Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)=[CH:5][C:4]=1[C:32]([F:35])([F:34])[F:33])#[N:2].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][N:9]([CH2:27][C:28]([F:29])([F:30])[F:31])[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:32]([F:33])([F:34])[F:35])[CH:5]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N(CCOc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
To a solution of 1,1-dimethylethyl [4-({2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl}oxy)phenyl]carbamate (0.132 g, 0.262 mmol; Example 27B) in CH2Cl2 (5 mL) at rt was added Et3SiH (0.10 mL, 0.66 mmol), followed by TFA (2 mL). The mixture was stirred 40 min and slowly poured into satd NaHCO3. The whole was extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo, yielding 0.098 g of the title compound as a colorless gum which was used without further purification: MS (APCI) m/z 404 (M+1).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[OH:4])#[N:2].[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:4][CH:3]([C:1]#[N:2])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)=[O:25])[C:22]1([CH3:27])[CH3:28]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 106.1 %

Procedure:
A mixture of 468.6 g (2.08 moles) (cyano)(3-phenoxyphenyl)methanol and 2500 ml toluene was placed in a flask and heated to 40° C. During an 80-85 minute period, 509 g (2.24 moles) of (cis)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride prepared as described in Step B, and 186 g (2.35 moles) of pyridine were added under nitrogen. Upon completion of the addition, the reaction mixture was stirred 2.5 hours at 40° C. After cooling, the reaction mixture was washed successively with 1000 ml of water, 1000 ml of 1 N hydrochloric acid, 1000 ml of 1 N sodium hydroxide, twice with water, and once with an aqueous solution of sodium chloride. After being dried over magnesium sulfate, the solution was filtered through Celite and the solvent stripped using a rotary evaporator. Residual solvent was removed in a vacuum oven. A total of 918.3 g of 93.6% (cyano)(3-phenoxyphenyl)methyl cis-3-(2,2dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate was obtained.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2F)=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.Cl.[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1(C)C(C)=CC=CC=1>[CH2:21]([N:28]1[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([OH:12])[CH:8]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNCc1ccccc1
Reactant: O=C(c1ccc(O)cc1F)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Oc1ccc2c(C3CC3)nn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropyl(2-fluoro-4-hydroxyphenyl)methanone (6.51 g) which can be prepared according to the method described in Reference example 2, etc., sodium acetate (14.3163 g; manufactured by Wako Pure Chemical Industries, Ltd.), and benzylhydrazine-dihydrochloride (10.72 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (180 mL). By using a dean-stark apparatus, the mixture was stirred overnight at reflux. After cooling to room temperature, the mixture was added with water and extracted twice with ethyl acetate. The organic layer was washed twice with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, insoluble matters were dissolved by adding n-hexane to the residue and the title compound was obtained as a crude product (10.97 g).
Reaction SMILES: [Cl-:1].[K+].[Cl:3][C:4]1[C:5]([F:14])=[C:6]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[CH:7]=[O:8].ClCl>ClC1C=CC=CC=1C(F)(F)F>[Cl:3][C:4]1[C:5]([F:14])=[C:6]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:7]([Cl:1])=[O:8]
Reactant: [Cl-]
Reactant: O=Cc1cc(F)c(F)c(Cl)c1F
Agent: ClCl
Agent: FC(F)(F)c1ccccc1Cl
Agent: [K+]
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Yield: 376.2 %

Procedure:
100 ml of 2-chlorobenzotrifluoride and 4.5 g of potassium chloride were placed at 110° C. in a chlorination apparatus with UV irradiation and 50 g of 3-chloro-2,4,5-trifluorobenzaldehyde in 50 ml of 2-chlorobenzotrifluoride were subsequently added dropwise with exclusion of air. After addition of 10 ml of the solution, chlorine was added at the rate at which it was absorbed. The metered addition was continued until the entire amount of the aldehyde used had reacted (gas chromatographic monitoring). Distillation of the reaction mixture gave 52 g of 3-chloro-2,4,5-trifluorobenzoyl chloride having a boiling point of 92° C./20 mbar.
Reaction SMILES: C([C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@@H:5]1[OH:13])(O)=O.[N:14](C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[NH2:14][C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:13]
Reactant: O=C(O)[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@H]1c2ccccc2C[C@H]1O

