Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:21])([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:6][NH:7][C@H:8]([C:12]([O:14]C)=[O:13])[CH:9]([CH3:11])[CH3:10]>C1COCC1.O>[F:4][C:5]([F:21])([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: C=CCCCC(F)(F)CN[C@H](C(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCC(F)(F)CN[C@H](C(=O)O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (6 eq.) was added to a stirred mixture of methyl N-(2,2-difluorohept-6-en-1-yl)-L-valinate 73 in THF and water (2/1 v/v, 0.013 M) and the mixture was stirred at 60° C. After 1 h, it was cooled to RT and THF was evaporated under reduced pressure. Aqueous 1N HCl was added until pH=5, and the aq. phase was extracted with EtOAc. Drying over Na2SO4, filtration and evaporation under reduced pressure afforded the title compound that was used in the following step without further purification. MS (ES+) m/z 250 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][C:12]([C:14]1[C:23]2[C:22]3[N:24]([CH3:27])[N:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][CH:15]=1)=O)C>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12]([C:14]1[C:23]2[C:22]3[N:24]([CH3:27])[NH:25][CH2:26][C:21]=3[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][CH:15]=1)=[O:11]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1c[nH]c2c1-c1c(cnn1C)CCC2
Product: CN1NCC2=C1c1c(C(=O)Nc3ccccc3F)c[nH]c1CCC2

Procedure:
The title compound is prepared according to Example 9 using 2-fluoroaniline and 1-methyl-4,5,6,7-tetrahydro-1H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester. Electrospray mass spectrum: m/z 325 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([NH2:29])[CH:20]=1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:18])[C:9]1[CH:10]=[CH:11][C:12]([C:13](=[O:15])[NH:29][C:21]2[CH:20]=[N:19][C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Reactant: Nc1cnc2ccccc2c1
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A solution of 4-(tert-butoxycarbonyl-methyl-amino)-benzoic acid (3.36 g, 13.4 mmol), O-benzotriazol-1-yl-N,N,N,N′N′-tetramethyluronium hexafluorophospate (HBTU) (5.22 g, 13.8 mmol) and N,N-diisopropylethyl (4.8 mL, 27.5 mmol) in acetonitrile (200 mL) was stirred at ambient temperature for ten minutes. Quinolin-3-ylamine (1.93 g, 13.4 mmol) was added, and the solution was heated at reflux for 20 hours. The solvent was evaporated in vacuo, and the residue was partitioned between 1 N aqueous sodium hydroxide and dichloromethane. The product was purified by flash silica gel chromatography, using 67% ethyl acetate in hexane as the eluant to give the product as a colorless solid, 4 g (80%). MS: m/z 378 (MH+). 1H NMR (CDCl3): 1.51 (s, 9 H), 3.29 (s, 3 H), 7.33 (d, 2 H), 7.53 (d of d, 1 H), 7.65 (d of d, 1 H), 7.85 (d, 2 H), 8.04 (d, 1 H), 8.70 (br s, 1 H) and 8.86-8.91 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:20][CH2:19][CH3:18])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1CCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC#N
Solvent: CCO
Product: CCCC(c1ccccc1OC)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7 mmole), K2CO2 (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oil obtained was purified on a flash chromatography column. The material thus purified was a light yellow oil (2.73 g, 53%). This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) in ethanol. The 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidine maleate crystals formed on concentration and subsequent cooling to 0° C. These were collected and dried to yield 2.05 g, m.p.=132°-133° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH3:37])[C:21]1=[O:38])=[O:18])[CH3:16]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH3:37])[C:21]2=[O:38])=[O:18])[CH3:16])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (20:80).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.[N+:25](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:26].C(O[K])(C)(C)C.O>COCCOC>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:26]#[N:25])[CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Solvent: O
Product: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
At 0° C. to a solution of bis(3-(trifluoromethoxy)phenyl)methanone (3 g, 8.6 mmol), prepared as described in Procedure 11, in DME (60 mL) was added 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.3 g, 17.1 mmol) and tBuOK (25.7 mL, 1.0 M solution in tBuOH, 25.7 mmol). The reaction mixture was allowed to warm to rt and stirred for 18 h. H2O (100 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with sat. NaCl (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO chromatography (150 g) using hexane/EtOAc (0-5% over 30 min, 5-20% over 20 min) to give 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile as a yellow oil at a retention time of 46 min (1.4 g, 45% yield). HPLC: RT=4.13 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.45 ppm, 2H, t, J=8.13 Hz; 7.30 ppm, 2H, d, J=7.91 Hz; 7.23 ppm, 2H, d, J=9.23 Hz; 7.17 ppm, 2H, s; 5.17 ppm, 1H, s.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(CCC=O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Reaction time: 72 h
Yield: 49.6 %

