Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1NC(=O)C(C#N)=CC=1C(=O)CC.C(C1C=C(C#N)C(=O)NC=1CC)(=O)C.[CH3:29][C:30](=[O:36])[CH2:31][C:32](=[O:35])[CH2:33][CH3:34].CO[CH:39](OC)[N:40]([CH3:42])[CH3:41]>CN(C)C=O>[CH3:39][N:40]([CH:42]=[C:31]([C:32](=[O:35])[CH2:33][CH3:34])[C:30](=[O:36])[CH3:29])[CH3:41]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC(C)=O
Agent: CCC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: CCc1[nH]c(=O)c(C#N)cc1C(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)C(=CN(C)C)C(C)=O
Reaction time: 8 h

Procedure:
A-2. 1,2-Dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrile--A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said 3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile, m.p. 265°-268 ° C. with decomposition. The mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrile. Although preliminary attempts to separate the two compounds by fractional crystallization were unsuccessful, it is contemplated that the two compounds would be separable by other conventional separation techniques, e.g., chromatography.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:19])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2ccccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2ccccc2c1Cl

Procedure:
3-Butyryl-4(1H)-quinolone (21.5 g) and phosphoryl chloride (80 ml) were heated under reflux for 45 minutes. Excess phosphoryl chloride was evaporated in vacuo, the residue poured onto ice and neutralised with sodium hydrogen carbonate. Extraction with dichloromethane, drying and evaporation gave 3-butyryl-4-chloroquinoline (22 g) as a brown oil, which solidified on standing. This was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=1[C:18]([O:20]CC)=[O:19].[OH-].[Li+].C(O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
Ethyl 2-(6,7-dimethoxyquinolin-4-yloxy)-5-methoxybenzoate (143 mg) and lithium hydroxide (78 mg) were suspended in a mixed solvent composed of ethanol (10 ml) and water (1 ml), and the suspension was stirred at room temperature overnight. The solvent was then removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the resultant solution was neutralized with 12N hydrochloric acid. The mixture was then extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure to give the title compound (140 mg, yield 100%).
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[C:16]([CH3:18])([CH3:17])[CH:15]([C:19]([OH:21])=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:22].C1(N2C(C)(C)C(C(O)=O)C3C(=CC=CC=3)C2=O)CC1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:17][C:16]1([CH3:18])[CH:15]([C:19]([OH:21])=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:22])[NH:7]1
Reactant: COc1ccc(CN2C(=O)c3ccccc3C(C(=O)O)C2(C)C)cc1OC
Agent: CC1(C)C(C(=O)O)c2ccccc2C(=O)N1C1CC1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)NC(=O)c2ccccc2C1C(=O)O
Temperature: 70 °C

Procedure:
To 2-(3,4-dimethoxy-benzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid (9.6 g, 26 mmol), prepared in manner analogous to 2-cyclopropyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid, is added thioanisole (36 mL, 304 mmol) and trifluoroacetic acid (360 mL). The resulting solution is heated to 70° C. for 13 h. The reaction is then cooled to room temperature and concentrated in vacuo to near dryness. The resulting purple oil is purified via silica gel flash chromatography (dichloromethane-methanol, 1:0 to 9:1, with 0.5% acetic acid) to furnish 3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid as an off-white foam; MS (ESI) m/z 220.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccn1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc([N+](=O)[O-])ccn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 101.2 %

