Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][O:23][CH3:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C([O-])(=O)C.[Na+]>C(O)C>[CH2:28]([O:30][N:31]=[C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][O:23][CH3:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:29]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(COC)C(=O)CO3)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(COC)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 40 mL of absolute ethanol were added in sequence 0.90 g (2.5 mmol) of 2-propionyl-3-hydroxy-5-(N-methoxymethyl-3-oxo-(2H)-1,4 benzoxazin-6-yl)-cyclohex-2-en-1-one, 0.31 g (3.2 mmol) of ethoxyamine hydrochloride and 0.26 g (3.2 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then partitioned between 200 mL of water and 50 mL of dichloromethane. The organic layer was separated, dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as an oily residue which crystallized upon standing. The crude solid was triturated in warm ether and the above-named product was isolated by filtration as a white solid which melted at 101°-103° C. in a yield of 0.60 g (60 percent of theoretical). 1H NMR (CDCl3): d1.05-1.52 (m, 6H, both --CH2CH3 's), 2.58-3.65 (m including 2H,OCH2C=0), 5.33 (s, 2H, --NCH2O), 6.85-7.30 (m, 3H, aromatic H's), 15.05 (broad s, 1H, enol H); (Compound 8).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH2:9]([CH2:11][NH2:12])[OH:10].C(O)(=O)C(C)(C)C.CCCCCCC>ClCCl.O.C1(C)C=CC=CC=1>[OH:10][CH2:9][CH2:11][N:12]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[CH3:6]
Reactant: NCCO
Reactant: CC(=O)CCC(C)=O
Agent: CC(C)(C)C(=O)O
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1CCO
Temperature: 115 °C

Procedure:
A mixture of hexan-2,5-dione (5 g), ethanol amine (26.7 g) and pivalic acid (23.26 g) in a solvent mixture containing n-heptane: tetrahydrofliran: toluene (4:1:1, 50 mL) was refluxed with stirring at 110-120° C. Water formed during the reaction was removed azeotropically during 3 to 4 hrs. The reaction mixture was cooled and the solvent was removed. The residue obtained was dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL), water (30 mL), and then with brine (30 mL), dried (Na2SO4) and the solvent was evaporated. The crude compound obtained as an oily mass, was purified by column chromatography (silica gel 100-200), using ethyl acetate:hexane (2:8) as an eluent to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
To a stirred mixture of 4-aminophenylacetic acid (15.0 g) and o-tolylisocyanate (10.2 ml) in CH2Cl2 (200 ml) was added triethylamine (13.8 ml). After 1 h the resulting homogeneous solution was concentrated under reduced pressure, dissolved in water (100 ml) and acidified to pH 2 with 1N HCl. The off-white ppt was filtered, suspended in THF (200 ml) and 10 ml conc. HCl was added. The resulting homogeneous solution was concentrated under reduced pressure and recrystallized from EtOAc (800 ml) to give 22 g of the title compound as a white solid. MP 221-2° C.; MS [M+1]+ 285.2; Analysis calcd. for C16H16N203: C (67.59), H (5.67), N (9.85). Found: C (67.22), H (5.78), N (9.69).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH3:9].[F:10][C:11]1[C:16]([OH:17])=[CH:15][N:14]=[C:13]2[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=[CH:20][C:12]=12.O.C(#N)C>CN(C=O)C>[CH2:8]([O:17][C:16]1[C:11]([F:10])=[C:12]2[CH:20]=[CH:19][NH:18][C:13]2=[N:14][CH:15]=1)[CH3:9]
Reactant: CCBr
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cnc2[nH]ccc2c1F
Temperature: 60 °C
Yield: 23.7 %

Procedure:
Potassium carbonate (3.49 g, 25.3 mmol) and bromoethane (1.10 g, 10.1 mmol) were added to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (2.6 g, 8.43 mmol) in DMF (5 mL). The reaction was heated to 60° C. in a sealed tube for 24 hours and then filtered. After concentration, the filtrate was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, water/ACN, 90/10→10/90, 20CV) to yield 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridine (360 mg, 12% yield) as a solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([O-:33])=[O:32].