Procedure:
Oily 4-methyl-4-nitropentanal (4.0 g, 28 mmol), hydantoin (4.0 g, 40 mmol) and sodium carbonate (2.8 g, 20 mmol) were added to 50% aqueous acetonitrile (200 ml) and the mixture was refluxed with stirring for 3 days. The reaction mixture was concentrated and extracted three times with ethyl acetate. The organic layer was concentrated to dryness to give 5-(4-methyl-4-nitropentylidene)hydantoin (3.15 g, 13.9 mmol, yield 50.0%).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[NH:15][C:14](=[O:18])[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C>O1CCCC1>[CH2:10]1[CH2:9][NH:8][CH2:17][C:16]2[NH:15][C:14](=[O:18])[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=3[C:11]1=2
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c(=O)c3ccccc23)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c(c3ccccc13)CCNC2
Temperature: 60 °C
Yield: 117.3 %

Procedure:
6-Oxo-1,4,5,6-tetrahydrobenzo[c]-1,7-naphthyridine-3(2H)-carboxylic acid tert-butyl ester (1.13 g) was added to tetrahydrofuran (30 ml) and dissolved by stirring the mixture at 60° C. 4N Hydrochloric acid-ethyl acetate (20 ml) was added, and the mixture was stirred with heating at 60° C. for 1 hr. The reaction mixture was ice-cooled, and the precipitated solid was collected by filtration, washed with ethyl acetate and dried to give 1,3,4,5-tetrahydrobenzo[c]-1,7-naphthyridin-6(2H)-one (884 mg, yield 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][C:30](Cl)=[O:31].[OH-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][C:30]([NH:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1)=[O:31]
Reactant: O=C(Cl)COc1cccc(Cl)c1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)COc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A cis/trans mixture of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (800 mg) was initially introduced into the reaction vessel with 540 μl triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (approx. 15 mg) in 20 ml methylene chloride, 790 mg (3-chlorophenoxy)acetyl chloride (1.05 molar equivalents) were added dropwise at −20° C. and the mixture was stirred overnight, while warming to room temperature. For working up, the mixture was rendered alkaline (pH>10) with one molar sodium hydroxide solution and extracted with diethyl ether (3×20 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated to dryness. The crude product obtained (1.53 g) was chromatographed on silica gel (3.0×17 cm) with 100 ml diethyl ether followed by 500 ml diethyl ether/methanol (v:v=2:1). 346 mg of the more polar diastereoisomer of 2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamide were obtained and, as a solution in 5 ml 2-butanone and 5 ml ethyl acetate, were converted into the corresponding hydrochloride by addition of 16 μl water and 110 μl chlorotrimethylsilane (322 mg of a white solid, m.p. 220° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[N:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[N:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(-c2nnco2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nnco3)cc2)CC1

