Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([CH3:34])[CH:25]=1)=[CH2:23].CC1C=C(C)C=C(C)N=1>ClCCCl>[CH3:34][C:26]1[CH:25]=[C:24]([CH:22]2[CH2:4][C:3](=[O:5])[CH2:23]2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: C=Cc1ccc(C(=O)OC)c(C)c1
Reactant: CC(=O)N(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)c1ccc(C2CC(=O)C2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of N,N-dimethylacetamide (5.5 mL) in DCE (20 mL) under nitrogen at −15° C. was added a solution of trifluoromethanesulfonic anhydride (10 mL) in DCE (50 mL) dropwise. The mixture was then stiffed for 10 min at −15° C. to make solution A. To another flask was added methyl 4-ethenyl-2-methylbenzoate (compound 231.1, 5.30 g, 0.03 mol, 1.00 equiv). A solution of 2,4,6-trimethylpyridine (5.5 mL) in DCE (80 mL) was added dropwise at −15° C. The resulting mixture was added into solution A dropwise under an inert atmosphere of nitrogen. The resulting solution was stiffed overnight at 80° C. After cooling to ambient temperature, the mixture was carefully quenched with water. The resulting mixture was extracted with 2×200 mL of ethyl acetate, and the combined organic layers were washed with 3×400 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50-1:5) as eluent to furnish 2.95 g (45%) of methyl 2-methyl-4-(3-oxocyclobutyl)benzoate as a brown oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].CO[C:9]([CH3:11])=[CH2:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:29](=O)(O)[O-:30].[Na+]>ClCCl>[CH3:6][O:5][CH:1]([O:4][CH:9]([CH3:11])[CH3:10])[C:2]([O:30][CH3:29])=[O:3]
Reactant: C=C(C)OC
Reactant: COC(=O)CO
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C(OC)OC(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl glycolate (5 ml, 64.8 mmol) and 2-methoxypropene (12.5 ml, 130.5 mmol) in dry dichloromethane (15 ml) at 0° C. was added catalytic amount of pyridinium p-toluene-sulfonate (100 mg). The mixture was stirred at 0° C. for 2 hours. Saturated sodium bicarbonate solution was added and methylene chloride layer was separated, dried over anhydrous magnesium sulfate. Solvent was evaporated and the product was distilled over anhydrous potassium carbonate under reduced pressure (20 mmHg) at 62°-64° C. (yield=9.9 g, 94%), 1H NMR (300 MHz, D6 -acetone) d:1.28 (6H, s), 3.15 (3H, s), 3.67 (3H, s), 4.01 (2H, s).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:12])/[CH:7]=[C:8](\[CH:10]=O)/[CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16].[CH2:18](N(CC)CC)C>O>[CH2:1]([O:5][C:6](=[O:12])[CH:7]=[C:8]([CH3:9])[CH:10]=[CH:16][CH:15]=[C:14]([CH:13]=[O:17])[CH3:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)/C=C(/C)C=O
Reactant: CCN(CC)CC
Reactant: CCCCO
Solvent: O
Product: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
212.6 G. of 2-formyl-but-2-ene-4-triphenyl-phosphonium chloride and 95 g. of 3-formyl-crotonic acid butyl ester are introduced into 1100 ml. of butanol and treated at 5° C. with a solution of 57 g. of triethylamine in 60 ml. of butanol. The reaction mixture is subsequently stirred for 6 hours at 25° C., then cooled and introduced into water and thoroughly extracted with hexane. The hexane phase is washed first repeatedly with methanol/water (6:4 parts by volume), then with water, dried over sodium sulphate and filtered. The filtrate is isomerized for 12 hours by shaking with iodine. The iodine is removed by the addition of sodium thiosulphate. The filtrate is washed again with water, dried and evaporated under reduced pressure. The remaining 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester boils, after rectification, at 102°-105° C./0.09 mm Hg.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[CH:24]([C:29](Cl)=[O:30])[CH2:23][CH2:22][C:21]2=[O:32]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[CH:24]([C:29]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:30])[CH2:23][CH2:22][C:21]2=[O:32]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C1CCC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCC(=O)c3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Yield: 108.3 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 1.0 g of 6.7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 0.97 g of the title compound, melting at 275°-278° C. (dec.).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:28]#[N:29].C(N)CN>CN1CCCC1=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:28]#[N:29])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(Br)cc2)cc1NCc1ccccc1
