCCN(C)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
N,N,N'-Trimethyl-1,3-diaminopropane (0.31 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.28 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 120 hour reaction time) and the product purified by chromatography on silica gel eluted with 1-8% ethanol in dichloromethane containing 0.5% ammonium hydroxide: Yield 86 mg, 69%; HPLC (40/60) 7.57 minutes (>99%); mp 187-190.5° C.; TSPMS 441/443 (MH+, 100%);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)#[CH:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:15]1([NH:14][C:12]([C:10]2[N:11]=[C:6]3[CH:5]=[CH:4][C:3]([C:1]4[N:21]=[N:22][NH:23][CH:2]=4)=[CH:8][N:7]3[CH:9]=2)=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3c[nH]nn3)ccc2n1
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
123 mg of 6-ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 46 mg of sodium azide, 38 mg of ammonium chloride and 5 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 20 minutes in a microwave machine set at 170° C. and then for a further 30 minutes under the same conditions, followed by addition of 46 mg of sodium azide and 38 mg of ammonium chloride, and finally concentrated at 50° C. under reduced pressure. The residue is taken up in 20 mL of ethyl acetate and 20 mL of water. The aqueous phase is extracted twice with 20 mL of ethyl acetate and the combined organic phases are washed with 30 mL of saturated brine and then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a gradient of dichloromethane and methanol (from 100/0 to 90/10). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 36 mg of N-phenyl-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of an off-white solid.
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]2[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=2[CH3:30])[CH:15]=1)[CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl.O=[Mn]=O>[CH3:13][CH:3]([C:2](=[O:1])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]2[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=2[CH3:30])[CH:15]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC1=C(/C=C/c2cccc(C(O)C(C)CNC(=O)OC(C)(C)C)c2)C(C)(C)CCC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC1=C(/C=C/c2cccc(C(=O)C(C)CNC(=O)OC(C)(C)C)c2)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-tert-butyl 3-hydroxy-2-methyl-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propylcarbamate (0.2728 g, 0.64 mmol) in CH2Cl2 (10 mL) under argon was added MnO2 (2.4751 g, 28.5 mmol). The mixture was stirred at room temperature overnight. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave (E)-tert-butyl 2-methyl-3-oxo-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propylcarbamate as an oil. (Yield 0.1333 g, 49%): 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 6.75 (dd, J=16.4, 0.8 Hz, 1H), 6.38 (d, J=16.4 Hz, 1H), 4.96 (br s, 1H), 3.76-3.81 (m, 1H), 3.40 (t, J=6.0 Hz, 2H), 2.04 (t, J=6.0 Hz, 2H), 1.76 (s, 3H), 1.61-1.72 (m, 2H), 1.46-1.51 (m, 2H), 1.40 (s, 9H), 1.19 (d, J=7.2 Hz, 3H), 1.06 (s, 6H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of fluorene (MW 166, 0.36M, 59.76 g), N-bromosuccinimide (MW 178, 0.36M, 64.1 g), benzoyl peroxide (MW 242, 0.0036M, 0.87 g) and carbon tetrachloride (360 ml) was stirred at reflux for 3 hours. After cooling to room temperature and screening, the filtrates were evaporated under reduced pressure to yield a dark oil, which after crystallisation from methanol gave 46.1 g of the title product (55% yield) as a yellow solid, m.p. 102°-104° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CC(C)([O-])C.[K+].O.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]([F:17])([F:18])[CH2:3][C@@H:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: CC(CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@H](CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
10 g of 4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide (diastereomer ratio 2(S):1(R), prepared by a method similar to that described in step c)above) was dissolved in tetrahydrofuran (25 ml) with stirring. Potassium t-butoxide (2.02 g) was then added, together with tetrahydrofuran (5 ml). The resultant solution was then stirred for one hour, by which time complete equilibration of the diastereomers had occured, as monitored by HPLC analysis. Water was then added with cooling to maintain the temperature at 20°-25° C. The solution was then stirred for 10 minutes, and then toluene (25 ml) was added, and the stirring was continued for a further 15 minutes. The organic layer was then separated, washed with water (12.5 ml) and concentrated by distillation at atmospheric pressure to a temperature of 110° C. The volume was adjusted to 80 ml by adding toluene, and the mixture heated under reflux. Petroleum ether (b.p. 100°-120° C.) (80 ml) was then added. The solution was then allowed to cool to 40° C., seeded with (R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide and held at 40° C. for 2 hours. The mixture was then allowed to cool to 30° C., and was stirred overnight. The crystalline product was then filtered off, washed with petroleum ether (b.p. 100°-120° C.) and dried at 65° C. to afford 3.20 g (32%) of (R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide contaminated with about 6% of the undesired (S) diastereomer. ##STR2##
Reaction SMILES: [NH:1]([C:22]([O:24]CC1C=CC=CC=1)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:32]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:33](C(O)=O)[CH2:34][CH2:35][C:36](=[O:38])[NH2:37].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C=O)C>[NH:32]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:33]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(N)=O)C(=O)O
Reactant: CN(C(=O)CNC(=O)OCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 15 h

Procedure:
0.85 g of Z-Gly-MePhe-NHNHCONH2 is subjected to catalytic reduction in methanol, dissolved in 10 ml of DMF, and after ice-cooling, 0.50 g of BOC-(D)-Gln-OH, 0.40 g of HONB and 0.45 g of DCC are added. The mixture is stirred for 15 hours, the precipitated DCU filtered off and the solvent distilled off. The residue is dissolved in n-butanol, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is distilled off, treated with ether and filtered to obtain a powder. Yield 0.82 g; m.p. 124°-128° C.; [α]D24 -36.5° (c=1.0, DMF); Rf1 0.11.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=O)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:16]1([C:14]2[CH2:2][C:1](=[O:3])[C:4]3[C:5](=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)[N:13]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1cccc3ccccc13)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CC(c2cccc3ccccc23)=Nc2cc3c(cc21)OCO3

Procedure:
The synthetic procedure of target compounds 153 is illustrated in Scheme 11. The starting 2-amino-4,5-methylenedioxy-acetophenone (148) was first reacted with naphthalene-1-carbonyl chloride (149) to give N-(6-Acetyl-1,3-benzodioxol-5-yl)naphthalene-1-carboxamide (150). Then, the intermediate (150) was subjected to cyclization in dioxane, in the presence of NaOH, to afford 2-(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-one (151). Compound 151 was first reacted with tetrabenzylpyrophosphate in THF, in the presence of NaH, to yield Dibenzyl 2-(1-naphthalenyl)-6,7-methylenedioxyquinolin-4-yl Phosphate (152). Compound 152 was then subjected to catalytic hydrogenation in MeOH to give its diphosphoric acid (153).