Procedure:
Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole and N-BOC-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1.[CH2:16]([OH:19])[CH2:17][OH:18]>O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:18][CH2:17][CH2:16][OH:19])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(N=C=O)cc1
Reactant: OCCO
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
(4-Isocyanatophenoxy)-acetic acid methyl ester 4 (15 g, 72.46 mmol) was added to ethylene glycol (30 ml) at room temperature. The reaction was exothermic and the temperature rose to 42° C. Later the reaction mixture was stirred at room temperature for 16 hours. Water (100 ml) was added and crude 5 was filtered, dried and purified by column chromatography on silica gel using chloroform as eluant to get pure 5 (16.17 g, 82.9%) as an off-white powder with an m.p between 85.5-87.5° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)=[CH:4][CH:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>>[CH3:13][S:14]([C:17]1[CH:22]=[C:21]([C:2]2[S:6][C:5]([C:7]3[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=3)=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: Cn1ccc(-c2ccc(Br)s2)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 85 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
A stirred mixture of 3-(5-bromothiophen-2-yl)-1-methyl-1H-pyrazole (0.20 g, 0.83 mmol), 3-methanesulfonyl-phenylboronic acid (0.20 g, 1.0 mmol), K2CO3 (345 mg, 2.5 mmol), Cl2Pd(dppf).DCM (82 mg, 10 mol %) and H2O (0.6 mL) in dioxane (6 mL) was sparged with Argon for 5 min and then heated at 85° C. as a sealed flask. After 6 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/DCM, 2:98 to 5:95) to give the title compound (0.11 g, 42%) as a white solid. 1H-NMR (CD2Cl2): δ 8.15 (1H, m), 7.89 (1H, m), 7.80 (1H, m), 7.60 (1H, m), 7.40 (2H, m), 7.29 (1H, d), 6.50 (1H, d), 3.91 (3H, s), 3.07 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].[Na+].Cl>O1CCCC1>[F:14][C:4]1[CH:3]=[C:2]([C:17]([OH:18])([CH3:19])[C:16]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CC(=O)C(=O)[O-]
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 71 %

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (5 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added dropwise, with stirring, to magnesium turnings (0.49 g.) in dry tetrahydrofuran (13 ml.). When the addition was complete, the mixture was stirred and boiled under reflux for one hour. A suspension of sodium pyruvate (2.2 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added rapidly to the refluxing solution. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring for a further hour. The mixture was then cooled in an ice-bath and dilute hydrochloric acid (5N; 50 ml.) was added. The mixture was stirred and extracted with ether. The extract was then extracted with aqueous potassium carbonate (1N) and this extract acidified with dilute hydrochloric acid. The precipitate which separated, was collected and dried to give 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid, m.p. 166°-9° C. in 71% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:18]=4[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:25][C:12]1[N:11]=[C:10]([F:26])[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([C:19]5[CH:20]=[N:21][CH:22]=[CH:23][C:18]=5[C:17]([NH2:24])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:27]1[C:29]([F:32])=[N:11][CH:10]=[CH:9][CH:14]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@]2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using (S)-7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine (14c-2) in step 3. MS m/z=447.5 [M+H]+. Calculated for C23H12ClF2N5O.C2HF3O2: 561.85 (TFA salt) 1H NMR (400 MHz, MeOH) δ ppm 7.15 (s, 1H) 7.22 (s, 1H) 7.35 (ddd, J=7.14, 5.18, 1.76 Hz, 1H) 7.64 (d, J=8.80 Hz, 1H) 7.78 (d, J=8.61 Hz, 1H) 7.91 (ddd, J=9.88, 7.73, 1.76 Hz, 1H) 8.15 (d, J=4.70 Hz, 1H) 8.22 (d, J=5.09 Hz, 1H) 8.77 (s, 1H) 9.02 (d, J=5.28 Hz, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:34])([C:30]([F:33])([F:32])[F:31])[C:23]([F:29])([F:28])[C:24](I)([F:26])[F:25].CN(C)P(=O)(N(C)C)N(C)C.Cl>[Cu].C(OCC)(=O)C>[F:21][C:22]([F:34])([C:30]([F:31])([F:32])[F:33])[C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:2][F:1])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=2[CH:14]=1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc21
Temperature: 70 °C
Yield: 51.3 %

Procedure:
A mixture of 0.30 g of ethyl 2,2-bis(fluoromethyl)-6-iodo-2H-1-benzopyran-4-carboxylate, 3.50 g of nonafluoro-butyl iodide, 0.30 g of copper powder, 0.32 g of cuprous iodide and 3 ml of hexamethylphosphoric triamide was stirred with heating at 70° C. for 22 hours, added another 1.75 g of nonafluorobutyl iodide, and stirred with heating at 150° C. for 5 hours. A mixture of 2N HCl and ethyl acetate was added to the reaction mixture, and insoluble materials were separated off using a celite. An organic layer was taken up, and an aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resultant residue was purified with silica gel column chromatography (developing solution, methylene chloride:hexane=5:1) to obtain 0.19 g of ethyl 6-nonafluorobutyl-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]([C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[CH:9]=[CH:10][N:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:8]3[CH:9]=[CH:10][N:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]3=[CH:14][N:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nccn2c(-c3ccc(F)cc3)ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nccn2c(-c3ccc(F)cc3)ncc12

