Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][C:3]=1[F:15].[CH:16]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[C:4]([CH3:16])[C:3]=1[F:15]
Reactant: CC(C)[N-]C(C)C
Reactant: Fc1cc(OC2CCCCO2)ccc1Br
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(OC2CCCCO2)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-(4-bromo-3-fluorophenoxy)tetrahydro-2H-pyran (1200 mg, 4.4 mmol) was dissolved in tetrahydrofuran (22 mL, 0.2M) under nitrogen and cooled to −78° C. To this was added (600 mg, 5.6 mmol) lithium diisopropylamide in solution dropwise over 5 minutes. The reaction mixture was stirred for 1 h at −78° C. Methyl iodide (948 mg, 6.5 mmol) was then added dropwise. The reaction was stirred at −78° C. for 30 min and allowed to warm to RT overnight. The mixture was quenched with water and 10 mL of saturated aqueous ammonium chloride solution. The reaction was extracted with diethyl ether (3×). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 1.17 g (93%) of a light yellow mix of solid and oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.78 (m, 3 H) 1.85-1.93 (m, 2 H) 1.95-2.08 (m, 1 H) 2.21 (d, J=2.34 Hz, 3H) 3.61 (m, J=11.27, 3.98, 3.98, 1.46 Hz, 1 H) 3.78-3.88 (m, 1 H) 5.41 (t, J=3.12 Hz, 1 H) 6.81 (dd, J=8.98, 1.37 Hz, 1 H) 7.27 (d, J=16.98 Hz, 1 H)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[I:17]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([I:17])[CH:13]=[CH:12][N:11]=1
Reactant: II
Reactant: Fc1cccnc1Cl
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1c(I)ccnc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.4 %

Procedure:
A solution of lithium di-isopropylamide (2N in tetrahydrofuran/ethylbenzene/heptane, 155 mL, 310 mmol) was added dropwise over 40 minutes to solution of 2-chloro-3-fluoropyridine (31.0 g, 235 mmol) in tetrahydrofuran (200 mL) at −70° C. and the resulting mixture stirred for 4 hours. A solution of iodine (69.0 g, 200 mmol) in tetrahydrofuran (100 mL) was added dropwise over 30 minutes and the resultant mixture was stirred for 30 minutes at −70° C. then allowed to warm to room temperature over 1 hour. The reaction mixture was poured onto aqueous sodium metabisulphite solution (20% w/v, 2 L) and extracted with diethyl ether (3×300 mL). The combined organic extracts were washed with aqueous sodium metabisulphite solution (20% w/v, 2 L) and water (200 mL), dried over Na2SO4 and evaporated under reduced pressure to yield an oil. The resultant oil was triturated with diethyl ether to yield the title compound as a red/brown solid (28 g, 46% yield). 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J=5.0 Hz, 1H), 7.66 (ddd, J=5.0, 4.0, 0.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][S-:11].[Na+].CCCCCC>C1COCC1.O.II>[Cl:1][C:2]1[N:7]=[C:6]([S:11][CH3:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C[S-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (5 g, 27.32 mmol) in THF:water (1:1, 40 mL), was added sodium thiomethoxide (2.15 g, 30.01 mmol) at 0° C., and the mixture was stirred at rt for 4 h. TLC showed completion of starting material and formation of a slightly polar spot (TLC system: hexane charred in iodine). The reaction mixture was concentrated, water (20 ml) was added, and the product was extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate and concentrated to afford the desired compound as a white solid (5 g, 94.8%). MS m/z: 195.2 (ES+, M+H).
Reaction SMILES: FC1C=CC=C(F)C=1C(NC1C=CC(C2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:16]C=2C)=CC=1)=O.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.CCO>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15](=[S:16])[NH2:14]
Reactant: Cc1sc(-c2ccccn2)nc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=S)c1ccccn1
Yield: 100.6 %

