Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]#[C:11][CH2:12][N:13]1[C:21]2[C:20](Cl)=[N:19][CH:18]=[N:17][C:16]=2[CH:15]=[CH:14]1)(C(C)(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[NH2:27].O>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]2[C:21]3[N:13]([CH2:12][C:11]#[C:10][CH2:9][OH:8])[CH:14]=[CH:15][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Solvent: O
Solvent: CC(C)O
Product: OCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
5-(4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (408.3 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421.0 mg) was added, and the mixture was stirred at 80° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (6 mL), a 1.0 M solution (2 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) and crystallized from hexane/ethyl acetate to give the title compound (425 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[NH3:34]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:7])[NH2:34]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)O
Reactant: N
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(2-naphthoxy)ethoxy]phenyl]propionic acid (2.08 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture was heated at 80° C. for 90 min. After cooled to room temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (0.98 g, 47%). HRMS calcd for C23H23NO5: 393.4364. Found: 393.4363. MA calcd for C23H23NO5: C, 70.22%; H, 5.89%; N, 3.56%. Found: C, 70.54%; H, 5.87%; N, 3.54%.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(=[O:3])[CH3:2].CC(C)=O>P([O-])([O-])([O-])=O>[C:1]([O:4][C@@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(=[O:3])[CH3:2].[C@H:5]1([OH:4])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CC(=O)OC1C=Cc2ccccc21
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1C=Cc2ccccc21
Product: O[C@@H]1C=Cc2ccccc21
Temperature: 37 °C
Reaction time: 48 h
Yield: 44.6 %
Yield: 46.1 %

Procedure:
1.0 g (5.75 mmol) of racemic 1-acetoxyindene and 57.5 mg of lipase PS (made by Amano Seiyaku Sha, derived from Pseudomonas bacterium) were suspended in 58 ml of phosphate buffer (0.1M)-acetone mixed solution (9:1 V/V) and stirred at 37° C. for 48 hours. The reaction solution was filtered on Celite to remove lipase. The liltrate was extracted with diethyl ether and the extracted solution was dried on magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to silica gel column chromatography (eluate:ethyl acetate-hexane, 1:10 V/V) to separate into 446 mg (yield 44.6%) of (S)-1-acetoxyindene and 350 mg (yield 46.1%) of (R)-inden-1-ol respectively. The specific rotations and optical purities thereof were as shown below. The optical purities were determined by high speed liquid chromatography (column: chiral cell OD, eluate: isopropanol-hexane, 1% V/V).
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].[Al:10]>>[O-:3][Si:1]([O-:4])=[O:2].[O-:3][Si:1]([O-:4])=[O:2].[Na+:6].[Al+3:10]
Reactant: [O-][Si]([O-])([O-])[O-]
Reactant: [Al]
Agent: [Na+]
Product: O=[Si]([O-])[O-]
Product: [Al+3]

Procedure:
U.S. Pat. No. 2,739,073 issued on Mar. 20, 1956 to Bertorelli and was assigned to the J. M. Huber Corporation. In this patent, a dilute sodium silicate solution and a dilute aluminum salt are added slowly to a diluting aqueous medium to produce a precipitated sodium alumino silicate having a specific gravity of from 2.10 to 2.26 and substantially all of the particles are less than 0.5 microns in diameter.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH:5]1[OH:11])=[N+:2]=[N-:3].Cl[C:13]1[N:17]([CH3:18])[N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].[F-].[K+].O.[CH3:25]S(C)=O>>[N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:13]2[N:17]([CH2:18][CH3:25])[N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:7][CH2:6][CH:5]1[OH:11])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCNCCC1O
Reactant: CS(C)=O
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Product: CCn1ncc([N+](=O)[O-])c1N1CCC(O)C(N=[N+]=[N-])CC1
Temperature: 60 °C