Procedure:
One gram of the hydroxamic acid of (1R,2S)-1-carboxy-2-hydroxyindane is reacted with equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran at room temperature using the procedure of Bittner, Grinberg and Kartoon (Tet. Lett. 23, 1965-8 (1974)). The product is isolated by acidification and extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-amino-2-indanol is isolated as a light yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:5]1([N:4]2[CH2:3][CH2:2][O:1][C:19]2=[O:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCNc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCCN1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under N2, a solution of N-(2-hydroxyethyl)aniline (500 mg, 3.65 mmol) and triethylamine (1 mL, 7.29 mmol) in THF (2 mL) was added slowly to a solution of triphosgene (360 mg, 1.21 mmol) in THF (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for one hour. The reaction was then quenched with a saturated solution of sodium bicarbonate (4 mL) and extracted with methylene chloride (3×4 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (5%-35% EtOAc/CH2Cl2) gave 3-phenyl-1,3-oxazolidin-2-one. LCMS (ES) m/z 164.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:7]>C(#N)C>[C:2]([NH:4][C:6](=[O:7])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)(=[O:3])[NH2:1]
Reactant: NC(N)=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: NC(=O)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1.20 g. (20 mmole) of urea and 2.02 g. (10 mmole) of p-nitrophenyl chloroformate in a dry flask under nitrogen were added 10 ml. of dry acetonitrile. The reaction mixture momentarily became clear and then a precipitate formed. The mixture was stirred for 18 hours at room temperature and the precipitate was filtered, washed with water and dried under vacuum. The dried product was triturated with ether and redried to yield 1.0 g. of crystalline product.
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH2:4][C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8]>>[Cl:3][CH:4]([Cl:1])[C:5]([F:13])([F:14])[C:6]([F:11])([F:12])[C:7]([F:9])([F:8])[F:10]
Reactant: ClCl
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCl
Product: FC(F)(F)C(F)(F)C(F)(F)C(Cl)Cl

Procedure:
For example, to prepare 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane, 2,2,3,3,4,4,4-heptafluorobutanol and p-toluenesulfonyl chloride are reacted to form 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate are reacted to form 1-chloro-2,2,3,3,4,4,4-heptafluorobutane. Finally, chlorine and the 1-chloro-2,2,3,3,4,4,4-heptafluorobutane are reacted to form the 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=1/[CH:18]=[CH:19]/[C:20](/[CH3:29])=[CH:21]/[CH:22]=[CH:23]/[C:24](/[CH3:28])=[CH:25]/[CH2:26][OH:27].C(N(CC)CC)C>ClCCl>[CH3:28]/[C:24](/[CH:23]=[CH:22]/[CH:21]=[C:20](\[CH3:29])/[CH:19]=[CH:18]/[C:11]1[C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH2:15][C:10]=1[CH3:9])=[CH:25]\[CH2:26][O:27][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C1CCCC(=O)O1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/COC(=O)CCCC(=O)O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Glutaric anhydride (220 mg, 1.93 mmol) and retinol (500 mg, 1.75 mmol) were dissolved in dichloromethane (5 mL) in an amber-colored vial. Triethylamine (513 ul, 3.68 mmol) was added and the vial was flushed with argon. Reaction mixture was allowed to stir at room temperature for 4 hours. The material was concentrated and purified by silica gel chromatography with a dichloromethane/methanol gradient. Fractions were pooled and concentrated to yield yellowish oil (700 mg). The product was verified by NMR.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([C:21]([O:23][CH3:24])=[O:22])[CH:5]=1.S(OC)(O[CH3:29])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH3:29])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([C:21]([O:23][CH3:24])=[O:22])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1N(C)S(=O)(=O)c1ccc(C)cc1
Yield: 85.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.43 g (10.8 mmol)) in DMF (10.0 ml), 4′-chloro-2′-methoxycarbonyl-p-toluenesulfonanilide (3.33 g (9.80 mmol)) was added under cooling with ice and with stirring. After 15 minutes' stirring under cooling with ice, dimethyl sulfate (1.02 g (10.8 mmol)) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. Then, resulting reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 2.95 g (85%) of 4′-chloro-2′-methoxycarbonyl-N-methyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([O:11]C)=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1.O[Li].O.Cl>CO.O>[NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1
Reactant: COC(=O)c1cc2[nH]ncc2s1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2[nH]ncc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (F-5) (4.2 g, 18.7 mmol) in MeOH (50 mL) was added a solution of LiOH.H2O (3.1 g, 74.8 mmol) in water (5 mL). The reaction mixture was stirred at room temperature overnight. Then 1N HCl was added to adjust to pH to ˜5, the resulting precipitate was collected and dried to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][C:13]1[O:17][N:16]=[CH:15][CH:14]=1>CO.O>[O:17]1[C:13]([CH2:12][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=[N:16]1
Reactant: BrCc1ccno1
Reactant: Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCc2ccno2)cc1
Yield: 99.9 %