Procedure:
The solution of 2 (0.5 g, 1.73 mmol) in THF (100 mL) with phenyltrimethylammonium tribromide (0.68 g, 1.8 mmol) was heated at 60° C. for 2 hr. Then the solution was quenched with water and extracted with EtOAc (3×50 mL). The combined EtOAc solution was concentrated to give the crude product, which could be used directly for the next step without further purification. The solution of resulting crude product with pyridine-2-carbothioamide (0.24 g, 1.74 mmol) in EtOH was heated at 70° C. overnight. The solution was diluted with water and extracted with EtOAc. Column chromatography (Hexanes/EtOAc=1/1) afforded compound 2 in 51% overall yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH3:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:17]=2)[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[BH3-]C#N.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH3:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:17]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2ccc3ccn(C[C@H](C)NC(=O)OC(C)(C)C)c3c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3c(c2)N(C[C@H](C)NC(=O)OC(C)(C)C)CC3)cc1
Reaction time: 4 h
Yield: 93.9 %

Procedure:
(S)-{2-[6-(4-Methoxy-phenyl)-indol-1-yl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (1.80 g) was dissolved in acetic acid (25 mL) and CH2Cl2 (10 mL) and cooled to 0° C. NaCNBH3 (1.41 g) was added in portions and the resulting mixture was allowed to stir for 4 hours. The reaction mixture was diluted with ethyl acetate and extracted with concentrated NaOH solution. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (gradient of ethyl acetate in hexanes) to give the title compound as a brown oil (1.7 g).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=[CH:11][C:12]([OH:14])=[O:13].[CH3:15][CH:16](O)[CH3:17].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1/[CH:10]=[CH:11]/[C:12]([O:14][CH:16]([CH3:17])[CH3:15])=[O:13]
Reactant: O=C(O)C=Cc1ccco1
Reactant: CC(C)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)/C=C/c1ccco1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
1.46 ml of thionyl chloride (20 mmol) were added to a solution of 1.38 g of 3-(2-furyl)acrylic acid (10 mmol) in 10 ml of chloroform and 0.1 ml of DMF. The solution was warmed to 70° C. and kept at this temperature for 1 h, then the solvents were removed under reduced pressure and the residue was dissolved in 6.6 ml of DCM and 3.3 ml of pyridine and subsequently cooled to 0° C. 0.96 ml of 2-propanol (12.5 mmol) was added, the temperature was increased to RT and the reaction mixture was stirred for 2.5 h. It was acidified with 30 ml of 1 M hydrochloric acid and extracted with 150 ml of ethyl acetate. The organic phase was washed with aqueous sodium hydrogencarbonate solution, dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. 1.72 g (yield: 96%) of the title compound were obtained. LC/MS (Method D) (M+H-isopropyl)+ 139
Reaction SMILES: C([O:8][CH2:9][CH3:10])(OCC)OCC.C(OC)(OC)(OC)CCCC.[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]2[C:34]3[N:42]([CH3:43])[C:41]([CH3:44])=[N:40][C:35]=3[CH:36]=[N:37][C:38]=2[CH:39]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.[Pd]>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]2[C:34]3[N:42]([CH3:43])[C:41]([CH3:44])=[N:40][C:35]=3[CH:36]=[N:37][C:38]=2[CH:39]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[CH3:43][N:42]1[C:34]2[C:33]3[CH:10]=[C:9]([OH:8])[CH:30]=[CH:39][C:38]=3[N:37]=[CH:36][C:35]=2[N:40]=[C:41]1[CH3:44]
Reactant: CCOC(OCC)OCC
Agent: [Pd]
Agent: CCCCC(OC)(OC)OC
Agent: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1C
Solvent: CCO
Product: Cc1nc2cnc3ccc(O)cc3c2n1C

