Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:12][CH2:13]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Yield: 77.4 %

Procedure:
tert-Butyl{1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 147, 190 mg, 0.47 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 110 mg of the crude product as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([NH:7][C:8]2[C:21]3[CH2:20][CH2:19][C:18]4[N:17]=[C:16]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[NH:15][C:14](=[O:29])[C:13]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>[Pd].COCCOCCOC>[C:1]([C:3]1[CH:31]=[CH:30][C:6]([NH:7][C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[N:17]=[C:16]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[NH:15][C:14](=[O:29])[C:13]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(=O)[nH]1)-c1cccc(Nc3ccc(C#N)cc3)c1CC2
Agent: [Pd]
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Solvent: COCCOCCOC
Product: CC(C)(C)C(=O)Nc1nc2ccc3c(Nc4ccc(C#N)cc4)cccc3c2c(=O)[nH]1
Yield: 57.6 %

Procedure:
To a solution of sodium ethoxide, prepared by reacting sodium (0.28 g, 12 mmol) with ethanol(6 ml), was added guanidine hydrochloride (1.2 g, 12 mmol) and the mixture was briefly stirred at reflux. A solution of methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.63 g, 1.5 mmol) in ethanol (6 ml) was added and the reaction mixture was stirred at reflux under nitrogen for 18 hours. The solution was diluted with water (50 ml), neutralized with acetic acid, and the resulting precipitate filtered and dried at 110° C. under reduced pressure. A solution of the solid in pivalic anhydride (10 ml) was refluxed for ~5 minutes and then concentrated under high vacuum. The residue was eluted on silica gel (30 g) with ethyl acetate:methylene chloride (1:9) and the resulting solid recrystallized from diethyl ether, the slurry diluted with hexane, filtered, and the solid dried at 100° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.48 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.23 (s, 9H, t-butyl), 2.67 (s, 4H, ArCH2 's), 6.68 (d, J=9 Hz, 2H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.26 (t, J=8 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 2H, Ar), 8.38 (d, J=8 Hz, 1H, Ar), 8.53 (s, 1H, C7 -NH), 11.28 (br s, 1H, N2H), 12.16 (br s, 1H, C3 -NH). A solution of the pivalamide (0.15 g) and 10% palladium on carbon (70 mg) in diglyme (5 ml) was stirred at reflux under nitrogen for 10 hours. Pivalic anhydride (2×0.5 ml, 4.9 mmol) was added at 5 and 9 hours. The solution was diluted with diglyme (15 ml), filtered hot through celite, and concentrated under high vacuum. The residue was purified by chromatography on silica gel (15 g) eluting with ethyl acetate:methylene chloride (1:9) and then recrystallization from methanol. The solid was filtered and dried at 90° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (86 mg). 1H NMR (DMSO-d6, 200 MHz) δ: 1.26 (s, 9H, t-butyl), 6.85 (d, J=9 Hz, 2H, Ar), 7.49-7.60 (m, 4H, Ar), 7.72 (t, J=8 Hz, 1H, Ar); 8.29 (d, J=9 Hz, 1H, Ar); 9.07 (s, 1H, C7 -NH), 9.61 (d, J=9 Hz, 1H, Ar), 11.25 (br s, 1H, N2H), 12.32 (br s, 1H, C3 -NH). Mass spectrum (CI-CH4) 412 (M+1, 100%). Anal. Calculated for C24H21N5O2.17/100H2O: C, 69.54; H, 5.19; N, 16.89. Found: C, 69.56; H, 5.23; N, 16.88.
Reaction SMILES: C([O:3][C:4]1(OCC)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@H:6]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:5]1)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.O>[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@H:6]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:5]1
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](c1ccccc1)N1CCC(=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 96.9 %

Procedure:
4,4-Diethoxy-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine (4.0 g, 9.2 mmol) was dissolved in a mixture of trifluoroacetic acid/water (9:1) (100 ml) at 0° C. and stirred for 2 hours at this temperature. The mixture was basified with half saturated aqueous sodium carbonate, extracted with ethyl acetate and dried (MgSO4) for 2 hours and filtered. The solvent was removed in vacuo and the residue was left in a vacuum own at 40° C. for two days, which afforded 3.23 g (98%) of 4-oxo-1-((S)-1-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine as a solid.
Reaction SMILES: N#[C:2][Br:3].C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:31]=[CH:30][C:14]2[O:15][C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH:19]([S:20][CH2:21]CN(C)C)[C:13]=2[CH:12]=1.CCCCCC>C(Cl)(Cl)Cl>[Br:3][CH2:2][CH2:21][S:20][CH:19]1[CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[O:15][C:14]2[CH:30]=[CH:31][C:11]([F:10])=[CH:12][C:13]1=2
Reactant: N#CBr
Reactant: CN(C)CCSC1Cc2ccccc2Oc2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)C(SCCBr)Cc1ccccc1O2
Reaction time: 0.33 h

