Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:11].C([Sn](CCCC)(CCCC)C=C)CCC.[Na].C(NN)=O>C1(C)C=CC=CC=1.CO>[CH:10]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[CH2:11]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: N#Cc1ccc(Br)cn1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: NNC=O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=Cc1ccc(C#N)nc1

Procedure:
A 5-vinylpicolinonitrile intermediate (1-2) was prepared by adding 5-bromopicolinonitrile (1-1), tetrakis(triphenylphosphine) (Pd(PPH3)4), and 2,6-di-t-butyl-4-methylphenol (BHT) in toluene, adding tributyl(vinyl)stannane thereto, and reacting the resulting mixture at 80° C. for 24 hours. The intermediate (1-2) was added to a methanol solution, in which sodium metal was dissolved, and reacted at 70° C. for 3 hours and then cooled. Formohydrazide (1-3) was added to the reaction solution and reacted at 70° C. for 15 minutes. Then, the temperature was lowered to 25° C. and the reaction solution was reacted for 24 hours until yellow crystals were formed. Upon completion of the reaction, the yellow crystals were collected by filtration, and 2-(4H-1,2,4-triazol-3-yl)-5-vinylpyridine (1-4) was purified by column chromatography using chloroform and methanol as solvents.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH-].[NH4+:25].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4]([NH2:25])=[O:5]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]benzoyl chloride (16 g, 0.036 mol) in methylene chloride is cooled to 0° C., treated dropwise with 9.2 mL of a 30% ammonium hydroxide solution (0.071 mol), stirred at 0° C. for 30 minutes, stirred at room temperature overnight and poured into water. The aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid, mp 115°-116° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[C:10](=[CH:15][C:16]([F:19])([F:18])[F:17])[C:11]([F:14])([F:13])[F:12]>[OH-].[Na+]>[F:12][C:11]([F:14])([F:13])[CH2:10][C:15]1([C:16]([F:19])([F:18])[F:17])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
11 g of pyrocatechol were dissolved in 200 ml of dimethylfomamide, and 18 g of 45% strength by weight aqueous sodium hydroxide solution were added. 20 g of 2-chloro-1,1,1,4,4,4-hexafluoro-2-butene were added dropwise at 75° C. to the mixture. Stirring was continued for 30 minutes at 75° C. The mixture was then poured into 500 ml of ice-water and extracted with diethyl ether. The organic phase was washed with water, dried with magnesium sulphate and concentrated. Finally, the product was distilled under a high vacuum. The yield was 15 g (=56%) the boiling point was 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -59.0 and -84.6 ppm; 1H-NMR: 3.02 ppm.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:31]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([CH2:27][CH3:28])[C:18]4=[O:29])[CH2:13][CH2:12]3)=[C:8]([O:35][CH:36]([CH3:38])[CH3:37])[C:7]=2[F:39])[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[C:31]([CH:32]3[CH2:33][CH2:34]3)=[CH:30][C:9]([CH2:10][N:11]3[CH2:12][CH2:13][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([CH2:27][CH3:28])[C:18]4=[O:29])[CH2:15][CH2:16]3)=[C:8]([O:35][CH:36]([CH3:38])[CH3:37])[C:7]=2[F:39])[CH2:5][CH2:4]1
Reactant: CCc1c(C(=O)OC)ccn(C2CCN(Cc3cc(C4CC4)c(C4CC4)c(F)c3OC(C)C)CC2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(C(=O)O)ccn(C2CCN(Cc3cc(C4CC4)c(C4CC4)c(F)c3OC(C)C)CC2)c1=O
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A 2 M aqueous sodium hydroxide solution (2 mL) was added to an ethanol (8 mL) solution of methyl 1-(1-(4,5-dicyclopropyl-3-fluoro-2-isopropoxybenzyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (358 mg), and the mixture was stirred at 80 C for 3 hours in a nitrogen atmosphere. The solvent in the reaction mixture was distilled off under reduced pressure. The obtained residue was dissolved in water, and the solution was neutralized with 2 M hydrochloric acid, followed by extraction with a mixed solution of ethyl acetate and THF. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was crystallized (ethyl acetate/hexane) and further recrystallized (ethyl acetate/hexane) to obtain the title compound (258 mg).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1cccc(F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11FN4, 279. Found, 279.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[N:12]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Ic1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(F)cc3c2C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2c(c3cc(F)ccc3n2-c2ccccc2)C1
Temperature: 150 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
A mixture of 8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (0.455 g, 1.57 mmol), CuI (0.012 g, 0.065 mmol) and K3PO4 (0.579 g, 2.73 mmol) was suspended in toluene (5 mL) under Ar. To this mixture was added iodobenzene (0.145 mL, 1.30 mmol) and N,N′-dimethylethylenediamine (0.028 mL, 0.26 mmol) and then the reaction vessel was quickly sealed and the mixture was heated with stirring at 150° C. (oil bath temperature) for 16 h. The cooled reaction mixture was subsequently filtered (Celite) and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (SiO2/hexanes-ethyl acetate, 80:20 to 20:80) to give the title compound (0.267 g, 46%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.41 (m, 1H), 7.33 (m, 2H), 7.15 (m, 2H), 6.87 (m, 1H), 4.66 (s, 2H), 3.77 (m, 2H), 2.70 (m, 2H), 1.51 (s, 9H); LCMS: m/e 367 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[CH:14]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:15]1([C:13]#[C:14][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCCc2nc(Cl)ccc21