Reactant: N#C[Cu]C#N
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 14.9 %

Procedure:
20 mg of 4-(benzylamino)-6-[(4-bromophenyl)amino]pyridine-3-carboxyamide (the compound of Example 54) was dissolved in 0.4 mL of 1-methyl-2-pyrrolidinone, to which 5 mg of copper cyanide (I) was added, and stirred at 180° C. for 3 hours. After cooling, a 30% aqueous solution of ethylenediamine was added to the reaction mixture, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to obtain 2.3 mg (13%) of the title compound as a light brown solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6]>C(#N)C.O>[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]=1[OH:15])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1cccc([N+](=O)[O-])c1O
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
Acetyl nitrate obtained by mixing acetyl anhydride (1.35 g, 13.3 mmol) with fuming nitric acid (13.3 mmol) at 0° C. was dropped into a solution of 2-tert-butylphenol (2.00 g, 13.3 mmol) in acetonitrile (30 ml) at −20° C. followed by stirring for 5 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (60 g of silica gel; developing solvent, hexane:acetone=3:1) to provide 600 mg (yield 23%) of 2-tert-butyl-6-nitrophenol as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][CH:38]1[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1.484 g, 5.37 mmol) in dry dichloromethane (60 ml) was added triethylamine (1.88 ml, 13.49 mmol), 2-chloro-1-methylpridinium iodide (1.60 g, 6.26 mmol), and 4-amino-1-BOC-piperidine (1.30 g, 6.49 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography on an Isco Combiflash (40 g silica gel, 40 mL/min, 254 nM, 15% to 100% EtOAc/hexane over 14 column volumes then 100% EtOAc for 4 column volumes; title compound eluted at 65% ethyl acetate/hexane) to afford the title compound as a pale orange solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH3:27].O>CN(C=O)C>[CH3:22][O:23][CH2:24][CH2:25][N:26]([CH3:27])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNCCOC
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCCN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 2-fluoro-5-nitrobenzotrifluoride (250 mg, 1.2 mmol) in DMF (4 mL) and added triethylamine (242 mg, 2.39 mmol). N-(2-methoxyethyl)methylamine (179 mg, 1.32 mmol) was added to the reaction mixture and it was stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted with EtOAc (2×). The combined organic washes were washed with brine and dried over Na2SO4. After concentration the remaining residue was purified by column chromatography (100% CHCl3 to 1:1 MeOH:CHCl3) to give the title compound. MS 265 [M−H]−, 267 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:12].C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
Commercially available p-hydroxybenzaldehyde (50 g) was dissolved in pyridine (400 ml), followed by dropwise adding octyl chloroformate (85 g) under ice cooling, heating on a water bath, allowing to stand overnight, adding toluene (300 ml), further adding 6N-hydrochloric acid, separating the liquid layer, further washing with 2N-NaOH aqueous solution, washing with water, drying, and distilling off toluene to obtain a raw product of p-octyloxycarbonyloxybenzaldehyde (75 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH2:32][CH3:33])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (67.6 mg, 0.150 mmol) in tetrahydrofuran (1.0 mL) was added sodium hydride (60% in oil, 7.2 mg, 0.18 mmol) at 0° C. After 15 min iodoethane (60.0 μL, 0.75 mmol) was added. After being stirred for 8 h at 40° C., the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium, hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-300 ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (58.2 mg, 0.122 mmol, 81%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:28])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of the product from Example 