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:40]([C:37]1[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:39][CH:38]=1)(=[O:41])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 4-nitrophenylsulphonyl chloride (105 mg, 0.474 mmol), diisoproylethylamine (0.084 mL, 0.474 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydrogen sulfate (1N). The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 1:1 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (254 mg, 88%) as a foam. H1-NMR (chloroform-D3): 0.90 (m, 6H), 1.60 (m, 7H), 2.90 (m, 5H), 3.68 (m, 2H), 3.87 (m, 4H), 4.17 (m, 1H), 4.83 (d, 1H), 5.02 (m, 1H), 5.64 (d, 1H), 7.23 (m, 5H), 7.99 (d, 2H), 8.38 (d, 2H). MS(ESI): 630(M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[CH:6][N:7]=1.[NH2:24][C@@H:25]([C:28]1[CH:33]=[C:32]([I:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[CH2:26][OH:27].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:24][C@@H:25]([C:28]3[CH:33]=[C:32]([I:34])[CH:31]=[C:30]([F:35])[CH:29]=3)[CH2:26][OH:27])=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc([C@@H]2CC[C@@H](O)C2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: N[C@H](CO)c1cc(F)cc(I)c1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc([C@@H]2CC[C@@H](O)C2)nc1-c1ccc(C(=O)N[C@H](CO)c2cc(F)cc(I)c2)c(F)c1
Yield: 45.2 %

Procedure:
To a mixture of (4-(3-amino-6-((1R,3R)-3-hydroxycyclopentyl)pyrazin-2-yl)-2-fluorobenzoic acid) (6 mg, 0.019 mmol), (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol (8.96 mg, 0.028 mmol), HOAt (5.15 mg, 0.038 mmol) and EDC (7.25 mg, 0.038 mmol) in DMF (1 ml) was added DIEA (0.036 ml, 0.208 mmol). The resultant mixture was stirred over night at RT. The mixture was diluted with EtOAc, washed with water three times and brine, dried with Na2SO4, filtered and concentrated to afford the crude product as a light yellow viscous liquid. This crude was purified by prep HPLC to afford desired product (6 mg, 45.2% yield) as a light yellow solid, a TFA salt. LC-MS: (MH+) 581.0 at 0.726 min. 1H NMR (400 MHz, CD3CN) δ ppm 1.56-1.82 (m, 2H) 2.01-2.30 (m, 3H) 3.47 (t, J=8.61 Hz, 1H) 3.73-3.92 (m, 3H) 4.32-4.45 (m, 2H) 5.05-5.19 (m, 1H) 7.16-7.27 (m, 1H) 7.48 (dt, J=8.12, 1.81 Hz, 1H) 7.56-7.71 (m, 4H) 7.74-7.81 (m, 1H) 7.97 (t, J=7.83 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br>CC(O)=O.CCOC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Br:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2,4-dinitroaniline (2.2 g, 12 mmol) in 40 ml of AcOH was added 1.0 ml of Br2 dropwise and reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to provide 2.9 g (11 mmol, 92%) of 2,4-dinitro-6-bromo-aniline which was characterized by NMR and used in a following reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11](OC)[CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:32]([C@H]1COC(=O)N1C(=O)[C@@H](OCC)[C@H](O)C1C=CC(OCCC2N=C(C3C=CC=CC=3)OC=2C)=C(C)C=1)C1C=CC=CC=1.C([SiH](CC)CC)C.C([C@H]1COC(=O)N1C(=O)[C@@H](OCC)CC1C=CC(OCCC2N=C(C3C=CC=CC=3)OC=2C)=C(C)C=1)C1C=CC=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O.C1COCC1>[CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH3:32])[CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Reactant: CCO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1)C(=O)O
Agent: CCO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)O

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R) -2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 99.3%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li+].CCC[CH2-].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])=[CH:17][CH:16]=1.O>C1COCC1>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[CH2:24][NH:23][S:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:13])=[CH:16][CH:17]=1)(=[O:36])=[O:35]
Reactant: COC(=O)c1ccc(CS(=O)(=O)NCc2ccc(OC)cc2OC)cc1
Reactant: C1COCCN1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(C(=O)N3CCOCC3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of morpholine (0.69 ml) in THF (10 ml) was added, at −78° C., N-butyllithium (1.6 M, 3.3 ml), and the solution was stirred for 10 min. A solution of 4-[(2,4-dimethoxybenzylsulfamoyl)methyl]benzoic acid methyl ester (1 g) was added and the solution was warmed up to room temperature and stirred for a further 30 minutes. After the addition of water (100 ml), the mixture was extracted with ethyl acetate (2×50 ml). The organic phases were dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (450 mg) with a molecular weight of 434.5 g/mol (C21H26N2O6S).