Procedure:
To a mixed solution of 4-aminothiophenol (600 mg) and sodium hydroxide (276 mg) in methanol (10 ml) and water (6 ml), a solution of 5-bromomethyl isoxazole (932 mg) in methanol (5 ml) was added at 0° C. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to give 4-[(isoxazol-5-ylmethyl)sulfanyl]aniline (988 mg) as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](Cl)(Cl)=[S:12].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: COc1ccccc1CN
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1CN=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 2-methoxybenzylamine (1.80 g) in diethylether (20 ml) was added dropwise under ice-cooling for 10 minutes thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour. To the reaction solution was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-methoxybenzyl)isothiocyanate (2.35 g, yield: 99%) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccccc1C(=O)Cl
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccccc1C(=O)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (200 mg, 0.76 mmol) was dissolved in dichloromethane (5 mL) at -78° C. and treated with 4-methylmorpholine (0.17 mL, 1.55 mmol, 2 eq.) and 2-methoxy-benzoyl chloride (0.11 mL, 0.74 mmol). The solution was allowed to warm to 0° C. and stir for 1 hour. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 3% methanol in dichloromethane to give 268 mg (90%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[O:16][C:17]([CH2:20]Cl)=[N:18][N:19]=3)=[CH:13][N:12]3[CH:22]=[CH:23][N:24]=[C:11]3[C:10]=2[Cl:25])=[C:4]([F:26])[CH:3]=1.[I-].[K+].[NH3:29]>O1CCCC1>[NH2:29][CH2:20][C:17]1[O:16][C:15]([C:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:26])=[C:10]([Cl:25])[C:11]3[N:12]([CH:22]=[CH:23][N:24]=3)[CH:13]=2)=[N:19][N:18]=1
Reactant: Fc1cc(Br)ccc1Nc1c(-c2nnc(CCl)o2)cn2ccnc2c1Cl
Reactant: N
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: NCc1nnc(-c2cn3ccnc3c(Cl)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(4-Bromo-2-fluoro-phenyl)-[8-chloro-6-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-7-yl]-amine (38 mg, 0.083 mmol) was dissolved in tetrahydrofuran (1 mL). Potassium iodide (14 mg, 0.083 mmol) was added and then ammonia (7 M solution in methanol, 0.30 mL, 2.08 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (gradient of 20:1 dichloromethane/methanol to 5:1) to yield the desired product (26 mg, 71%) as a yellow solid. MS ESI (+) m/z 437, 439 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.33 (s, 1H), 8.17 (d, 1H), 7.70 (d, 1H), 7.51 (dd, 1H), 7.16 (d, 1H), 6.65 (t, 1H), 3.94 (s, 2H). 19F (376 MHz, DMSO-d6)−128.3 (t).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].[CH2:8]([OH:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].CN1CCOCC1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])/[CH:5]=[CH:6]/[O:18][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[CH3:2]
Reactant: C#CC(=O)OCC
Reactant: C=CCCCCCCCCO
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: C=CCCCCCCCCO/C=C/C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
The reaction was performed in standard glassware under an atmosphere of N2. To 150 ml of diethylether were added 9.8 g (0.1 mol) propiolic acid ethyl ester, 15.6g (0.1 mol) dec-9-en-1-ol and 10.1 g (0.1 mol) N-methylmorpholine. This solution was kept without stirring at room temperature for 24 hours. The mixture was evaporated under vacuum and the residue purified by bulb to bulb distillation (bp: 85-90° C.; 0.006 mbar) to yield 23.2 g (916%) of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[N:9]([C:31]([C:30]3[CH:34]=[C:35]([O:39][CH3:40])[C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=3)=[O:32])[CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)N(C(=O)c1cc(OC)c(OC)c(OC)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a solution of 225 (300 mg, 0.83 mmol) in DCM (5 ml) was added TEA (0.23 ml, 1.65 mmol) and 3,4,5-trimethoxybenzoyl chloride (228 ml, 0.99 mmol). The reaction mixture was stirred at rt for 12 h. Water (10 ml) was added and the aqueous layer was extracted with DCM (3×30 ml). The combined organic phases were washed with sat. aq. NaHCO3 (10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, gradient elution 100% hex to 100% EtOAc over 25 min) afforded the title compound (240 mg, 52%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.04 (18H, d, J=6.7 Hz, 6×CH3CH), 1.14-1.24 (3H, m, 3×CH), 1.55 (6H, s, 2×CH3), 2.74 (2H, s, CH2), 3.80 (3H, s, OCH3), 3.85 (6H, s, 2×OCH3), 3.86 (3H, s, OCH3), 4.19 (2H, s, CH2), 6.53 (1H, s, CH), 6.56 (2H, s, 2×CH), 6.71 (1H, s, CH). LC/MS (ES+) tr=0.2.23 min, m/z 580.24 (M++Na). HRMS (ES+) calcd for C31H47NO6Si (M++H) 558.3245, found 558.3237.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[C:5]1(=[O:22])[N:20]2[C:21]3[C:12](=[CH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=42)[CH2:11][CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]1.C(=O)(OCC)OCC.Cl>C(O)C>[CH2:2]([CH:6]1[C:5](=[O:22])[N:20]2[C:21]3[C:12](=[CH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=42)[CH2:11][CH:10]=[CH:9][C:8]=3[CH2:7]1)[CH3:3]
Reactant: O=C1CCC2=C3C(=Cc4ccccc4N13)CC=C2
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CCC1CC2=C3C(=Cc4ccccc4N3C1=O)CC=C2