Procedure:
To a solution of 2-amino-4-nitropyridine (3.0 g, 0.018 mol) in pyridine (40 mL) was added acetic anhydride (5.2 mL 0.055 mol). The reaction mixture was allowed to stir for 30 h at rt. Water was added to the solution and the resulting solid was collected and washed with water and dried under vacuum to give N-(4-nitropyridin-2-yl)acetamide as a brown solid (3.3 g, 99%). 1HNMR (300 MHz, CDCl3) δ: 8.90 (s, 1H), 8.50 (d, 1H), 8.30 (br s, 1H), 7.8 (dd, 1H), 2.3 (s, 3H); LCMS: (FA) ES+ 182.2.
Reaction SMILES: OC1C(C)=CC(N)=CC=1C.[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>O>[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[N:32][NH:31][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:26][CH:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cc1cc(N)cc(C)c1O
Agent: Cc1cc2c(c(C)c1O)C(=O)C(=O)N2
Agent: Cl
Solvent: O
Product: Cc1cc2c(c(C)c1O)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from 4-hydroxy-3,5-dimethylaniline according to Procedure A. The title compound was prepared from 5-hydroxy-4,6-dimethyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ2.18 (s, 3H), 2.47 (s, 3H), 6.50 (s, 1H), 7.22 (s, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.99 (s, 1H), 10.78(s, 1H), 12.98 (s,1H); APCI−MS: m/z 359 (M−H)−. Anal. Calcd for C16H16N4O4S.0.25 H2O: C, 52.67; H, 4.56; N, 15.35; S, 8.79. Found: C, 52.69; H, 4.47; N, 15.33; S, 8.87.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[OH-].[Na+].[F:54][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:54])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: F[B-](F)(F)F
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. The pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 12.5 mL) while the temperature was maintained below 20° C. 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (2.4 g, 6.813 mmole) was added and stirring continued for an additional 3 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford 4.5 g of crude flurithromycin. This material was recrystallized as described in Example 1 to yield 2.6 g (51% yield) of flurithromycin.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].[N:20]([Si](C)(C)C)=[N+:21]=[N-:22].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[CH:12]([N:9]1[C:10]2[CH:11]=[C:3]([C:1]3[NH:22][N:21]=[N:20][N:2]=3)[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[C:7]([CH3:15])=[CH:8]1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
To a stirred suspension of methyl 6-cyano-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.951 mmol) in azidotrimethylsilane (1.0 mL, 7.53 mmol) in a small vial was added tetrabutylammonium fluoride trihydrate (300 mg, 0.951 mmol). The reaction was heated to 85° C. and stirred for 18 hr (attached a small reflux condensor). (The reaction became a semi-solid mass.) The reaction was taken up in EtOAc (75 mL), washed with 1N HCl (75 mL) (stirred till dissolved). The organic phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF40-80g, 0 to 3% MeOH/CH2Cl2 with 0.1% HOAc) gave the product methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.28 g, 0.935 mmol, 48.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=1.3 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 4.86 (quin, J=6.6 Hz, 1H), 3.94 (s, 3H), 2.33 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 300.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[C:5]=1[OH:12])([O-:3])=[O:2].[CH2:13]([N:15](CC)CC)C.CN(C1C=CC=CN=1)C.[Cu]C#N>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:13]#[N:15])[C:5]=1[OH:12])([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1Br