Procedure:
7-Benzyloxy-1,2-dimethyl-1H-imidazo[4,5-c]quinoline was prepared according to the methods described in Parts A-C of Example 31. In Part C, triethyl orthoformate was used in lieu of trimethyl orthovalerate. A solution of 7-benzyloxy-1,2-dimethyl-1H-imidazo[4,5-c]quinoline in ethanol was added to a Parr vessel with 10% palladium on carbon. The reaction was placed under hydrogen pressure (35 psi, 2.4×105 Pa) for 20 hours. The reaction mixture was then filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid with heating, and the hot solution was filtered and concentrated under reduced pressure. The resulting beige solid was dissolved in 1 N aqueous hydrochloric acid, and deactivated carbon was added. The solution was heated, filtered, and treated with 50% aqueous sodium hydroxide. A precipitate formed and was isolated by filtration to provide 1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-ol as a solid, mp >300° C.
Reaction SMILES: II.[Mg].[CH:4]1(Br)[CH2:7][CH2:6][CH2:5]1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]=1I)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Br-].[Zn+2].[Br-].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.CN(C=O)C.C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]=1[CH:4]1[CH2:7][CH2:6][CH2:5]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: BrC1CCC1
Reactant: CCOC(=O)c1cc(OCC)c(I)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)c(C2CCC2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A catalytic amount of iodine was added to a mixture of magnesium (10.8 g) and THF (180 mL), then a THF (90 mL) solution of cyclobutyl bromide (30 g) was slowly added thereto at room temperature, and the mixture was stirred at the same temperature as above for 2 hours. A THF (120 mL) solution of zinc bromide (50.0 g) was added to the reaction mixture at 0° C., and the mixture was stirred at the same temperature as above for 2 hours. The zinc reagent (140 mL) prepared above was added to a mixture of ethyl 3-(benzyloxy)-5-ethoxy-4-iodobenzoate (10 g), tris(dibenzylideneacetone)dipalladium(0) (0.644 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.482 g), and DMF (100 mL), and the resultant mixture was stirred at 100° C. for 16 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature. Then, ethyl acetate was added thereto, and the mixture was filtered through celite. The filtrate was washed with water and saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.5 g).
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:16]=[C:15]([F:17])[CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].CCN(C(C)C)C(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([N:6]1[C:5]2[N:20]=[CH:21][C:2]([CH2:23][CH2:22][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:3][C:4]=2[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][C:15]([F:17])=[N:16][C:7]1=2)[CH3:19]
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Reactant: C=Cc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(F)nc21

Procedure:
8-Bromo-2-fluoro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (70 mg, 0.2 mmol) was coupled with 4-vinylpyridine in the presence of bis(triphenylphosphine)palladium(II) chloride and (i-Pr)2NEt as described in example 1h. The product was hydrogenated as described in example 3b. Purification by flash chromatography (elution with methanol-dichloromethane) and recrystallization (diethyl ether-petroleum ether) afforded 26 mg of the title compound as white crystals, m.p. 109°-111° C.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[C:17]([OH:19])=[O:18].O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].S(Cl)(Cl)=O>N1C=CC=CC=1>[OH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[C:17]([O:19][N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])=[O:18]
Reactant: O=C(O)c1cnc2cccnc2c1O
Reactant: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(ON1C(=O)CCC1=O)c1cnc2cccnc2c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.7 %