Reaction SMILES: BrBr.[CH3:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=[CH:7][C:6]([CH3:18])=[N:5]1.[S-:19][C:20]#[N:21].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[CH3:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]3[N:15]=[C:20]([NH2:21])[S:19][C:13]=3[CH:12]=2)=[CH:7][C:6]([CH3:18])=[N:5]1
Reactant: Cc1cc(COc2ccc(N)cc2)n(C)n1
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(COc2ccc3nc(N)sc3c2)n(C)n1
Yield: 80.6 %

Procedure:
add, dropwise, a solution of 0.103 cm3 of dibromine in 3 cm3 of glacial acetic acid at around 20° C. to a solution of 0.44 g of 4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]aniline and 0.787 g of potassium thiocyanate in 6 cm3 of glacial acetic acid. After stirring for about twenty hours, the reaction mixture is poured into 50 cm3 of water. The pH of the solution obtained is adjusted to 8-9 by adding solid potassium carbonate. A gum forms. After stirring for about an hour, the beige solid that formed is drained, washed three times with 20 cm3 of water, then dried in a desiccator under reduced pressure (0.2 kPa) in the presence of phosphoric anhydride. We obtain 0.448 g of 6-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-1,3-benzothiazol-2-amine in the form of a beige powder, which has the following characteristics:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1.[CH2:33]=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:33][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1
Reactant: C=O
Reactant: CC(Nc1cc(-c2cc(N3CC4CC3CN4)c3ccccc3n2)ccn1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@H](Nc1cc(-c2cc(N3C[C@@H]4C[C@H]3CN4C)c3ccccc3n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 60 mg (0.14 immol) {4-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-quinolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.11 mL (1.42 mmol) formaldehyde 37% water solution, 113 mg (1.8 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+): 436 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH2:48][OH:49])=[CH:31][CH:30]=1.[OH-].[Na+]>ClCl.C(Cl)Cl.CC#N.CCOCC.CCCCCC.CCOC(C)=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH:48]=[O:49])=[CH:31][CH:30]=1
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: ClCl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of Dess-Martin periodinane (1.04 gm, 2.45 mmol) in dry CH2 Cl2 (12 ml) was treated with t-butanol (182 mg, 2.46 mmol) and stirred at room temperature for 15 minutes. A slurry of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol (555 mg, 1.89 mmol) in CH2Cl2 (10 ml) and CH3CN (2 ml) was then added and stirring was continued for 25 minutes. The mixture was diluted with Et2O (50 ml) and poured into 1N NaOH (25 ml) and stirred for 5 minutes. The phases were separated and the organic layer was washed successfully with 1N NaOH, H2O, and brine, then dried (Na2 SO4). Filtration and removal of the solvent afforded a solid. The solid was dissolved in hot hexane/EtOAc and the resulting solution was cooled to 0° C., filtered and stripped to give a residue which was chromatographed (Flash, Merck SiO2, 20% EtOAc in hexane). 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde was obtained as a white solid (458 mg, 83%). Analytically pure material was obtained by recrystallization from hot hexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1Br.[CH:16]1(B(O)O)[CH2:18][CH2:17]1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH:16]1[CH2:18][CH2:17]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1C1CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