Reactant: CCN(CC)CC
Agent: N#C[Cu]
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(O)c1C#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in dimethyl formamide (2 mL) followed by the addition of triethylamine (0.175 g, 1.73 mmol). The addition of a catalytic amount dimethylamino pyridine was then made, followed by addition of copper (I) cyanide (155 mg, 1.73 mmol). The mixture was allowed to stir at 80° C. for 4 hours. The solvent was evaporated and chromatography of the resulting solid on silica gel (2%MeOH/CH2Cl2) gave the desired product (70 mg, 91%). 1H NMR (CD3COCD3): d 8.30 (d, 1H), 7.15 (d, 1H), 2.61 (s, 3H).
Reaction SMILES: [F:1][C:2](I)([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[NH:12]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:13]([C:17]([N:19]1[CH2:34][CH2:33][CH2:32][C@H:20]1[C:21]([NH:23][C@H:24]([C:28](OC)=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15]>C(OCC)C>[NH:12]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C@H:13]([C:17]([N:19]1[CH2:34][CH2:33][CH2:32][C@H:20]1[C:21]([NH:23][C@H:24]([C:28]([C:2]([C:3]([C:4]([F:7])([F:6])[F:5])([F:9])[F:8])([F:10])[F:1])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Add perfluoropropyl iodide (6.6 mL, 48.0 mmol, from Aldrich, stabilized with Cu) dropwise, under N2, to a -78° C. solution of Boc-Val-Pro-Val-OCH3 ] (3.89, 9.0 mmol) in anhydrous diethyl ether (100 mL). Add methyllithium-lithium bromide complex (28.5 mL, 42.0 mmol) at a rate which maintains an internal reaction temperature below -70° C. Stir the reaction mixture at -78° C. for 1 hour, then remove the cold bath and continue stirring for 5 minutes. Pour the reaction mixture into H2O (100 mL) and acidify the aqueous phase with 1N HCl. Extract the aqueous phase with additional diethyl ether (100 mL) and dry (MgSO4) the combined ethereal extracts. Remove the solvent in vacuo and purify the resultant yellow foam by flash chromatography (4.0×25 cm column eluted with 3:1 Et2O-hexane) to yield the title compound as a white foam. (Yield: 654 mg, 13%). FT-IR (KBr) 3423, 3292, 2972, 2937, 2879, 2823, 2771, 2739, 2253, 1755, 1687, 1635, 1525, 1444, 1392, 1367, 1348, 1313, 1232, 1178, 1126, 1041, 1018, 966, 922, 910, 877, 837, 798, 756, 736, 667, 650, 632, 596 cm-1 ; 1H NMR (300 MHz, CDCl3)δ 7.63 (d, 1H, J=8.2 Hz, NH), 5.44 (d, 1H, J=9.2 Hz, NH), 5.02 (dd, 1H, J=7.8, 4.5 Hz, CH of Val), 4.64 (dd, 1H, J=8.0, 3.0 Hz, CH of Pro), 4.30 (dd, 1H, J=9.2, 6.8 Hz, α-CH of Val), 3.80-3.74 and 3.66-3.60 (pr m, 2H, CH2N), 2.31-1.92 (series of m, 6H, β-CH of Val, CH2CH2), 1.44 (s, 9H, t-Bu), 1.02 (d, 3H, J=7.0 Hz, CH3), 0.98,(d, 3H, J=6.9 Hz, CH3), 0.94 (d, 3H, J=6.7 Hz, CH3), 0.88 (d, 3H, J=6.9 Hz, CH3); 13C NMRδ 193.3, 193.0, 192.7, 172.9, 171.1, 155.7, 118.7, 115.8, 111.3, 108.9, 108.6, 108.2, 105.9, 79.6, 77.3, 77.2, 76.9, 76.6, 59.7, 59.3, 56.8, 47.8, 31.4, 29.0, 28.3, 26.9, 25.1, 19.9, 19.8, 19.7, 19.5, 19.4, 17.5, 17.4, 16.3, 16.1; 19F NMR (376.3 MHz, CDCl3)δ -80.91 (t, CF3), -119.03 and -120.43 (AB quartet, J=297 Hz, CF2), -126.62 (s, CF2), MS (CI/CH4) m/z (rel. intensity) 566 (MH+, 100). HRMS (C23H34F7N3O5) (M+) calcd 566.2492, obsd 566.2475.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[CH:3]([OH:5])[CH3:4].[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[CH:3]([OH:5])[CH3:4]
Reactant: [H][H]
Reactant: CC1=CCC(CCC(C)C(C)O)C1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(O)C(C)CCC1CCC(C)C1(C)C
Yield: 97.3 %