Reactant: C#Cc1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1CCCc2nc(C#Cc3ccccc3)ccc21
Yield: 14.7 %

Procedure:
To a solution of 2-chloro-7,8-dihydro-6H-quinolin-5-one (0.2 g, 1.1 mmol) and ethynylbenzene (0.17 g, 1.6 mmol) in triethylamine (7 ml) under an argon atmosphere was added tetrakis (triphenylphosphine) palladium (0.02 g, 0.062 mmol). The mixture was heated at reflux for 3 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.04 g, 15%).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)=[CH:14][CH:13]=[C:12]([C:27]([F:30])([F:29])[F:28])[CH:11]=2)=[O:6])[CH3:3]>S(Cl)(Cl)=O>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:1])=[O:23])=[CH:20][CH:19]=1)=[CH:14][CH:13]=[C:12]([C:27]([F:30])([F:29])[F:28])[CH:11]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Nc1ccc(C(=O)Cl)cc1
Yield: 200.4 %

Procedure:
A suspension of 4-[[3-ethoxycarbonyl-7-(trifluoromethyl)-4-quinolyl]amino]benzoic acid hydrochloride (2.51 g) in thionyl chloride (25 ml) was stirred under reflux for 4 hours and concentrated to dryness in vacuo to give 4-[[3-ethoxycarbonyl-7-(trifluoromethyl)-4-quinolyl]amino]benzoyl chloride hydrochloride (2.62 g) as yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][NH:10][C:11]2=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[C:17]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu](I)I.O1CCOCC1>[Br:15][C:16]1[C:17]([CH3:23])=[C:18]([N:10]2[CH2:9][C:8]3[C:12](=[CH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:11]2=[O:14])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)NC2
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(Br)cccc1N1Cc2ccc(C(C)(C)C)cc2C1=O
Temperature: 105 °C
Yield: 66 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 107c (775 mg, 4.10 mmol), 2,6-dibromotoluene (2.05 g, 8.19 mmol), cesium carbonate (2.67 g, 8.19 mmol), N,N′-dimethylethylenediamine (361 mg, 4.10 mmol) and 1,4-dioxane (15 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (390 mg, 2.05 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 105° C. for 16 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 80:20 hexanes/ethyl acetate) to afford 107d in 66% yield (972 mg) as an amorphous off-white solid: mp 120-122° C.; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=1.5 Hz, 1H), 7.68 (dd, J=8.0, 1.5 Hz, 1H), 7.60 (dd, J=8.0, 1.5 Hz, 1H), 7.46 (dd, J=8.0, 0.5 Hz, 1H), 7.22 (dd, J=8.0, 1.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 4.67 (s, 2H), 2.31 (s, 3H), 1.40 (s, 9H); MS (ESI+) m/z 358.1 (M+H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].CC(C(NCC(O)=[O:21])=S)C(N)=N.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[C:2]([OH:21])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(C(=N)N)C(=S)NCC(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
In order to maintain xylose dehydrogenase expression during the fermentation, 0.5 mM ITPG was added for 24 hours after OD600 reached 10. Strains continued growing by the addition of glucose.
Reaction SMILES: F[B-](F)(F)F.[N:6]1([O:15]C(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:32]([N:39]1[CH2:44][CH2:43][N:42]([CH:45]([CH2:49][NH:50][C:51](=[O:73])[C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]3[C:61]([C:69]([F:72])([F:71])[F:70])=[N:62][N:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=34)=[CH:54][CH:53]=2)[C:46](O)=[O:47])[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Si](ON)(C(C)(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:32]([N:39]1[CH2:44][CH2:43][N:42]([CH:45]([C:46](=[O:47])[NH:6][OH:15])[CH2:49][NH:50][C:51](=[O:73])[C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]3[C:61]([C:69]([F:71])([F:72])[F:70])=[N:62][N:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=34)=[CH:54][CH:53]=2)[CH2:41][CH2:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(NCC(C(=O)O)N1CCN(Cc2ccccc2)CC1)c1ccc(OCc2c(C(F)(F)F)nn3ccccc23)cc1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(C(=O)NO)N1CCN(Cc2ccccc2)CC1)c1ccc(OCc2c(C(F)(F)F)nn3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
106 g (0.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 0.2 ml (1.2 mmol) of diisopropylethylamine are added to a solution of 190 mg (0.3 mmol) of 2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)benzoylamino]propanoic acid in 10 ml of dimethylformamide. After stirring for 20 minutes at ambient temperature, 53 mg (0.4 mmol) of O-tert-butyldimethylsilylhydroxylamine diluted in 3 ml of dimethylformamide are added. The reaction medium is stirred at ambient temperature for 18 h, then hydrolysed with 1 ml of a 5% aqueous solution of citric acid and 2 ml of water and stirred for 1 h. The mixture is then brought to pH=8 with a saturated aqueous solution of sodium hydrogen carbonate then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is precipitated in a heptane/ethyl acetate mixture then filtered. The solid obtained is recrystallized in ethyl acetate. 41 mg (21%) of N-[2-(4-benzylpiperazin-1-yl)-2-hydroxycarbamoylethyl]-4-(2-trifluoromethylpyrazolo-[1,5-a]-pyridin-3-ylmethoxy)benzamide are obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C1(C)C=CC=CC=1.[C:21]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:28][S:27][CH:26]1Br)(=[O:23])[CH3:22].[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].C(N(CC)CC)C.C(#N)C>[C:21]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:28][S:27][C@H:26]1[O:13][C:12]1[C:6]2[O:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc2cccc(O)c2o1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc2cc(C(C)=O)oc12