Yield: 53 %

Procedure:
A solution of 5-azidoazepan-4-ol (2.5 g, 16.0 mmol) was dissolved in dry DMSO (20 mL) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.70 g, 15.4 mmol) and potassium fluoride (3.71 g, 64 mmol) were added. The mixture was heated at 60° C. for 16 hr, allowed to cool to room temperature, poured into water (300 mL) and extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-azido-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a yellow gum (2.5 g, 53%). 1H NMR (400 MHz, CDCl3) δ 8.18-7.95 (m, 1H), 4.16-4.07 (m, 2H), 3.80 (tt, J=9.1, 3.1 Hz, 1H), 3.67-3.59 (m, 1H), 3.42-3.18 (m, 4H), 2.51 (d, J=2.9 Hz, 1H), 2.24-2.12 (m, 2H), 2.07-1.87 (m, 2H), 1.46 (t, J=7.3 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C1C=CC=CC=1.N1CCCCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:26]1)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of m-nitrobenzaldehyde (1.67 g), 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate (4.20 g), benzene (40 ml) and piperidine (0.05 g) was refluxed for 4 hours, during which time the water produced was removed using a Dean-Stark trap. The mixture was washed with water and dried (MgSO4). The solvent was then distilled off and the residue was purified by column chromatography on silica gel (100 g) [eluent: ethyl ether-ethyl acetate (10:1, v/v)] to give 2-(4-benzhydryl-1-piperazinyl)ethyl 2-(3-nitrobenzylidene)acetoacetate as an oil. Yield 4.37 g.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:18])=[CH:9][C:10]1[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[C:8]([CH3:18])=[CH:9][C:10]1[S:14][C:13]([C:15]([O:17][C:21]2[CH:29]=[CH:28][C:24]([C:25](=[NH:26])[NH2:27])=[CH:23][CH:22]=2)=[O:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)c1ccc(O)cc1
Reactant: CC(=Cc1ccc(C(=O)O)s1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)s1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
5-(2-(tert-Butoxycarbonyl)-1-propenyl)-2-thiophenecarboxylic acid (0.51 g, 1.89 mmol) and 4-hydroxybenzamidine hydrochloride (0.33 g, 1.89 mmol) were dissolved in pyridine (10 mL), WSC hydrochloride (0.54 g, 2.8 mmol) was added, and the mixture was stirred overnight. The mixture was purified by high performance liquid chromatography and freeze-dried to give the title compound (0.63 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[CH3:19]O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH3:19])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)C1CCCC(O)N1C(=O)OC(C)(C)C
Reactant: CO
Product: COC(=O)C1CCCC(OC)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude 6-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 36, obtained in the previous step is dissolved in methanol (500 mL) and treated with Dowex-50 (1.0 g). After stirring at rt for 3 hr, the solution is filtered and concentrated in vacuo, and the residue is purified over silica (hexanes/ethyl acetate, 5:1) to afford 2.1 g of the desired product. 1H NMR (CDCl3) δ 5.43 (br s, 0.5H), 5.28 (br s, 0.5H), 4.88 (br s, 0.5H), 4.66 (br s, 0.5H), 3.73 (s, 3H), 3.33 (s, 3H), 2.32 (m, 1H), 1.87 (m, 2H), 1.70–1.40 (m, 3H), 1.51 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(N1CCC(CO)CC1)(OC(C)(C)C)=O>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:6][CH:5]3[CH2:3][CH2:2][NH:1][CH2:9][CH2:4]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: Clc1ccc2[nH]c3c(OCC4CCNCC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is N-Boc-4-piperidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.43 (s, 1H), 8.11 (d, J=2.0 Hz, 2 H), 7.43 (d, J=8.8 Hz, 2 H), 7.29 (dd, J=8.4, 2.0 Hz, 2 H), 4.16 (d, J=6.4 Hz, 2 H), 3.18-3.08 (m, 2 H), 2.70 (td, J=12.4, 2.4 Hz, 2 H), 2.22-2.10 (m, 1 H), 2.09-1.98 (m, 2 H), 1.50-1.38 (m, 2 H); MS (ESI) m/z 436.2 (M−H)−; MS (ESI) m/z 438.1 (M+H)+