133A (229.4 mg, 0.6861 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 55 mg, 1.372 mmol) in N,N-dimethylformamide (3 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 hour, then added methyl iodide (0.171 mL, 2.744 mmol) and let stir at room temperature for 2 hours. The solvent was removed by rotary evaporation under vacuum. The residue was taken up in water (30 mL) and extracted with methylene chloride (50 mL). The organic phase was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation under vacuum to afford the title compound as a maroon-colored solid (239 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH:12]([C:14]([CH2:16][CH3:17])=[O:15])=[CH2:13].[CH3:18][OH:19].O>>[CH2:12]([C:14]1([O:19][CH3:18])[CH2:16][CH2:17][C:8]2[C:6](=[C:5]([CH3:9])[C:4]([CH3:10])=[C:3]([OH:11])[C:2]=2[CH3:1])[O:15]1)[CH3:13]
Reactant: CO
Reactant: C=CC(=O)CC
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: O
Product: CCC1(OC)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
Trimethylhydroquinone was reacted with ethyl vinyl ketone by the procedure of Example 1 to give (±)-2-ethyl-6-hydroxy-2-methoxy-5,7,8-trimethylchroman as a beige powder, m.p. 96.5°-98.5° from methanol-H2O.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[CH2:2]([C:1]1[NH:13][CH2:12][CH2:11][N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCN
Reactant: CCCCCCCC(=O)O
Product: CCCCCCCC1=NCCN1
Yield: 95 %

Procedure:
The procedure described in Example 5 is followed except that 288 parts of n-octanoic acid and 132 parts of ethylenediamine are employed. 319 parts of 2-n-heptylimidazoline (95% of theory, based on octanoic acid employed) of boiling point 133° C./5.32 mbar are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.B(Br)(Br)[Br:22]>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6]([Br:22])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(F)cc(NC(=O)c2c(N)ncnc2Cl)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc(Br)c1C(=O)Nc1cc(O)cc(F)c1
Yield: 78.2 %

Procedure:
4-Amino-6-chloro-N-(3-fluoro-5-methoxyphenyl)pyrimidine-5-carboxamide (458 mg, 1.54 mmol) was treated with boron tribromide (1M in dichloromethane, 0.46 ml, 4.6 mmol) an using dichloromethane (7 ml) as a solvent according to the method described in Example 23. The solid residue (394 mg, 71% yield) was used in the next synthetic step without further purification. Purity 91%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(NC(C)C)(C)C.C([Li])CCC.[C:23](O)(=O)[C:24](O)=[O:25]>CCCCCC.C(N=CC)(C)(C)C.ClP(=O)(OCC)OCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:23]/[CH:24]=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)C(=O)O
Agent: CC=NC(C)(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C=O)cc1
Reaction time: 72 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction was worked up after 3 days. The following reagents were used: 4-methoxybenzaldehyde (13.5 g), diisopropylamine (32.2 mL). 1.6M n-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the oxalic acid catalyzed hydrolysis was done overnight at room temperature and then at 85° C. for 2 hours, furnished 12.5 g of crude product which was crystallized from ether-hexane to yield 10 g of (E)-3-(4-methoxyphenyl)-2-propenal, mp 58.5°-60° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=O)=O.[Cl:20]C1C=C2C(=CC=1)NC=C2CC(N)(C)C.[CH3:35][C:36]1[NH:37][C:38]2[C:43]([C:44]=1[CH2:45][C:46]([NH2:49])([CH3:48])[CH3:47])=[CH:42][C:41]([CH3:50])=[CH:40][CH:39]=2>>[ClH:20].[CH3:35][C:36]1[NH:37][C:38]2[C:43]([C:44]=1[CH2:45][C:46]([NH:49][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:18])[CH3:19])([CH3:47])[CH3:48])=[CH:42][C:41]([CH3:50])=[CH:40][CH:39]=2
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)COc1ccccc1OCCOS(C)(=O)=O
Reactant: Cc1ccc2[nH]c(C)c(CC(C)(C)N)c2c1
Product: Cc1ccc2[nH]c(C)c(CC(C)(C)NCCOc3ccccc3OCC(C)C)c2c1
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2 -(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(2,5-dimethyl-1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(2,5-dimethyl-1H- indol-3-yl)-1,1-dimethylethyl]{2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl}amine hydrochloride, m.p. 216°-218° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[CH:6]=1.[I:21]N1C(=O)CCC1=O>C(#N)C.O>[NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[C:6]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1