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
A mixture composed of 1.93 g (14.1 mM) of anhydrous zinc chloride, 1 g (5.7 mM) of 2-acetyl-7-hydroxybenzofuran and 2.2 g of molecular sieve 13× is stirred into 13 ml of toluene and 13 ml of acetonitrile. The mixture is brought to 90° C. and 1.42 g (14.1 mM) of triethylamine and 2.22 g (6.27 mM) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide are added, while maintaining the mixture at the temperature of 90° C. The mixture maintained at 90° C. is then stirred for 20 minutes. The mixture is subsequently cooled, 65 ml of a 0.5 N solution of sodium hydroxide are added, and the resulting mixture is stirred for one hour. The medium is filtered and the precipitate is washed with ethyl acetate. The filtrate is subsequently separated by settling out. The organic phase is washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography, elution being carried out with a cyclohexane/ethyl acetate mixture (7/3; v/v). The desired product is obtained in the form of a yellowish solid with a yield of 37%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17](O)=O)=[CH:8]1.O.[OH-].[Na+].C1C[O:26][CH2:25]C1>>[OH:26][CH2:25][CH2:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][CH:8]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCCCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 80 %

Procedure:
To a stirred suspension of LiAlH4 (3.24g) in THF (200 mL) at 0° C. and under N2 atmosphere was added tropwise a THF solution (50 mL) containing indole-3-acetic acid (10.0 g). After the addition was complete, the reaction was heated at reflux for 3 h, after which time the mixture was cooled to 0° C. and water (3.3 mL) added, followed by 15% NaOH (3.3 mL), and finally additional water (9.9 mL). The reaction was filtered and the filter cake washed with Et2O. The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to yield 3-(2hydroxyethyl)indole (VI; 7.4 g; 80%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=2)[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[Cl:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[C:19]([C:28]#[N:29])[N:18]=[C:17]2[O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: N#Cc1cc2ccc(Cl)cc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (201 mg, 1.076 mmol) in THF (5 mL) at 0° C. was added NaH (81 mg, 1.35 mmol). The reaction mixture was stirred at RT for 30 minutes. Next, 1,7-dichloroisoquinoline-3-carbonitrile (200 mg, 0.897 mmol) was added and the reaction mixture was warmed to RT over a 1 hour period. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and the resulting mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative TLC eluting with petroleum ether and ethyl acetate (PE/EtOAc=3:1) to give the title compound (200 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1H), 7.65-7.71 (m, 3H), 5.74 (br, 1H), 3.46-3.69 (m, 4H), 2.23 (s, 1H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.[ClH:52]>CCOCC.CO>[ClH:52].[CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 66 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (200 mg, 0.284 mmol) was deprotected in HCl in ether/methanol (2/3 ml) to afford 120 mg (66% yield) of the titled compound. MS: m/z=605.2 (M+1).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH3:35])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH:20]=[CH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1.O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH3:35])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH:20]=[CH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cccnc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cccnc3)CS[C@H]12)c1csc(N)n1
Yield: 39.7 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-trans mixture) (0.8 g) in methanol (6 ml), tetrahydrofuran (3 ml) and conc.hydrochloric acid (0.5 g) were stirred for 3 hours at ambient temperature. The resulting solution was added to a mixture of ethyl acetate and water and adjusted to pH 7.5 with 20% aqueous potassium carbonate. The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid under ice-cooling. The precipitate was filtered off, washed with ice-water and dried over phosphorus pentoxide in vacuo to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-trans mixture) (0.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccccn1-c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 g (26.3 mmol) 2-hydroxypyridine, 2.9 ml (26.3 mmol) 2,4-difluoronitrobenzene, are dissolved in 100 ml acetone, combined with 4.0 g (28.9 mmol) potassium carbonate and stirred for one day at ambient temperature. The undissolved matter is filtered off and the salt residues are rinsed with acetone. The combined organic phases are evaporated to dryness. The residue is purified by chromatography (silica gel; eluant: cyclohexane-ethyl acetate gradient).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[C:32]([CH3:33])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-methyl-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 483.1.