Procedure:
To a mixture of 2.3 g of cyanogen bromide and 5.0 g of potassium carbonate in 40 ml of chloroform is added portionwise over a 50 minutes span a solution of 4.8 of 2-fluoro-10,11-dihydro-11-[β-(dimethylamino)ethylthio]dibenz[b,f]oxepin, free base of Example 32, in 85 ml of chloroform. After total addition, the mixture is stirred for 20 minutes before being filtered. The filtrate is evaporated to leave an oil which is treated with three portions of boiling hexane. The combined hexane portions are evaporated leaving an oil which is chromatographed through a silica gel column with an eluant of methylene chloride and is recrystallized from cold hexane to give a white powder, mp 46°-48° C. of 11-[β-(bromo)ethylthio]-2-fluoro-10,11-dihydrodibenz[b,f]oxepin.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[O:8])=[C:5]([CH3:16])[CH:4]=1)=O.Cl.[NH2:18][OH:19]>CO.O>[OH:19][N:18]=[CH:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[O:8])=[C:5]([CH3:16])[CH:4]=1
Reactant: NO
Reactant: COC(=O)NC(=O)c1ccc(C=O)cc1C
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)NC(=O)c1ccc(C=NO)cc1C
Yield: 102.8 %

Procedure:
In a solution of 41 mg of methyl N-[4-formyl-2-methyl benzoyl]carbamate in 4 mL of methanol and 1 mL of water, 15 mg of hydroxylamine hydrochloride was added at room temperature with stirring, and continued to stir at the same temperature for 1.5 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 45 mg of the aimed product as white crystal.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:14]([O:9][C@@H:3]([CH2:2][Cl:1])[CH2:4][C:5]([O:7][CH3:8])=[O:6])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: COC(=O)C[C@@H](O)CCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@H](CCl)O[Si](C)(C)C(C)(C)C
Yield: 113.9 %

Procedure:
A solution of (R)-methyl 4-chloro-3-hydroxybutanoate (15 g, 98.7 mmol) in CH2Cl2 (240 mL) was stirred overnight with tert-butyl-chloro-dimethyl-silane (17.82 g, 118.2 mmol), imidazole (33.6 g, 493.5 mmol) and a catalytic amount of DMAP (0.6 g, 4.92 mmol.) at room temperature under N2. The reaction mixture was poured into water (150 mL) and acidified to pH 6-7 by dropwise addition of cold aqueous HCl (0.5 M). The aqueous phase was extracted with CH2Cl2 (3×60 mL). The combined organic phases were washed with sat. Na2CO3 solution, brine, dried over anhydrous Na2SO4 and concentrated to give (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (30 g, crude).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[FH:7].[O:8]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9]1>O.[Cl-].C([N+](CCCCCCCCCCCCCCCCCC)(C)C)CCCCCCCCCCCCCCCCC>[F-:7].[OH:8][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][N+:2]([CH2:3][CH2:4][OH:5])([CH3:6])[CH3:1]
Reactant: CN(C)CCO
Reactant: F
Reactant: CCCCCCCCCCC1CO1
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: [Cl-]
Solvent: O
Product: CCCCCCCCCCC(O)C[N+](C)(C)CCO
Product: [F-]
Temperature: 95 °C
Reaction time: 6 h

Procedure:
44.57 g of dimethyl ethanolamine (0.5 mole) were diluted with 420.65 g of water, followed by the addition of 19.38 g of an aqueous 41.3% hydrofluoric acid solution (0.4 mole). A clear solution was formed. After the solution had been heated to 95° C., 94.0 g of 1,2-epoxydodecane (0.5 mole) and 3.5 g of a 75% dispersion of distearyl dimethyl ammonium chloride (as phase transfer catalyst) were added, after which the reaction mixture was stirred for 6 hours at 95° C. Finally, another 4.84 g of the 41.3% hydrofluoric acid solution (0.1 mole) were added. A clear yellow solution of the 2-hydroxydodecyl-2-hydroxyethyl dimethyl ammonium fluoride containing 73.1 m vals of quaternary ammonium compound (QUAT) per 100 g of the aqueous solution was obtained.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1cc(F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask is added methyltriphenylphosphonium bromide (2.79 g, 7.8 mmol) and anhydrous ethyl ether (40 mL). The suspension is then cooled down to −78° C. and BuLi (6.77 mmol, 4.23 mL 1.6 M solution in hexane) is added dropwise. After the addition, the bright yellow mixture is warmed up to 0° C. and stirred for 30 min and cooled down to −78° C. again. To this mixture, a solution of 3-fluoro-5-trifluoromethyl-benzaldehyde (1 g, 5.2 mmol) in anhydrous ethyl ether (6 mL) is added drop by drop. After the addition, the mixture is slowly warmed up to room temperature and stirred for 14 hr. The precipitate is removed by filtration and washed with ethyl ether (2×5 mL). The filtrate is concentrated by distilling off ethyl ether at ˜60° C. bath temperature. The resulted higher boiling point liquid is purified by pass through a short column (silica gel) with hexane. After removing the hexane under vacuum (˜150 mmHg), the resulted crude 1-fluoro-3-trifluoromethyl-5-vinyl-benzene is used directly for next step.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[CH2:20]([NH2:24])/[CH:21]=[CH:22]/[CH3:23].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:24][CH2:20]/[CH:21]=[CH:22]/[CH3:23])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: C/C=C/CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C=CCNc1nc(NC/C=C/C)nc2ccc([N+](=O)[O-])cc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 80.9 %