To a solution of 400 mg (1.413 mmol) 2-bromo-4-trifluoromethyl-benzoic acid methyl ester, 146 mg (1.696 mmol) cyclopropyl boronic acid, 1.21 g (4.946 mmol) tri-potassium phosphate monohydrate and 40.9 mg (0.141 mmol) tricyclohexyl phosphine in 6 ml toluene and 0.3 ml water under nitrogen at room temperature, was added 15.9 mg (0.0707 mmol) palladium acetate. The mixture was stirred in a 100° C. oil bath for 4 hours and overnight at room temperature under nitrogen. The mixture was cooled to room temperature. Water was added and the mixture extracted with ethyl acetate. The organic layer was washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified on silica gel (eluent: heptane/ethyl acetate 0 to 10%) to provide 0.24 g (71%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Li+].CC([N-]C(C)C)C.Br[CH2:27][C:28]([CH3:30])=[CH2:29]>C1COCC1>[CH3:29][C:28](=[CH2:27])[CH2:30][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: C=C(C)CBr
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-Boc-piperidine-4-carboxylic acid methyl ester (2.00 g, 8.22 mmol) in THF (40 mL) was cooled to −78° C. Under nitrogen, a 2.0 M THF solution of LDA (6.17 mL, 12.3 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes before a solution of 3-bromo-2-methylpropene (1.60 g, 11.9 mmol) in THF (2 mL) was added. After the reaction was stirred for 1 hour at this temperature, a sample was taken for LC-MS analysis and it showed that the reaction was completed. The reaction was quenched by adding saturated ammonium chloride solution (5 mL) and the mixture was allowed to warm up to room temperature. The mixture was then extracted with EtOAc (50 mL twice). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrates were concentrated and the crude product was purified by column chromatography eluting with 0-30% ethyl acetate/hexane to give the title compound. LC-MS (IE, m/z): 242.21 [M−56+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17])[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[N:3]([CH:4]=1)[C:16](=[O:17])[C:15]([CH2:12][CH2:13][CH3:14])=[C:21]([CH3:23])[N:1]=2)=[O:7]
Reactant: CCCC(C(C)=O)C(=O)OCC
Reactant: COC(=O)c1ccc(N)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCc1c(C)nc2ccc(C(=O)OC)cn2c1=O
Temperature: 150 °C
Reaction time: 42 h

Procedure:
Methyl 6-amino-nicotinate (4g) was reacted with ethyl 2-propylacetoacetate (17.3 g) in the presence of p-toluensulphonic acid (0.16 g) under stirring at 150° C. for 42 hours. After cooling and dilution with hexane the precipitate was filtered and crystallized from methanol, thus giving 2.9 g of 2-methyl-3-propyl-4-oxo-4H-pyrido[1.2-a]pyrimidine-7-carboxylic acid methyl ester m.p. 98°-99° C., which were reacted with benzaldehyde (7 g) in methanol (100 ml), in the presence of sodium methoxide (1.78 g), under stirring at reflux temperature for 144 hours. After cooling the reaction mixture was concentrated in vacuo and diluted with ethyl ether: the precipitate was filtered, washed with ether and then dissolved in water. After acidification with acetic acid the precipitate was filtered and washed with water until neutral: crystallization with methanol gave 1.1 g of 2-trans-(2-phenyl-ethenyl)-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 250°-252° C., NMR (DMSO d6): vinylic protons δHβ =7.60(d), δHα =8.05(d) p.p.m., JHαHβ =16 Hz.