Procedure:
To a solution of dimethylformamide (47.5 kg) containing pyridine (4.7 kg), there were added 4-hydroxy-1,5-naphthyridine-3-carboxylic acid (2.8 kg) and N-hydroxy-succinimide (2.2 kg). To the mixture, there was dropwise added thionyl chloride (2.1 kg) while stirring at room temperature, and stirring was continued for 5 hours at the same temperature. The precipitated crystals were collected by filtration, washed with acetone and dried under reduced pressure to give 4.3 kg of N-(4-hydroxy-1,5-naphthyridine-3-carbonyloxy)succinimide. Purity, 97%
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([O:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:16]2[C@H:7]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15]2)=[O:4].[C:33](Cl)(=[O:35])[CH3:34].[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-].[Na+]>ClCCl>[C:33]([C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][CH2:15][C@@H:16]3[C@@H:7]([C:8]=2[CH:9]=1)[C@H:6]([O:5][C:3](=[O:4])[C:2]([CH3:32])([CH3:31])[CH3:1])[CH2:23][C@@:21]1([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]1[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4ccccc4[C@H]3[C@H](OC(=O)C(C)(C)C)C[C@]12C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)[C@@H]1[C@@H](CC2)[C@@H]2CC[C@H](OC(=O)C(C)(C)C)[C@@]2(C)C[C@H]1OC(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A solution of the diester (26A) (42 mg, 0.095 mmol) and acetyl chloride (0.1 ml, 0.11 g, 1.41 mmol) in dry dichloromethane (1 ml) was treated with anhydrous aluminium chloride (63 mg, 0.47 mmol) at room temperature. After being stirred to 30 min, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with dichloromethane and worked up in the usual manner to give an oil which was chromatographed on silica (2 g). Elution with ether-light petroleum (1:5) gave the product (27) (43 mg, 93%), as an oil, νmax 1730 and 1685 cm-1 (C=O), δ (250 MHz) 7.75 (1 H, dd, J 8 and 1.5 Hz, 3-proton), 7.64 (1 H, d, J 1.5 Hz, 1-proton), 7.20 (1 H, d, J 8 Hz, 4-proton), 5.52 (1 H, dt, J 10.5 and 5.5 Hz, 11-proton), 4.66 (1 H, dd, J 9 and 7 Hz, 17-proton), 2.89 (2 H, t, J 7 Hz, 6-protons), 2.53 (3 H, s, CH3CO), 2.37-1.25 (11 H, m), 1.23 (18 H, two s, OBut), 0.89 (3 H, s, 18-CH3), M+ (ammonia chemical iionization) 500 (M+NH3).
Reaction SMILES: [N+:1](C1C=C2C(=CC=1)N1N=NN=C1C=N2)([O-:3])=[O:2].OO.[N+:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]1[N:32]=[N:33][N:34]=[C:27]1[C:26](=[O:35])[NH:25]2)([O-:21])=[O:20].OS(O)(=O)=O.[N+]([O-])([O-])=O.[K+]>O.CC(O)=O>[N+:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[N+:1]([O-:3])=[O:2])[N:28]1[N:32]=[N:33][N:34]=[C:27]1[C:26](=[O:35])[NH:25]2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc2c(c1)ncc1nnnn12
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2n2nnnc12
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n2nnnc12
Temperature: 85 °C

Procedure:
The nitrotetrazoloquinoxaline (23) (1.84 g, 8.51 mmol) was added to a mixture of 15 ml of glacial AcOH and 20 ml of 30% H2O2 and heated at 85° C. in an oil bath for 16 hours. Upon cooling, the mixture was diluted with H2O (50 ml) and the precipitate collected by filtration. Recrystallization from 40 ml of 50% aq. DMF gave 1.29 g of yellow flocculant needles comprising 7-nitrotetrazolo[1,5-a]quinoxalin-4(5H)-one (24). This nitrotetrazoloquinoxalinone (3.00 g, 12.9 mmol) was added to conc. H2SO4 (40 ml) and treated with KNO3 (1.43 g, 14.1 mmol) with warming to 50° C. under N2. The mixture was poured onto 600 ml of ice-H2O, and a light yellow solid collected by filtration and washed with H2O, yielding 7,8-dinitrotetrazolo[1,5-a]quinoxalin-4(5H)-one (25).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:69]/[O:70][CH3:71])/[C:15]([NH:17][C@@H:18]2[C:67](=[O:68])[N:20]3[C:21]([C:51]([O:53]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:52])=[C:22]([S:25][CH2:26][C:27]4[CH:28]=[N:29][N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:31]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1>C1(OC)C=CC=CC=1.ClCCl>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:69]/[O:70][CH3:71])/[C:15]([NH:17][C@@H:18]2[C:67](=[O:68])[N:20]3[C:21]([C:51]([OH:53])=[O:52])=[C:22]([S:25][CH2:26][C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)CS[C@H]12)c1csc(N)n1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cn[nH]c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
Under nitrogen atomosphere, 1 ml of trifluoroacetic acid was added slowly to a solution of 500 mg of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate in anisole (0.5 ml) and dichloromethane (1.5 ml) at 0° C. The mixture was warmed to a room temperature and stirred for 2 hours. The mixture was poured into IPE and the resulting precipitate was collected by filtration. The precipitate was dissolved in pH 6.86 buffer and chromatographed on a HP-20 (eluent: water-methanol). The eluate was lyophilized to afford 171.6 mg of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C.[CH2:10]([C:12](=[C:18]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](OCC)=[O:14])[CH3:11]>CCOCC>[CH2:10]([C:12](=[C:18]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][OH:14])[CH3:11]
Reactant: CCOC(=O)C(CC)=C(c1ccccc1)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCO
Product: CCC(CO)=C(c1ccccc1)c1ccc(OC)cc1
Temperature: 0 °C
Yield: 76.7 %

