Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:45](Cl)=[O:46])[C:34]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:45]([C:33]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:37][CH:36]=4)=[C:29]([CH3:28])[CH:30]=[CH:31][CH:32]=3)=[O:46])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(N)cc2C1
Reactant: Cc1cccc(C(=O)Cl)c1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NC(=O)OC(C)(C)C)C3)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To a solution of (5-amino-indan-2-yl)-carbamic acid tert-butyl ester (12.5 mmol) in methylene chloride (75 mL) is added diisopropylethyl amine (3.3 g, 25 mmol) followed by a solution of 6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid chloride (12.6 mmol) in methylene chloride. After stirring 16 h, the reaction mixture is poured into ethyl acetate and washed with 1N HCl, NaHCO3 solution, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a solid. Recrystallization from toluene gives {5-[(6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carbonyl)-amino]-indan-2-yl}-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]=NO)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)[OH:18]>>[Cl:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[C:9]2[C:10]=1[C:13](=[O:18])[C:12](=[O:16])[NH:11]2
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(C(=O)O)c(Cl)c1
Product: O=C1Nc2ccc(C(=O)O)c(Cl)c2C1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-chloro-4-[(-2-(hydroxyimino)ethanoyl)amino]benzoic acid (300 mg, 1.24 mmol) was dissolved in concentrated sulfuric acid (5 mL). It was stirred at 80° C. for 3 h. The reaction mixture was cooled to rt, poured into ice water and it was extracted twice with ethylacetate. The title compound was obtained as an orange solid (256 mg, 92%) containing 12% of the regioisomer (6-chloro-2,3-dioxoindoline-5-carboxylic acid).
Reaction SMILES: C=CC(O)=O.C(O)C(N)(CO)CO.Cl.COC(C1C=CC(O)=CC=1)=O.[CH:26]1[N:30]([CH2:31][O:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])[C:29]2[N:38]=[C:39]([NH2:43])[N:40]=[C:41]([O-:42])[C:28]=2[N:27]=1.[Na+]>>[CH:26]1[N:30]([CH2:31][O:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])[C:29]2[N:38]=[C:39]([NH2:43])[N:40]=[C:41]([OH:42])[C:28]=2[N:27]=1
Reactant: Nc1nc([O-])c2ncn(COC(CO)CO)c2n1
Agent: C=CC(=O)O
Agent: COC(=O)c1ccc(O)cc1
Agent: Cl
Product: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Yield: 2 %

Procedure:
The Carbopol 934P and Poloxamer 407 (BASF Corp.) are first suspended in the TRIS HCl buffer (0.1 M) and the components are mixed under agitation overnight at 4° C. to ensure complete dissolution. The methylparaben is added and further stirring allowed until complete dissolution is observed. Ganciclovir sodium is mixed in while maintaining stirring to produce a 2.0% ganciclovir mucoadhesive, thermoreversible gel formulation. The mixture is maintained below room temperature until use.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18]([O:21][C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.Cl.CN(C)CC(O)=O.O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:24][CH:23]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(I)cc2)C1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Oc3ccc(Cl)cc3)cc2)C1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
4-chlorophenol (495 mg, 3.85 mmol), the product from step 1 (1 g, 2.57 mmol), cesium carbonate (1.67 g, 5.14 mmol), copper iodide (51 mg, 0.27 mmol), and N,N-dimethylglycine HCl (35 mg, 0.249 mmol), were taken into anhydrous dioxane (12 mL) in a nitrogen flushed 20 mL vial. The reaction was heated to 90° C. for 24 h. The mixture was concentrated to dryness, and the resulting oil was partitioned between water and ethyl acetate. The aqueous layer was washed with ethyl acetate 3×. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The compound was purified by flash column chromatography (20:1 silica ratio, eluted with 20% ethyl acetate in hexane) to obtain the title product (1 g, ˜90%).;LCMS; m/z 390 (M) 88% pure; 1H NMR (400 MHz, DMSO); δ 1.41 (s, 9H), 2.00-2.20 (m, 2H), 3.32-3.60 (m, 4H), 4.98 (s, 1H), 6.76 (d, 2H, J=8.8,), 6.94-7.03 (m, 4H), 7.19 (d, 2H), J=8.8,), 9.70 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].O=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[C:3]([CH:5]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.257 g, 6.42 mmol) in tetrahydrofuran (32 mL) at 0° C. under a nitrogen atmosphere was added diethyl cyanomethylphosphonate (1.19 g, 6.72 mmol) (purchased from Aldrich). The reaction was then stirred for 45 minutes at room temperature. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.00 g, 5.84 mmol) (purchased from Alfa Aesar) in tetrahydrofuran (8.8 mL) was introduced dropwise and the mixture was stirred for 16 hours. Brine and ethyl acetate were added and the layers separated. The aqueous layer was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford product, used without further purification in Step 2 (1.12 g, 99%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C(#N)C>[F:13][C:9]1[CH:8]=[C:7]([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(c1cccc(F)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
Methyl 2-bromo-2-(3-fluorophenyl)acetate (310 mg, 1.25 mmol), piperidine (0.15 ml, 1.51 mmol), and DIPEA (0.26 ml, 1.51 mmol) were dissolved in acetonitrile (15 ml) and stirred at room temperature for 16 hours. The solvent was evaporated and the crude was purified by flash chromatography (petroleum ether/EtOAc=9/1) to afford methyl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (224 mg, 71% yield) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:29][C:25]1[CH:24]=[C:23]([C:3]2[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]3[CH:2]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(F)c2)cn2c1CN(C(=O)OC(C)(C)C)CC2
Yield: 99.7 %