Procedure:
To a freshly prepared solution of sodium ethoxide in ethanol (from 0.35 g sodium metal and 10 ml ethanol) was added 6H-pyrido[3,2,1-de]acridin-1(2H)-one (1.2 g) portionwise over a period of 10 minutes. To the resulting dark red solution was slowly added diethyl carbonate (1.77 g) and the solution was then refluxed for 3 hours. The reaction mixture was cooled, acidified to pH 2 with concentrated HCl and then extracted with methylene chloride. The organic extract was washed with water and was then collected, dried and evaporated to dryness to obtain a light amber solid (1.8 g; m.p. 113°-118° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1C=C[C:6]2[C:7](C)=[N:8][O:9][C:5]=2[C:4]=1[CH:13]=[O:14].[CH3:15][O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH:13]=[O:14])=[C:5]([O:9][CH3:15])[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(C)noc2c1C=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(OC)c1C=O

Procedure:
Reaction of the commercially available 2-chloro-4-methoxy-pyridine-3-carbaldehyde (23) with NaOMe in MeOH affords 2,4-dimethoxy-pyridine-3-carbaldehyde (24).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:28]2=[O:30])=[CH:16][CH:17]=1
Reactant: OC(CNc1ccc(Br)cc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(c2ccccc2)CN1c1ccc(Br)cc1
Temperature: 0 °C
Yield: 151.2 %

Procedure:
A solution containing 2-(4-bromoanilino)-1-phenyl-1-ethanol (0.74 g, 0.00253 mol), N,N-diisopropylethylamine (1.01 g, 0.00786 mol) and N,N-dimethylaminopyridine (0.092 g, 0.00076 mol) in anhydrous dichloromethane (32 mL) was cooled to 0° C. and a solution of triphosgene (0.38 g, 0.00127 mol) in anhydrous dichloromethane (8 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature while stirring under an atmosphere of nitrogen for eighteen hours. The organic phase was washed with a saturated solution of sodium bicarbonate in water (40 mL), brine (30 mL) and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 3-(4-bromophenyl)-5-phenyl-1,3-oxazolan-2-one (0.62 g, 0.00192 mol) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[CH:38][CH:39]=[CH:40][C:27]3=4)=[O:25])=[CH:20][C:19]=2[F:41])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>CO.O1CCOCC1>[ClH:42].[ClH:42].[F:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 4-{3-[2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E49.1 (615 mg, 1.09 mmol) in methanol (2 ml) at 0° C. was treated with 4N HCl in dioxan (5 ml). The solution was allowed to warm to room temperature and stirred for 1 h. Solvents were removed in vacuo to give a white foam identified as the title compound (585 mg, 100%).