Procedure:
1.04 g (30 mmol) of LiAlH4 were suspended in 25 ml of dry ether. 1.38 g (30 mmol) of dry ethanol in ether were cautiously added to this suspension. 16 ml of this reagent were in 2 ml portions at 1 hour intervals added to a stirred solution of 1.86 g (6 mmol) of ethyl 2-ethyl-3-(p-methoxyphenyl)-3-phenylpropenoate in 16 ml of dry ether. After the reaction was complete, ice water was added cautiously and the precipitated aluminium salts were filtered off. The water layer was extracted with ether. The combined ether solutions were dried and evaporated to give 1.24 g (4.6 mmol, 77%) of the oily product as a mixture of E- and Z-isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:29][C:30]([F:47])([F:46])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:45][CH2:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]([F:47])([F:29])[F:46])=[CH:37][CH:36]=3)[CH:43]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 18 %

Procedure:
A solution of acid 4C (0.50 g, 1.8 mmol) in THF (30 mL) was added with DEPC (0.35 mL, 1.3 mol eq) and the mixture stirred at room temperature several minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.53 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc and washed with water and brine. The separated organic phase was dried over an. Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a pale yellow viscous oil (0.17 g). Yield=18%, 1HNMR (DMSO, 200 MHz) δ 2.98 (s, 3H), 4.22 (d, 2H), 5.08 (s, 1H), 5.85 (s, 1H), 7.4 (m, 3H), 7.65 (dd, 4H, J=8), 7.95 (s, 1H), 8.2 (d, 2H), 8.58 (d, 1H), 8.95 (t, 1H); [M+1] 525.93 (C23H19ClF3N3O4S requires 525.07).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)=[CH:5][N:4]=1)#[CH:2].I[C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[F:9][C:8]1[C:3]([C:1]#[C:2][C:18]2[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)=[N:4][CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)[CH:7]=1
Reactant: CC1(O)CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ncc(C2=CCC(C)CC2)cc1F
Product: CC1CC=C(c2cnc(C#Cc3ccc(OCCN4CCC(C)(O)CC4)cc3)c(F)c2)CC1

Procedure:
The product was prepared analogously to Example 48.1c from 130 mg (0.60 mmol) of 2-ethynyl-3-fluoro-5-(4-methylcyclohex-1-enyl)pyridine and 217 mg (0.60 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidin-4-ol (IP 15) (24 at RT, triethylamine as base). Yield: 15 mg (6% of theoretical); C28H33FN2O2 (M=448.572); calc.: molpeak (M+H)+:449; found: molpeak (M+H)+:449; HPLC-MS: 5.08 minutes (method H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].OO.S([O-])([O-])(=O)=[O:14].[In+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[In+3].CC1C(C)=CC(C)=C(O)C=1O>CC(C)CC(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:14])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=S(=O)([O-])[O-]
Agent: Cc1cc(C)c(O)c(O)c1C
Agent: OO
Agent: [In+3]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(O)c(C)c(C)c1O

Procedure:
In a vessel used in Example 52 were placed 100 g. (735 m. moles) of 2,3,5-trimethylphenol, 2.31 g. (23.1 m. moles) of 4-methyl-2-pentanone, 2.61 g. (46.0 m. moles) of 60 percent hydrogen peroxide and 1.0 g. of indium sulphate (In2 (SO4)3.9H2O), and the mixture was treated at 100° C. for 60 minutes. 2.16 g. (14.2 m. moles) of 3,4,6-trimethylcatechol and 0.64 g. (4.2 m. moles) of 2,3,5-trimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 40.0 percent.