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:17])([F:16])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>C(O)(=O)C>[F:3][C:4]([F:16])([F:17])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:1])=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1NCC(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)ccc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Bromine (2.33 ml, 2 eq.) in acetic acid (15 ml) was added dropwise to a stirred solution of N-(2,2,2-trifluoroethyl)-2-nitroaniline (4) (5.0 g, 23 mmol) inacetic acid (50 ml), in an ice bath. After the bromine addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature for 30 minutes and poured onto crushed ice. The resultant yellow-orange precipitate was collected by filtration, washed with H2O three times and air dried to give 6.0 g (88% yield) of N-(2,2,2,-trifluoroethyl)-4-bromo-2-nitroaniline (5): mp 118°-120° C.; MS m/e 298 (M+), 1HNMR (DMSO-d6) δ 4.33 (m, 2H), 7.28 (d, 1H, J=9.0 Hz), 7.72 (dd, 1H, J=2.2 Hz, 9.0 Hz), 8.18 (d, 1H, J=2.1 Hz), 8.31 (1H, -NH).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Yield: 70.58 %

Procedure:
To a stirred solution of [(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 4)(100 mg, 0.19 mmol) in DCM (2 mL) at 0° C. was added 50% TFA in DCM (4 mL) dropwise. After 2 h the mixture was evaporated and the residue was washed with ether to afford (S)-3-amino-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate (72 mg, 70.58%). LC-MS: 426 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:20]1([CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[CH:22]=1)[OH:21].[OH-:28].[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:21][C:20]4[CH:27]=[CH:26][CH:25]=[C:23]([O:24][C:17]([C:14]5[CH:15]=[CH:16][C:10]6[O:9][C:8]([C:5]7[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=7)=[N:12][C:11]=6[CH:13]=5)=[O:28])[CH:22]=4)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccc(-c2nc3cc(C(=O)Cl)ccc3o2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc3cc(C(=O)Oc4cccc(OC(=O)c5ccc6oc(-c7ccc(C)cc7)nc6c5)c4)ccc3o2)cc1

Procedure:
A mixture of 1c (5.42 g. 0.02 mole), resorcinol (1.10 g., 0.02 mole), and sodium hydroxide (0.8 g., 0.02 mole) was refluxed for 3 hours in a mixture of chloroform (50 ml.) and water (15 ml.). Upon cooling a solid separated between the layers which was filtered, air-dried, and amounted to 2.43 g. (42%) of 1f. UV (CH2CH2) λ max 306 nm (52,000), ε325 = 13,000.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][CH:40]([F:42])[F:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH:40]([F:42])[F:41])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: FC(F)CBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OCC(F)F)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 1-bromo-2,2-difluoro-ethane
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[N:15](CC3C=CC(C4C=CC=CC=4)=CC=3)[C:14]3[CH:29]=[C:30]([F:44])[C:31]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[N:39]([CH3:43])[CH:38]=[CH:37]5)=[C:32]([F:33])[C:13]=3[N:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:45].C1CCC=CC=1>[OH-].[OH-].[Pd+2].CCOC(C)=O.CCO>[CH3:1][O:2][C:3](=[O:46])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[NH:15][C:14]3[CH:29]=[C:30]([F:44])[C:31]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[N:39]([CH3:43])[CH:38]=[CH:37]5)=[C:32]([F:33])[C:13]=3[N:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:45]
Reactant: COC(=O)c1cc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCC=C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3[nH]2)ccc1C
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-[1-biphenyl-4-ylmethyl-4,6-difluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzoimidazol-2-yloxy]-2-methyl-benzoic acid methyl ester (900 mg, 1.467 mmol) and Pearlman's catalyst (20% Pd(OH)2 on carbon) (180 mg) in EtOAc-EtOH (2:1, 7 mL) was treated with cyclohexadiene (2351 mg), and the resulting reaction mixture was heated under microwave at 130° C. for 10 min, and then at 130° C. for another 10 min. The cooled reaction mixture was filtered through a Celite pad (washed with 10% MeOH—CH2Cl2), and the filtrate was absorbed onto silica gel and purified by ISCO flash chromatography to give desired product as a white foam.
