Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:31]=[CH:30][C:29]4[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=4[CH:23]=3)[N:17]=2)[CH2:12][CH2:11]1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>C1COCC1>[CH3:32][C:28]1([CH3:33])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]2[CH:23]=[C:22]([C:18]3[N:17]=[C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH2:9][CH:7]5[CH2:8][CH:6]5[CH2:4][OH:3])[CH2:15][CH2:14]4)[CH:21]=[CH:20][CH:19]=3)[CH:31]=[CH:30][C:29]1=2
Reactant: CCOC(=O)C1CC1CN1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCN(CC5CC5CO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.21 mmol) of 2-{4-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazin-1-ylmethyl}cyclopropanecarboxylic acid ethyl ester is dissolved in 4 ml of THF, and 1.05 ml (1.05 mmol) of diisobutylaluminium hydride (1.0 M in THF) are added. The reaction mixture is stirred at room temperature under nitrogen atmosphere for 18 h. Water is added to the reaction mixture, which is then briefly stirred, ethyl acetate is added, and the mixture is filtered through Celite. The filter cake is washed with ethyl acetate and methanol, and the mother liquor is evaporated. The residue is purified by column chromatography on silica gel.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:17]#[N:18].C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:17]#[N:18])[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: Brc1cncc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cncc(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
3-(Benzyloxy)-5-bromopyridine (5.38 g, 20.4 mmol, Harrowven et al. Tetrahedron, 2001, 57, 4447-4454) in DMF (33 mL) was stirred with copper cyanide (2.9 g, 32.6 mmol) at 160° C. for 7 hours. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate was added and the formed suspension was stirred at 50° C. for 15 minutes. After filtration the liquid phases were separated. The precipitate was triturated with 10% DMF in ethyl acetate (500 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) at 50° C. and filtration and phase separation were performed. The treatment of the precipitate with saturated aqueous sodium hydrogen carbonate solution and 10% DMF in ethyl acetate was repeated two times and the combined organic phases washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 65%) to yield 3.13 g 5-(benzyloxy)pyridine-3-carbonitrile.
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])(C)C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1.F[C:39](F)(F)[C:40]1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=C[CH:41]=1>>[F:37][C:20]([F:19])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:10]([C@@H:9]4[CH2:13][C@H:14]5[C@H:18]([CH2:39][CH2:40][CH2:41][CH2:17]5)[NH:8]4)=[O:12])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Product: O=C(N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21)[C@@H]1C[C@@H]2CCCC[C@@H]2N1

Procedure:
The title compound was prepared by substituting (2S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 262 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.66-8.59 (m, 1H), 8.32 (d, J=7.9, 1H), 7.67 (dd, J=8.9, 2.5, 1H), 6.36 (d, J=8.9, 1H), 4.38-4.29 (m, 1H), 3.94 (dd, J=10.6, 4.7, 1H), 3.72 (d, J=8.1, 1H), 3.58 (t, J=9.5, 2H), 3.33 (d, J=6.7, 1H), 3.23 (dd, J=9.4, 4.7, 1H), 3.18-2.94 (m, 1H), 2.80-2.68 (m, 1H), 2.66-2.57 (m, 1H), 2.27 (ddd, J=12.8, 10.6, 7.0, 1H), 2.15-2.05 (m, 1H), 1.96 (dddd, J=18.4, 16.6, 8.6, 4.9, 2H), 1.88-1.79 (m, 1H), 1.70-1.35 (m, 8H), 1.35-1.27 (m, 1H), 1.16 (tt, J=15.5, 6.5, 1H); MS (ESI+) m/z 423 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[O:13]=[C:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[C:15]([C:14](=[O:13])[CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(C#N)ccc1C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1ccc(C#N)cc1OC)C(C)=O

Procedure:
3 g (18.61 mmol) of 4-formyl-3-methoxybenzonitrile, 2.6 ml (20.47 mmol) of ethyl 3-oxobutanoate, 1.33 ml (23.26 mmol) of acetic acid and 0.18 ml (1.85 mmol) of piperidine are stirred in 70 ml of dry dichloromethane under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from diethyl ether. 5.01 g (98% of theory) of the title compound are obtained as E/Z isomer mixture in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][OH:2].C(N(CC)CC)C.[C:10]([O:14][C:15]([O:17]C([O-])=O)=O)([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:15]([NH:1][OH:2])([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:17]
Reactant: NO
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 362 %

Procedure:
To a solution of amino alcohol from Step 3 (2.60 g, 5.81 mmol) in DCM (60 mL) was added triethylamine (1.60 mL, 12.0 mmol) followed by tert-butyldicarbonate (1.50 g, 6.88 mmol) and the reaction was stirred overnight at RT. The final mixture was concentrated and purified by flash-chromatography over silica gel (eluted with Hexanes/AcOEt 80:20 to 20:80) to provide 2.80 g (88%) of Boc-amino alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[N:22]=1)=[O:20]>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:27][C:23]2[N:22]=[C:21]([C:19]([OH:20])=[O:18])[CH:26]=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: COC(=O)c1cccc(CBr)n1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)n1

Procedure:
6-(2′-Nitro-biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure B from from 4-hydroxy-2′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 2). Yield: 62 mg. Mass spectrum (ES) MH+=351.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][CH:5]1O)=[N+:2]=[N-:3].COCCN(S(F)(F)[F:31])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[N:1]([CH:4]1[CH:5]([F:31])[CH2:6][O:7][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(O)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol (660 mg, 2.34 mmol, intermediate 57) in DCM (12 mL) was added deoxo-Fluor® (50% in THF, 2.12 mL) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (22 mL), cooled to 0° C. and saturated aqueous NaHCO3 (20 mL) was carefully added. The aqueous layer was extracted with DCM (3×20 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-(5-azido-6-fluorooxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as an oil (440 mg). A solution of this oil (440 mg, 1.54 mmol) in THF/water (15 mL/2.8 mL) was treated with triphenylphosphine (487 mg, 1.86 mmol) and the reaction mixture was heated at 70° C. behind a blast shield for 18 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (15 mL), cooled to 0° C. and di-tert-butyl-dicarbonate (402 mg, 1.84 mmol) was added followed by DIPEA (0.8 mL, 4.62 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Water (20 mL) was added and the mixture extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-35% EtOAc/isohexane) followed by chiral prep SFC gave tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate as a white solid (223 mg, 27% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.37 (dd, J=10.5, 3.0 Hz, 1H), 4.89 (br s, 1H), 4.61 (ddd, J=49.1, 7.7, 3.2 Hz, 1H), 4.44 (dd, J=22.2, 15.0 Hz, 1H), 4.07 (s, 3H), 3.98-3.80 (m, 1H), 3.49 (d, J=5.3 Hz, 1H), 2.15-1.90 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10](Cl)=[O:11].[CH2:13]([C:16]#[N:17])[C:14]#[N:15].[NH4+]=[S:19]>O.CN(C)C=O>[NH2:15][C:14]1[S:19][CH:9]=[C:10]([OH:11])[C:13]=1[C:16]#[N:17]
Reactant: N#CCC#N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(O)csc1N
Temperature: 25 °C
Yield: 62 %

Procedure:
350 parts of triethylamine are added dropwise to a mixture of 178 parts of chloroacetyl chloride, 104 parts of malonodinitrile and 900 parts of dimethylformamide, while cooling with ice. The solution is stirred for a further hour at room temperature, after which it is introduced into a mixture of 294.5 parts of a 40% strength aqueous ammonium sulfide solution, 1000 parts of ice and 1000 parts of water, and the reaction mixture is stirred for a further 3 hours at room temperature. The precipitate formed is filtered off under suction, washed with water and dried. 137 parts (62% of theory) of 2-amino-3-cyano-4-hydroxythiophene are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[C:6]([CH3:16])[CH:5]=[C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[N:3]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:26][CH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:5][C:6]=2[CH3:16])[CH:13]=[CH:12][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(OCCCS(C)(=O)=O)nc(C)c1-c1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCCCS(C)(=O)=O)nc(C)c1-c1cccc(CBr)c1
Yield: 59.3 %

Procedure:
[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]phenyl]methanol (0.30 g) synthesized according to the methods in (Reference Example 5) and (Example 11) <Step 2> and carbon tetrabromide (0.34 g) were dissolved in methylene chloride (1.8 mL) and to the resultant solution, a solution of triphenylphosphine (0.34 g) in methylene chloride (0.9 mL) was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. From the reaction mixture, the solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=3:2) to obtain the subject compound (0.21 g) as a colorless liquid.
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[NH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O(C(C)(C)C)[K]>C1(C)C=CC=CC=1.C(OCC)C.O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)O[K]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: c1ccc(N(c2ccccc2)c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 50 mg (0.09 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.70 g (4.14 mmol) of Ph2NH and 0.58 g (5.17 mmol) of KO-t-Bu in 2 mL of toluene. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-pyridyldiphenylamine. LC-MS Found: 247.3 (M++1).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:30](O)[CH2:31][CH:32]([CH3:34])[CH3:33])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])(C(C)(C)C)(C)C.[CH:38](O)=[O:39]>CC(=O)OCC.O.[Zn]>[CH:38]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])=[O:39]
Reactant: CC(C)CC(O)c1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: O=CO
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CCc1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenyl)-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.055 mmol) in HCOOH (1 mL) was added Zn dust (35.6 mg, 0.55 mmol). The reaction was heated at 50° C. for 1 h, cooled to RT and diluted with EA (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4 and concentrated to give 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate. LCMS MH+ 444 and TR=1.738 min and 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate. LCMS: MH+ 446 and TR=1.956 min, (21 mg, 70% yield) as a solid. Used without further purification.
Reaction SMILES: B.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:13][CH3:14])=O)=[CH:5][CH:4]=1.CO.Cl>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][NH:13][CH3:14])=[CH:7][CH:8]=1
Reactant: CNC(=O)CCc1ccc(Br)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Borane in THF (1.0 M, 28 mL, 28 mmol) was added dropwise to a solution of 22A (1.6 g, 7.0 mmol) in THF (17.5 mL). After stirring the reaction mixture for 30 min at 0° C. the mixture was refluxed for 4 h. Methanol (20 mL) was added to the mixture at 0° C. followed by the addition of 20 mL 6.0 M HCl dropwise. After refluxing for 30 min the volatiles were removed in vacuo. 50% NaOH (12 mL) was added dropwise while maintaining the temperature below 30° C. The resulting mixture was diluted with water (100 mL) and extracted with diethyl ether (3×100 mL). The organics were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 22B (1.57 g, 97%) as a clear oil. MS (ESI) m/z 227.99/229.99 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]([NH2:26])=[C:19]2[NH:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:25]=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:26]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=3[C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Ethoxyacetyl chloride (3.81 g, 31.1 mmol) was slowly added to a chilled solution of 6-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (9.1 g, 28.3 mmol) in pyridine (60 mL). The reaction was allowed to warm to ambient temperature and then heated at reflux for three hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (200 mL). The resulting solution was washed with water (3×100 mL) and concentrated under reduced pressure. The concentrated solution was passed through a layer of silica gel (eluting with dichloromethane:methanol 95:5) and concentrated under reduced pressure to provide 3.6 g of 8-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[C:24](=[N:31]\[O:32][CH3:33])/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6]C)=[O:5].C1COCC1.C(O)C.[OH-].[Na+]>O>[OH:1][CH:2]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[C:24](=[N:31]\[O:32][CH3:33])/[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirring solution of methyl 3-hydroxy-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (0.015 g, 0.0334 mmol) in the mixture of THF and Ethanol was added NaOH (0.003 g, 0.075 mmol) in 0.5 mL of water at 0° C., then stirred at RT for 2 h. After the completion of the SM reaction mass was concentrated under vacuum to remove solvents and diluted with water. Aqueous portion was neutralized with 1N HCl up to neutral pH, then extracted with ethyl acetate organic layer was washed with water and brine, dried over anhydrous Na2SO4. Evaporation under vacuum yields the titled compound as white solid (0.008 g, yield: 13.70%). Purity: 96.8%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:9][N:10]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1)[CH3:12]
Reactant: Fc1cccc(Br)c1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C/C=C/c1cccc(F)c1)N(C)C(=O)OC(C)(C)C
Temperature: 112 °C
Yield: 108.4 %

Procedure:
A 180 mL thick-walled glass pressure tube was charged with 3-bromofluorobenzene (0.95 g, 5.41 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.08 g, 5.41 mmol), prepared as previously described, palladium(II) acetate (12.2 mg, 0.05 mmol), tri-o-tolylphosphine (65.92 mg, 0.22 mmol), triethylamine (3 mL, 21.52 mmol) and anhydrous acetonitrile (6 mL). The tube was flushed with nitrogen, sealed and the mixture was stirred and heated at 112° C. (oil bath temperature) for 66 h. The resulting mixture containing oily, brown solids, was cooled to ambient temperature and concentrated on a rotary evaporator. The resulting orange-yellow solids were diluted with water (20 mL) and extracted with CH2Cl2 (4×20 mL). The combined CH2Cl2 extracts were washed with saturated NaCl solution (30 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, and the residue was dried under high vacuum to produce a light-brown oil (1.72 g). The crude product was purified by column chromatography on silica gel (90 g), eluting with ethyl acetate-hexane (15:85, v/v). Selected fractions containing the product (Rf 0.29) were combined, concentrated by rotary evaporation and the residue was vacuum dried to give 1.36 g (85.8%) of a light-yellow oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O[CH2:18][CH:19]=[CH2:20])(=O)C>>[CH2:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCBr
Reactant: C=CCOC(C)=O
Product: C=CCCCCCCCCCCCCC
Yield: 32 %

Procedure:
n-dodecyl bromide was converted analogously to example 1 to its Grignard compound and the latter was reacted with allyl acetate in the manner described. 1-Pentadecene was obtained in 32% yield.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[C:36](=[O:37])[N:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[C:8]=1[CH3:43])=[O:6])[CH3:3].C(OCC)C>C(Cl)Cl.CCO>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[C:36](=[O:37])[N:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[C:8]=1[CH3:43])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Reaction time: 24 h

Procedure:
Anhydrous HCl gas was bubbled through a solution of 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg, 0.086 mmol, prepared as in Example 30) in CH2Cl2/EtOH at room temperature and the reaction was stirred for 24 h. Diethyl ether was added to the reaction mixture and a solid precipitated which was isolated and dried to 8-cyclopentyl-5-methyl-7-oxo-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester hydrochloride as a yellow solid (12 mg, 29%). mp 216˜218° C. M++1:. Calc'd. 478.6. Found 478.1. HPLC, retention time: 5.77 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:38]([O-])=[O:39].[NH4+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:20][CH2:21][N:22]([CH:38]=[O:39])[CH2:23][CH2:24]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 97.9 %

Procedure:
A mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained in stage 1.7 and 0.113 g of ammonium formate in 5 ml of ACN is irradiated under a microwave field at 140° C. for 1 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.62 g of the expected product.