Procedure:
A mixture of 105 g (0.5 mole) of 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol, 5.3 g of 5% palladium on carbon and 100 ml of ethanol was hydrogenated at 30°-45° C and 35-50 psi until the hydrogen uptake ceased. The mixture was filtered to remove the catalyst and the solvent was removed from the filtrate by distillation. The residual oil was fractionally distilled to yield 3-methyl-5-(2,2,3-trimethylcyclopentan-1-yl)pentan-2-ol: 93.2 g (97.3% yield); bp 105°-107° C (1.3 mm); mol wt 212 (ms);
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].Cl>O.C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:10][C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: NCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)NCc1cccc(Cl)c1
Reaction time: 72 h

Procedure:
3.22 g of sodium cyanate was added to a solution of 5.50 ml of 3-chlorobenzylamine in 40 ml of water and 40 ml of THF followed by dropwise addition of 48.6 ml of 1N HCl. After 3 days, the mixture was evaporated to dryness, the residue extracted with hot THF and the filtrate again evaporated to dryness. The residue was suspended in 180 ml of diethyl ether and the solid collected to give the title compound (7.91 g) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5](=[O:20])(=[O:19])[C@@H:6]2[C@@H:16]([Cl:17])[C:15](=[O:18])[N:7]2[C:8]=1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10].C(N(CC)CC)C.[SH:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1>C(#N)C>[C:11]([C:9]([C:8]1[N:7]2[C:15](=[O:18])[C@H:16]([Cl:17])[C@H:6]2[S:5](=[O:20])(=[O:19])[CH2:4][C:3]=1[CH2:2][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cn1nnnc1S
Reactant: CC(C)(C)C(=O)C1=C(CBr)CS(=O)(=O)[C@@H]2[C@@H](Cl)C(=O)N12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)C(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Yield: 49.3 %

Procedure:
A solution of 3-bromomethyl-4-tert-butylcarbonyl-7α-chloro-3-cephem 1,1-dioxide (65 mg), prepared as in Example 6, in dry acetonitrile (5 ml) was treated with triethylamine (0.025 ml) and 5-mercapto-1-methyl-1,2,3,4-tetrazole (26 mg). An immediate reaction took place (TLC monitoring). The solvent was removed in vacuo and the residue purified by flash-chromatography, thereby obtaining the title product as a white powder (35 mg)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=1[C:20]([O:22][CH3:23])=[O:21])(=O)=O.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:26][C:27]([F:38])([F:39])[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C:8]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(OC(F)(F)F)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a mixture of 1-(1,1-dimethylethyl) 3-methyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (2.5 g, P2), {4-[(trifluoromethyl)oxy]phenyl}boronic acid (1.52 g) and Pd(PPh3)4 (265 mg) under nitrogen, toluene (34 mL), ethanol (25 mL) and Na2CO3 (2M, 19 mL) were added in sequence. The mixture was stirred at 80° C. for 2 hours then the reaction mixture was allowed to reach room temperature. The aqueous phase was extracted with Et2O (2 times), the combined organic phases were dried on anhydrous Na2SO4 and the solvent was evaporated obtaining a crude product that was purified by flash-chromatography (eluting with ethyl acetate/cyclohexane from 1:9 to 3:7) to give the title compound (2.5 g)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[OH:51][CH2:52][C@@H]1NC[C@@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[C@@H:27]([CH2:52][OH:51])[CH2:26][C@H:24]([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC[C@H]1C[C@H](O)CN1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2C[C@@H](O)C[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (3S,5R)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride and isolated as white solid. MS(m/e): 417.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.CC1C=C[C:29]([C:32](C2N(C)C(CC(OC)=O)=CC=2)=[O:33])=CC=1.C(OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:32](=[O:33])[CH3:29])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) [prepared by the method described in Example 5, but substituting zomepirac methyl ester for tolmetin methyl ester in Step (a)] and acetic anhydride (0.375 ml, 3.96 mmol) in THF was stirred at 60° C. for 4 h. The solvents were removed under reduced pressure and the residue was crystallized from hexane-chloroform to give N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-acetamide (295 mg, 88%) as a solid, mp 194-195° C.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])[CH3:21]>C(O)COCCO.[Cl-].[Na+].O>[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[N:24]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1)[CH3:21]
Reactant: CCc1ccccc1N
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: CCc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 250 °C
Yield: 94.7 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(7.0 g, 25.8 mmol) was dissolved in diethylene glycol(30 ml) and 2-ethylaniline(6.7 g, 51 mmol) was added under nitrogen. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was diluted in brine(20 ml), then the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent to obtain 5.1 g of desired compound as solid in 53% of yield.