Reaction SMILES: O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:14][CH:15]1[C:30](=[O:31])[N:17]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:20][S:21][C@H:16]12.C[Si](C)(C)Cl.C[C:38](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:39].CN(C)C>C1COCC1.O.C(N(CC)CC)C>[C:24]([O:23][CH2:22][C:19]1[CH2:20][S:21][C@@H:16]2[CH:15]([NH:14][CH:38]=[O:39])[C:30](=[O:31])[N:17]2[C:18]=1[C:27]([OH:29])=[O:28])(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CN(C)C
Agent: C[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC=O)[C@H]2SC1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid toluene-p-sulphonate dihydrate (19.2 g., 40 mmole) in anhydrous THF (500 ml.) under nitrogen in a 1 liter flask was added triethylamine (dried over potassium, 27.76 ml., 200 mmole) then trimethylchlorosilane (20.18 ml., 17.36 g., 160 mmole) while maintaining the temperature at 20° with a cooling bath. After 30 minutes a further 10% of triethylamine and 10% of trimethylchlorosilane were added and the reaction mixture was allowed to stir for a further 2.5 hours. To the mixture was then added acetic formic mixed anhydride (7.04 g., 80 mmole) with cooling in an ice bath. A further 10% trimethylamine, 10% trimethylchlorosilane and 20% acetic formic mixed anhydride, and then yet a further 10% of all three reagents were added to achieve complete disappearance of starting material on t.l.c. Water was then added, the suspension was filtered on a sintered glass disc and the solid dried to give 3-acetoxymethyl-7-formylaminoceph-3-em-4-carboxylic acid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[CH:30][CH:29]=1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 6-methoxypyridin-3-ylcarbamate (0.244 g, 1.00 mmol, from Step 1) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and heated to 50° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (280 mg, 58%) as white crystals after trituration in diethyl ether. MS (APCI 10V) AP+ 485.30; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 3.76 (s, 3H) 6.38 (s, 1H) 6.69 (d, J=8.77 Hz, 1H) 7.03 (m, 2H) 7.12 (d, J=7.80 Hz, 1H) 7.21 (d, J=8.60 Hz, 1H) 7.4 (dd, J=8.5 Hz, 1 Hz, 1H) 7.73 (dd, J=8.9 Hz, 2.7 Hz, 1H) 8.14 (d, J=2.5 Hz, 1H) 8.20 (dd, J=8.77 Hz, 2.5 Hz, 1H) 8.49 (s, 1H) 8.55 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:21]([O-])=O)=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:21])=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1N
Yield: 93.8 %

Procedure:
A solution of methyl 5-tert-butoxycarbonylaminomethyl-2-nitrophenylacetate (6.8 g, 21 mmol) in methanol (250 mL) in the presence of 10% Pd/C was hydrogenated under atmospheric pressure of hydrogen at room temperature. The catalyst was removed by filtration through celite and the filtrate was concentrated to give 5.8 g of the title compound: 1H NMR (CDCl3) δ 7.02 (d, 1H, J=7.6 Hz), 7.00 (s, 1H), 6.67 (d, 1H, J=7.6 Hz), 4.72 (br, 1H), 4.18 (d, 2H, J=5.7 Hz), 4.05 (br, 2H), 3.55 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:32](OC(=O)C)(=[O:34])[CH3:33]>O.O1CCOCC1>[C:32]([N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:12]3[C:13](=[N:14][CH:15]=[N:16][C:11]=3[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[NH:17][N:18]=2)[CH2:21][CH2:22]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(N4CCNCC4)c23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
Analogously to Example 26, 100 mg (0.248 mmol) of 4-(3-chlorophenylamino)-3-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride and 103 mg (0.74 mmol) of potassium carbonate in 10 ml of water are reacted with 38 mg (0.37 mmol) of acetic anhydride in 10 ml of dioxane to form 3-(4-acetyl-piperazin-1-yl)-4-(3-chlorophenylamino)-1H-pyrazolo(3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=10.8; FAB-MS: (M+H)+=372.