Solvent: O
Solvent: CC#N
Product: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)4-cyanopyrrole (EP-372982 A2) in acetonitrile (20 ml ) was added N-iodosuccinimide (703 mg). The reaction was stirred at room temperature for 30 minutes, diluted with water (100 ml) and extracted with ether (100 ml). The organic fraction was separated, dried over MgSO4, filtered and evaporated to dryness, the residue was purified by column chromatography (silica, 20 g) eluted with dichloromethane:hexane (7:3) to give the title compound as a yellow crystaline material, m.p. 130-132° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[OH2:17]>>[F:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:5]/[C:4]([O:3][CH2:7][CH3:6])=[O:17])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.6 g. of sodium hydride (50% in mineral oil, pentane washed) is added in small portions to a solution of 45 g. of triethyl phosphonoacetate in 400 ml. of dry tetrahydrofuran stirred at 0° C. under nitrogen. The reaction mixture is allowed to warm to room temperature, stirred at room temperature for 1 hour and cooled to 10° C., a solution of 24.8 g. of 4-fluorobenzaldehyde in 25 ml. of dry tetrahydrofuran is adde dropwise, and the reaction mixture is stirred at room temperature for 18 hours, the reaction mixture being maintained under nitrogen throughout. Water is added to the reaction mixture. The reaction mixture is extracted twice with diethyl ether, and the organic layers are combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure to an oil. The oil is distilled at 15 mm. Hg. to obtain the product (28.3 g. (73%)), b.p. 142° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:17](#[N:21])[CH2:18][C:19]#[N:20].[O-]CC.[Na+]>C(O)C>[NH2:21][C:17]1[C:18]([C:19]#[N:20])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[C:13]([Cl:16])[CH:12]=2)[N:1]=1
Reactant: N#CCC#N
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(N)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a yellow solution of 2-amino-5-chlorobenzophenone (2.31 g, 10.0 mmol) in warm (82° C.) dry ethanol (20 ml) was added malononitrile (1.98 g, 30.0 mmol) followed by a solution of sodium ethoxide (9.6 ml of a 3.08 M solution in ethanol, 30.0 mmol). The reaction was heated at reflux for 48 hours, then cooled to room temperature, and the solid filtered off, which was washed with water, ethyl acetate, and dried under reduced pressure to provide 2-amino-6-chloro-4-phenylquinoline-3-carbonitrile as a yellow powder (2.44 g, 87% yield). TLC Rf=0.62 using 1:1 ethyl acetate:hexanes on a silica gel glass backed plate. 1H NMR (DMSO-d6; 400 MHz) δ 7.70-7.58 (m, 5H); 7.56-7.5 (m, 2H); 7.22-7.12 (m, 3H). LC MS (CI) shows M+H 280.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>>[C:11]1([CH3:12])[CH:10]=[CH:9][C:8]([S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][N:1]=[N+:2]=[N-:3])(=[O:6])=[O:7])=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-])cc1
Yield: 19 %

Procedure:
Sodium azide and tetraethylene glycol ditosylate were reacted according Example 7 p to yield 0.7 g (19%) of 8 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H), 3.38 (t, J=5.2 Hz, 2H), 3.55-3.70 (m, 12H), 4.16 (t, J=5.2 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 21.6, 50.7, 68.7, 68.8, 69.2, 70.0, 70.6-70.7, 127.9, 129.8, 133.1, 144.7 MS ESI (m/z): [M+H]+ calcd. for C15H24O6N3S, 374.2; found 374.2
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.O>CS(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:9]=1
Reactant: N#Cc1cc(F)c(F)cc1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Br)c(C#N)cc1F
Yield: 93.4 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (218 mg, 1.00 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (214 mg, 1.00 mmol) and DIEA (0.300 mL, 1.72 mmol) in DMSO (2 mL) was stirred at 100 C for 18 h. Water was added to induce precipitation. The precipitate was collected and dried on vacuum to give tert-butyl (1S,2R)-2-(5-bromo-4-cyano-2-fluorophenylamino)cyclohexylcarbamate as a solid (385 mg).