Procedure:
150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 2 ml of acetonitrile, and 305 mg (2.83 mmol) of trans-2-butenylamine hydrochloride and 0.39 ml (2.83 mmol) of triethylamine were added thereto, followed by stirring at 50° C. for 6 hours. To the reaction solution was water added, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 138 mg (yield: 80.9%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[C:13]=2[C:14](=[O:26])[N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[N:16]=3)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:30])=O.CN(C)C=O>ClCCl>[CH:1]1([C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[C:13]=2[C:14](=[O:26])[N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:30])=[O:22])=[CH:19][CH:18]=2)[N:16]=3)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a suspension of finely ground 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.19 g. 0.55 mmol) in dichloromethane (4 ml) was added oxalyl chloride (1.6 ml, 0.01 mol) followed by a drop of dimethyl formamide. The mixture was stirred under nitrogen at 45° C. for 8 h. The solvent was removed in vacuo to yield 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride as a pale yellow solid, LCMS m/z [M+MeOH—Cl]+ @ RT 1.46 min: 95% purity. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=1[CH2:31][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22]
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC(=O)c1ccccc1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 2-bromomethylbenzoate following General Procedure S.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[NH2:14].[N:19]([O-])=O.[Na+]>C(O)(=O)C.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]2[N:14]=[N:19][NH:13][C:8]=2[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reaction time: 1.5 h

Procedure:
3-(3-bromo-5-chlorophenoxy)-4-chlorobenzene-1,2-diamine (4.97 g, 14.3 mmol) in acetic acid (25 mL) was cooled to 15° C. under N2 and sodium nitrite (1.08 g, 15.7 mmol) in water (39.3 mL) was added dropwise. After 1.5 hours, the reaction was diluted with EtOAc (300 mL), and the organic phase was separated and washed with water (3×100 mL). The organic phase was then dried (MgSO4), filtered, concentrated to afford the title product. LRMS (M+1) 359.7.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[N:18]=[N:19][C:20]([OH:23])=[CH:21][CH:22]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[C:17](=[O:16])[CH:22]=[CH:21][C:20]([OH:23])=[N:19]1)#[N:2]
Reactant: Oc1ccc(O)nn1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2nc(O)ccc2=O)[C@@H]1O

Procedure:
A mixture containing I g of 6-cyano-2,2-dimethyl-3,4-epoxychromane, 1.1 g of 3,6-dihydroxypyridazine and 0.20 ml of a methanolic solution containing 357. of benzyltrimethylammonium hydroxide, in 5 ml of dioxane and 5 ml of dimethylformamide, is refluxed for 50 hours. It is concentrated under vacuum and the residue is then triturated in 15 ml of water. The precipitate formed is filtered off and washed with water and then isopropyl ether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.N1C=C(C(O)=O)C=NC=1.[C:25]([O:29][C:30](N1CCC(N)CC1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(NC1CCNCC1)c1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C(O)c1cncnc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cncnc2)CC1

Procedure:
In analogy to the procedure described in example 50k), pyrimidine-5-carboxylic acid piperidin-4-ylamide [prepared in analogy to the procedures described in examples 50 h) and 50i) by condensation of pyrimidine-5-carboxylic acid with 4-amino-piperidine-carboxylic acid tert-butyl ester to give 4-[(pyrimidine-5-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester followed by Boc cleavage with trifluoroacetic acid] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyano-borohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 403.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>CO>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][N:21]=[CH:4][C:3]2[C:2]([Br:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=2[Br:11])=[CH:16][CH:15]=1
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Reactant: NNc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C=NNc2ccc(F)cc2)c(Br)c1
Yield: 97 %