Procedure:
A mixture of 6.00 g (14.2 mmol) of 2-tert-butyl 8-ethyl 6-chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate, 13.4 g (212 mmol) of ammonium formate (CAS 540-69-2) and 0.6 g of 10% palladium-on-charcoal containing 50% water in 50 ml of methanol is stirred at reflux for 45 minutes. After cooling, the mixture is filtered through a Buchner funnel and the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, the solution is washed with aqueous 2N sodium hydroxide solution and then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure, to give 5.5 g of 2-tert-butyl 8-ethyl 7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in the form of a yellow oil.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH:13]([CH2:15]O)[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>ClCCl.C(OCC)C.CCOC(C)=O.CCCCCC>[N:36]([CH2:15][CH:13]1[CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)=[N+:37]=[N-:38]
Reactant: CC(C)(C)OC(=O)N1CC(CO)CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CN=[N+]=[N-])CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-(tert-butyldimethylsilyloxy)-5-(hydroxymethyl)piperidine-1-carboxylate from step B in dichloromethane (50 mL) was added triethylamine (4.67 g, 46.2 mmol) and methanesulfonyl chloride (2.65 g, 23.1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1.5 hours, then diluted with diethyl ether, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was dissolved in NMP. Sodium azide (3.00 g, 46.2 mmol) was added, and the resulting suspension was stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc/hexane, washed with brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound. MS (m/z): 271 (M-Boc+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].C(O)(=O)C.[OH:14][C:15]1[N:20]2[N:21]=[CH:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:19]2[N:18]=[CH:17][N:16]=1>O>[OH:14][C:15]1[N:20]2[N:21]=[CH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([N+:6]([O-:9])=[O:7])=[CH:26][CH:25]=3)=[C:19]2[N:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ncnc2c(-c3ccccc3)cnn12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2cnn3c(O)ncnc23)cc1
Reaction time: 1 h

Procedure:
To a mixture of conc. sulfuric acid (0.5 ml), conc. nitric acid (0.5 ml) and acetic acid (2 ml) is addded 4-hydroxy-8-phenylpyrazolo[1,5-a]-1,3,5-triazine (310 mg), and the mixture is stirred at 50°-60° C. After reacting for one hour, to the reaction mixture is added water. The insoluble material is separated by filtration, washed with water and hot methanol and dried to give the title compound (210 mg).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].[C:15](N1C=CN=C1)([N:17]1C=CN=C1)=O.CN>C1COCC1>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([NH:17][CH3:15])=[O:11])(=[O:4])=[O:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(S(N)(=O)=O)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of 5-(aminosulfonyl)-2-fluorobenzoic acid [prepared according to Chem. Pharm. Bull. 1995, 43, 582-7] (22.98 g, 105 mmol) in THF (500 mL) at room temperature under nitrogen was added carbonyldiimidazole (17 g, 105 mmol). After stirring for 2.25 h a solution of methylamine in THF (2M, 70 mL, 140 mmol) was added dropwise and the reaction was allowed to stir for 18 h. The crude reaction mixture was concentrated to a low volume and EtOAc (150 mL) was added to the resulting thick oil. This mixture was stirred and a granular precipitate formed which was collected by filtration. This crude product, contaminated with imidazole, was suspended in DCM (300 mL) and heated at reflux for 5 h. After cooling to room temperature the mixture was filtered to give the desired product (19.8 g, 81%) containing <2% w/w imidazole; 1H NMR δH (300 MHz, d4-MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1H, m), 8.29 (1H, d); MS m/z (TS+) 250 (MNH4+).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#N.[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH-:24].[Na+]>C(OCC)C.CO>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH:8]=[O:24]
Reactant: [OH-]
Reactant: CN(C)c1ccc(F)c(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Product: CN(C)c1ccc(F)c(C=O)c1
Reaction time: 19.5 h
Yield: 95.6 %

Procedure:
To a solution of 5-dimethylamino-2-fluorobenzonitrile (viii) (331 mg, 2.02 mmol) in dry diethyl ether (10 ml) stirred at room temperature under nitrogen, was added dropwise by syringe diisobutylaluminium hydride (2.8 ml, 1.0 M in toluene, 2.8 mmol, 1.4 eq) and stirring continued for 19.5 h. The solution was chilled in an ice-bath and methanol (1.0 ml) was added dropwise and the mixture stirred for 1 h before 1.0 M HCl (9 ml) was added and stirring continued for a further 1 h. The reaction mixture was basified with NaOH (0.4 g) then partitioned between ether (50 ml) and water (50 ml) and the aqueous layer re-extracted with ether (50 ml). The combined ether extract was washed with brine (50 ml), dried over MgSO4 and evaporated to give an orange oil (323 mg), which was subjected to column chromatography (silica gel, 30×170 mm) eluting with 100% dichloromethane, affording 5-dimethylamino-2-fluorobenzaldehyde (ix) as a bright yellow-green oil (228 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1[CH:23]=O)([CH3:15])([CH3:14])[CH3:13].N1CCCCC1>CO>[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1/[CH:23]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:14])([CH3:13])[CH3:15]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 92.6 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2.37 g, 12.7 mmol) was reacted with 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde prepared in Example 18 (4 g, 12.7 mmol) and piperidine (1.25 mL, 12.7 mmol) in methanol to give E/Z-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzylidene}-6-chloro-1,3-dihydro-indol-2-one as a yellow solid (Yield 5.46 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][NH:9][C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])=O)=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:10](=[O:11])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(NNC(=O)c1ccc(Cl)cc1)NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1

Procedure:
14.65 g (57.7 mmol) of 2-(4-chlorobenzoyl)-N-cyclopropylhydrazinecarboxamide from Example 2A are heated under reflux overnight in 60 ml 2 N aqueous sodium hydroxide. After cooling, the mixture is acidified to pH 1 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue is stirred with dichloromethane, and the resulting precipitate filtered off, then washed with dichloromethane and dried in vacuo. 10.9 g (69% of theory) of the target compound are thus obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]#[N:7])=[N:2]1.CC(C)([O-])C.[K+].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=[O:18]>CS(C)=O>[Br:14][C:15]1[C:16]([CH:17]=[O:18])=[C:19]([N:1]2[CH:5]=[CH:4][C:3]([C:6]#[N:7])=[N:2]2)[CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1cc[nH]n1
Reactant: O=Cc1c(F)cccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccn(-c2cccc(Br)c2C=O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
1H-pyrazole-3-carbonitrile (850 mg, 9.13 mmol) was dissolved in 15 mL of dry DMSO and potassium tert-butoxide (1.08 g, 9.13 mmol, Eq: 1.00) was added. The mixture was stirred at room temperature for 20 minutes and 2-bromo-6-fluorobenzaldehyde (3.71 g, 18.3 mmol, Eq: 2) was added. The mixture was stirred at room temperature overnight and then extracted with ethyl acetate and water. The organic layer was dried and concentrated. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 40% EtOAc in hexanes) to give 1-(3-bromo-2-formylphenyl)-1H-pyrazole-3-carbonitrile (1.83 g, 73%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:48]=[CH:47][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3/[C:33](=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])/[C:32]([F:46])([F:45])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:46][C:32]1([F:45])[CH2:31][CH2:30][N:29]([C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:48][CH:47]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2/[C:33]/1=[CH:40]/[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Yield: 95.4 %

Procedure:
Using 396 mg of o-phenylbenzoic acid, 0.290 ml of oxalyl chloride and 620 mg of methyl (Z)-[1-(4-aminobenzoyl)4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5ylidene]acetate, a similar procedure as in Reference Example 8 was repeated to obtain 878 mg of methyl (Z)-[4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[CH:7]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]([O:10]CC)=[O:9])C.CO>O>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][CH:7]([C:8]([OH:10])=[O:9])[C:6]([OH:20])=[O:5]
Reactant: CCOC(=O)C(CCOCCOC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCCC(C(=O)O)C(=O)O
Yield: 98 %

Procedure:
Sodium hydroxide (2.00 g, 50.00 mmol) in water (15 mL) was added to a stirred solution of diethyl[2-(2-methoxyethoxy)ethyl]malonate (Step 1) (2.35 g, 8.96 mmol). The reaction was kept at ambient temperature for 10 minutes before MeOH was removed in vacuo. The resulting solution was acidified to pH=1 by the addition of HCl (5 M). Diethyl ether was added and the two phases were separated. The aqueous phase was extracted three times with diethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to give the title compound as a colourless oil (1.81 g), 1H NMR (300 MHz, CDCl3) δ 7.16 (br s, 2H), 3.58 (m, 7H), 3.40 (s, 3H), 2.23 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH2:8][OH:9])#[N:2]>CO.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][OH:9])[CH:10]=[CH:11][CH:12]=1)#[N:2]
Reactant: N#Cc1cccc(C=CCO)c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1cccc(CCCO)c1

Procedure:
A solution of 3-cyanocinnamyl alcohol (4.1 g) in methanol (100 ml) was hydrogenated at 50 psi over 10% palladium on charcoal (0.5 g) for 1 hour. The catalyst was filtered off and the filtrate was evaporated to give the product as a pale oil.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.Cl[C:35]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:38]=[C:37]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:36]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.O>[C:47]1([C:37]2[N:36]=[C:35]([N:17]3[CH2:16][CH2:15][N:14]([CH2:13][C@:2]4([CH3:1])[O:6][C:5]5=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]5[CH2:3]4)[CH2:19][CH2:18]3)[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(c3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
Tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 393 (500 mg, 1.36 mmol) was dissolved in methylene chloride (2 ml). To the solution, trifluoroacetic acid (10 ml) was added followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and added methylene chloride (4 ml) and triethylamine (4 ml). The reaction mixture was stirred at room temperature for 5 minutes and then concentrated under reduced pressure, and the residue was dissolved in DMF (5 ml). To the solution, 4-chloro-2,6-diphenylpyrimidine (400 mg, 1.50 mmol) and DBU (0.2 ml, 1.36 mmol) were added followed by stirring at 100° C. for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and then the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford (S)-2-[4-(2,6-diphenylpyrimidin-4-yl)piperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (113 mg, yield 17%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[C:20]([C:28]1[CH:29]=[C:30]([C:33](O)=[O:34])[NH:31][CH:32]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:33]([C:30]1[NH:31][CH:32]=[C:28]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:29]=1)=[O:34]
Reactant: O=C(c1ccccc1)c1c[nH]c(C(=O)O)c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc(C(=O)c2ccccc2)c[nH]1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-benzoyl-1H-pyrrole-2-carboxylic acid. MS: 457.4 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(C)C.FC1C=CC=CC=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:3][CH:4]=1)=[O:12]
Reactant: C1CCNCC1
Reactant: CC(C)C(=O)c1ccc(F)cc1
Agent: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Fc1ccccc1
Solvent: CS(C)=O
Product: CC(C)C(=O)c1ccc(N2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
49.86 (0.30 mol) of 1-(4-fluorophenyl)-2-methylpropan-1-one, prepared by a Friedel-Crafts reaction from isobutyryl chloride with fluorobenzene analogously to European Patent Application No. 3,002, and 25.5 g (0.30 mol) of piperidine are dissolved in 120 ml of dimethyl sulfoxide, and the solution is heated to 110° C. together with 41.5 g (0.30 mol) of potassium carbonate. After 16 hours of stirring at 110° C. the suspension is cooled down and is poured onto an ice-water mixture. The crystals are filtered off, are washed with water and are recrystallised from hexane.