Procedure:
To a solution of 3-(4-fluorophenyl)-imidazo[1,5-a]pyrazine-8-carboxylic acid ethyl ester (440.0 mg, 1.54 mmol) in methanol (10 mL) is added in several portions a solution of 85% KOH (330 mg, 4.9 mmol) in water (3 mL) (additional water is added to suspend the solid that precipitated) and the mixture is warmed at reflux. The methanol is removed in vacuo and the residue is diluted with water (15 mL) and made acidic (pH=4) with 1 N aqueous HCl. The solid is collected by filtration washing with water and then ether to afford 3-(4-fluorophenyl)-imidazo[1,5-a]pyrazine-8-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.C1N2CCN(CC2)C1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(CCO)cc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(CCO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a stirred solution of the intermediate from Step A in THF (50 mL) was added DABCO (1.51 g, 13.5 mmol) and then p-toluenesulfonyl chloride (50 mL). The resulting mixture was stirred overnight at room temperature and then filtered to remove precipitated hydrochloride salts. The filtrate was concentrated under reduced pressure and DCM (50 mL) was added to the residue. The organic layer was then washed with water (1×100 mL), saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting material was purified by silica gel chromatography (70% EtOAc/hexane) to afford 1.25 g of the title intermediate (43% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][O:18][N+:19]([O-:21])=[O:20])=[O:14].[OH-].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>O.C(O)C>[O:28]1[CH2:27][CH:26]1[CH2:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][O:18][N+:19]([O-:21])=[O:20])=[O:14]
Reactant: O=C(Cc1ccc2ccccc2c1O)NCCO[N+](=O)[O-]
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Cc1ccc2ccccc2c1OCC1CO1)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 40 %

Procedure:
4.600 g (0.015 mole) of 1-hydroxy-N(2-nitroxyethyl)-2-naphthalene acetamide dissolved in a mixture of 4 ml of water, 1.436 g (0.021 mole) of 85% potassium hydroxide and 38 ml of ethanol were added slowly over a solution of 35.490 g (30 ml, 0.383 mole) of epichlorohydrin in 17 ml of ethanol, with temperature control. The mixture was stirred at room temperature for 22 hours. 150 ml of water were added and the mixture was concentrated at reduced pressure at 40° C. The mixture was extracted three times with 70 ml of ethyl acetate and dried over sodium sulphate. It was filtered and the solvent was removed at low pressure. The oil obtained was purified by column chromatography in silica gel (0.060-0.200 mm). 2.354 g (0.006 mole) of 1-(2,3-epoxy)propoxy-N-(2- nitroxyethyl)-2-naphthalene acetamide were obtained on eluting with a mixture of chloroform/methanol: 9/1 and removing the solvent at reduced pressure (m.p. 67°-71° C., Rf =0.41 TLC, silica gel Merck HPTLC-5629, chloroform 80/acetone 20). They were mixed with 8.88 g (12.8 ml, 0.150 mole) of isopropylamine in 80 ml of methanol and heated under reflux for 1 hour under anhydrous conditions. The product was concentrated at reduced pressure at 40° C. The oil obtained was redissolved in 80 ml of ethyl acetate and was extracted three times with 35 ml of 1N HCl. The acid extracts were pooled and were alkalized with the addition of powdered sodium carbonate and a solution of 1N NaOH to pH=12. The solution was treated twice with 50 ml of ethyl acetate. The organic extracts were pooled and washed twice with 25 ml of sodium chloride saturated water. It was dried over anhydrous sodium sulphate, was filtered and was concentrated at reduced pressure to give a residue which was purified by column chromatography on silica gel (0.060-0.200 mm). On eluting with a mixture of chloroform 90/methanol 20 and removing the solvent at reduced pressure until a constant weight, 1.113 g (17%) of an oil which solidified in amorphous form were obtained.