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (600 g, 2.16 mmol) (which may be prepared according to the method of Lulinski and Serwatowski, Journal of Organic Chemistry, 68, (2003), 5384), (4-fluorophenyl)hydrazine hydrochloride (351 mg, 2.16 mmol) and sodium acetate (180 mg, 2.19 mmol) were heated in methanol (15 ml) under reflux for 2 hours in a nitrogen atmosphere. The methanol was evaporated and the residue partitioned between dichloromethane (30 ml) and aqueous brine (30 ml). The organic phase was separated, combined with additional dichloromethane extracts (2×15 ml), washed with aqueous sodium bicarbonate (2×15 ml), passed through a hydrophobic frit and evaporated to give the title compound (809 mg).
Reaction SMILES: CS(NCC[NH:8][C:9]([C:11]1[C:12]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[CH:13][C:14]2[CH:19]=[N:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23](SCCO)[CH:22]=3)=[N:16][C:15]=2[N:31]=1)=[O:10])(=O)=O.C[Si](C)(C)[O-:42].[K+].[CH2:46]1[CH2:50][O:49]CC1>>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:32]=1[C:12]1[C:11]([C:9]([NH2:8])=[O:10])=[N:31][C:15]2[N:16]=[C:17]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:49][CH2:50][CH2:46][OH:42])=[CH:25][CH:26]=3)[N:18]=[CH:19][C:14]=2[CH:13]=1
Reactant: CS(=O)(=O)NCCNC(=O)c1nc2nc(Nc3cccc(SCCO)c3)ncc2cc1-c1c(Cl)cccc1Cl
Reactant: C[Si](C)(C)[O-]
Reactant: C1CCOC1
Agent: [K+]
Product: NC(=O)c1nc2nc(Nc3ccc(OCCO)cc3)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 100 °C

Procedure:
20 mg of the product from example 3 in 1 ml THF were mixed with 13.5 mg potassium trimethylsilanolate under Ar atmosphere. The mixture was heated to 100° C. for 20 min in a microwave reactor.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]1[O:24][C@@H:23]1[CH2:25]O.CCCCCC>C(Cl)Cl>[O:12]([CH2:25][C@H:23]1[O:24][CH2:22]1)[S:9]([C:8]([F:21])([F:20])[F:7])(=[O:10])=[O:11]
Reactant: OC[C@@H]1CO1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=S(=O)(OC[C@@H]1CO1)C(F)(F)F
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To pyridine (10.3 g, 0.13 m) in CH2Cl2 (300 ml) cooled to -23° in a dry ice/CCl4 bath was added trifluoromethanesulfonic anhydride (36.7 g, 0.13 m) in CH2Cl2 (100 ml) dropwise over 1/2 hour. While still cooling this mixture at -23°, (R)-glycidol (8.6 g, 0.116 m) in CH2Cl2 (100 ml) was added dropwise over 1/2 hour. After stirring for 5 minutes with cooling and 15 minutes without, an equal volume of hexane was added and the solids were filtered. Concentration of the solution at 30°/25 torr. left a residue which was distilled to give (S)-3-trifloxy-1,2-epoxypropane (40%); bp 35°-39°/0.2 mm; [α]D24 =14.7° (c=3.90, CHCl3); 1H NMR (CDCl3) 4.8 (1H, d of d, J=11, J=3 ), 4.4 (1H, d of d, J=11, J=3), 3.3 (1H, m), 2.9 (1H, t, J=4.5), 2.7 (1H, J=4.5, J=2).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:3]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41]1[CH2:45]OC[CH2:42]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=2)[C:3]=1[CH:26]([CH2:42][CH2:41][CH3:45])[C:27]([O:29][CH3:30])=[O:28]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Yield: 72.8 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.340 g; 0.78 mmol), LHMDS 1N in THF (1.17 mL; 1.17 mmol), 1-iodopropane (0.152 mL; 1.56 mmol) in DMF (3.9 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.271 g (73%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][CH2:15][F:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[F:16][CH2:15][CH2:14][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCF)cc1O
Temperature: 57.5 °C

Procedure:
A mixture of methyl 2,4-dihydroxybenzoate (5.04 g, 30 mmol), 1-bromo-2-fluoroethane (4.18 g, 2.46 mL, 33 mmol), potassium carbonate (4.55 g, 33 mmol) and potassium iodide (1 g) in DMF (20 mL) was heated overnight at 55-60° C. before it was poured into water (150 mL). The resulting white precipitate was filtered, redissolved in dichloromethane, dried (MgSO4), concentrated and diluted with hexane to afford the ether in two crops (1.30 g and 2.19 g). The first crop was characterized: