Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[F:7][C:8]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:9]=1[C:10](OC1C=CC=CC=1)=[O:11].Cl>CCCCCC.CN(C)C=O>[N+:3]([CH2:6][C:10]([C:9]1[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:8]=1[F:7])=[O:11])([O-:5])=[O:4]
Reactant: O=C(Oc1ccccc1)c1cc(F)c(F)cc1F
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Temperature: 0 °C

Procedure:
Sodium hydride (12 g, 60% in oil, 297 mmol) was rinsed with hexane (4×100 mL), flushed with anhydrous nitrogen, suspended in N,N-dimethylformamide (350 mL) and then treated with nitromethane (44 mL, 81 mmol). The resultant mixture was stirred at room temperature for 2.5 hours, cooled to 0° C. and then treated with a solution of phenyl 2,4,5-trifluorobenzoate (22.8 g, 90.0 mmol) in N,N-dimethylformamide (180 mL) over a period of two hours. The reaction mixture was kept at the same temperature overnight and stirring continued for an additional hour at room temperature. The mixture was poured into ice (400 g) with conc. hydrochloric acid (48 mL). The aqueous mixture was extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was dissolved in ether-hexane (1:1, 240 mL) and water (200 mL). The organic layer was separated, and the crystals which formed upon standing and cooling in the freezer were recovered by filtration and dried to yield 2-nitro-1-(2,4,5-trifluorophenyl)ethanone as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9](SC)=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].C(O[CH2:27][CH3:28])(=O)C>CN1CCCC1=O.ClC1C=CC=C(C(OO)=O)C=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9]([NH:14][CH2:15][CH2:16][C:28]2[CH:27]=[CH:9][N:8]=[CH:7][CH:6]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Reactant: CCOC(C)=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(methylthio)-4-(propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1, 9.0 g) in N-methylpyrrolidone (88 mL), meta-chloroperbenzoic acid (70 to 75% wt, 10.8 g) was added portionwise under ice cooling, and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture, meta-chloroperbenzoic acid (70 to 75% wt, 2.5 g) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in N-methylpyrrolidone (35 mL), N,N-diisopropylethylamine (11.9 mL) and 4-(2-aminoethyl)pyridine (6.3 mL) were added at room temperature, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, and then poured into water (400 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (A2, 9.2 g) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:16][CH2:15][C@@H:14]2[CH2:17][N:11]1[C:12](=[O:26])[N:13]2[O:18]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:16][CH2:15][C@@H:14]2[CH2:17][N:11]1[C:12](=[O:26])[N:13]2[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H]1CC[C@@H]2CN1C(=O)N2O

Procedure:
The compound (V) was reacted with triphenylphosphine (PPh3) in a suitable solvent such as tetrahydrofuran followed by addition of a catalytic amount of water to provide corresponding amine. This amino compound was further treated in situ with di-tert-butyl dicarbonate ((Boc)2O) in presence of a suitable base such as triethylamine to provide an amino protected compound, (2S, 5R)-2-(tert-butoxycarbonylaminomethyl)-6-benzyloxy-7-oxo-1, 6-diaza-bicyclo[3.2.1] octane (VI). The intermediate compound of Formula (VI) was subjected to hydrogenolysis using a catalyst such as 5% or 10% Palladium on carbon in presence of a hydrogen source such as hydrogen gas and in a suitable solvent such as methanol to provide debenzylated compound, (2S, 5R)-2-(tert-butoxycarbonylaminomethy)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1] octane (VII).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:46]1[N:47]=[C:48]([NH:51]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:49][CH:50]=1)\[C:12]([NH:14][C@@H:15]1[C:44](=[O:45])[N:17]2[C:18]([C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])=[C:19](/[CH:22]=[CH:23]\[C:24]#[C:25][CH2:26][CH3:27])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.[ClH:71]>C(O)=O>[ClH:71].[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:11](=[N:10]/[O:9][CH2:8][C:6]([OH:7])=[O:5])/[C:12]([NH:14][C@@H:15]2[C:44](=[O:45])[N:17]3[C:18]([C:28]([OH:30])=[O:29])=[C:19](/[CH:22]=[CH:23]\[C:24]#[C:25][CH2:26][CH3:27])[CH2:20][S:21][C@H:16]23)=[O:13])[N:47]=1
Reactant: CCC#C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Solvent: O=CO
Product: CCC#C/C=C\C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)O)c3csc(N)n3)[C@H]2SC1

Procedure:
A stirred solution of the product of stage (d) in formic acid (0.8 ml) was treated with 11M hydrochloric acid (56 μl). After 2.5 h the reaction mixture was filtered and the filtrate was added dropwise to vigorously stirred ether (50 ml). The precipitated solid was collected by filtration, washed with ether and dried in vacuo to give the title compound as a solid (78 mg); νmax (Nujol) 3280 (--NH), 2200 (C≡C), 1776 (β-lactam); τ(DMSO-d6) values include 0.27 (NH), 3.24 (--CH=CH--C≡C), 4.24 (--CH=CH--C≡C), 4.17 (7H), 4.72 (6H), 5.28 (OCH2CO2H), 7.68 (C≡C--CH2) and 8.86 (C≡C--CH2CH3).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.N([O-])=O.[Na+].[I-:16].[K+]>O.S(=O)(=O)(O)O.[Cu]I>[OH:11][C:4]1[CH:3]=[C:2]([I:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: [I-]
Agent: [Cu]I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(I)cc1O
Temperature: -10 °C
Reaction time: 36 h

Procedure:
To 20% sulfuric acid solution (650 ml) were added 4-amino-2-hydroxybenzoic acid and 200 ml of 20% sulfuric acid solution. The solution was cooled to −10° C. and a solution of sodium nitrite (47 g, 0.34 mol) in water (100 ml) was added over 5 hours. The solution obtained was added dropwise to a suspension of potassium iodide (69.5 g, 0.42 mol) and copper(I) iodide (69.5 g, 0.36 mol) in 370 ml of 20% sulfuric acid. The mixture was stirred for 36 hours at room temperature and was then filtered. The filtrate was extracted with ethyl acetate, washed twice with saturated sodium sulfite solution and twice with water. The organic phase was concentrated on a rotary evaporator under vacuum at 40° C. The properties of the final product were as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 12 h
Yield: 90.7 %

Procedure:
(4-Hydroxy-phenyl)-acetic acid methyl ester (1.0 g, 6.02 mmol) was dissolved in DMF (10 mL), and K2CO3(2.5 g, 18.06 mmol) was added thereto. Benzyl chloride (0.83 mL, 7.22 mmol) was added slowly thereto, and the mixture was stirred at 40˜50° C. for 12 hours. The reactant was cooled and concentrated under reduced pressure. The residue was added with water and then extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex=1/4) to obtain the title compound (1.4 g, 91%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:12][N:13]=2)[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (189 mg, 0.49 mmol), trimethylsilylacetylene (103 L, 0.73 mmol), triphenylphosphine (4 mg, 0.02 mmol), and triethylamine (102 μL, 0.73 mmol) were stirred in THF (4 mL) in a flask purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.024 mmol) was added, and after 10 min copper iodide (2 mg) was added. The reaction stirred for 18 h at r.t. The solution was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CHCl3) gave 168 mg (85%) of the title compound as a clear oil. MS (ES) [m+H] calc'd for C22H27N5OSi, 406; found 406.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25]([NH:24][C:22](=[O:23])[C:21]2[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=2[F:19])=[O:26])[CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]([F:17])=[C:11]([F:16])[C:12]([F:14])([F:15])[F:13]
Reactant: Nc1cc(Cl)c(OC(F)=C(F)C(F)(F)F)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)=C(F)C(F)(F)F)c(Cl)c1
Temperature: 40 °C

Procedure:
Dissolve 0.77 g 3,5-dichloro-4-(1,2,3,3,3-pentafluoropropenoxy) aniline in 8 mL 1,2-dichloroethane under an atmosphere of nitrogen at room temperature. Add 0.50 g 2,6-difluorobenzoyl isocyanate dissolved in 5.8 mL dichloroethane dropwise over a 10 minute period. Stir and warm to 40° C. for a 2 hour period. Chill in ice water bath and filter the white solid 0.93 g, mp 177°-80° C. Proton nmr and mass spectra were consistent with the proposed structure. Anal. calcd C17 H7Cl2F7N2O3 :C, 41.57; H, 1.44; N, 5.70. Found: C, 41.65; H, 1.31; N, 5.59.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.C1([NH2+]C2CCCCC2)CCCCC1.OS([O-])(=O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](C(=O)[O-])[C@H](c2ccc(Br)cc2)C1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](C(=O)O)[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of the product from step C (5 g, 10.46 mmol) in EtOAc (100 mL) was treated with 1M aq NaHSO4 (100 mL) at rt. The biphasic mixture was stirred for 12 h at rt and then separated. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated to afford the title compound. HPLC/MS: 297.0/299.0 (M+1); Rt=2.55 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35].CN1CCCC1=O>C(Cl)(Cl)Cl>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][CH2:2][NH:1][S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCN
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCNS(=O)(=O)CCCCl

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.228 g, 0.848 mmol) and N,N-diisopropylethylamine (0.604 mL, 3.39 mmol) in chloroform (6.67 mL) was cooled to 0° C. A solution of 3-chloropropanesulfonyl chloride (0.113 mL, 0.933 mmol) in chloroform (10 mL) was added. An analysis by HPLC indicated that the reaction was not progressing. N-Methylpyrrolidone (12 mL) was added, and the reaction went to completion. The solvents were removed under reduced pressure to provide N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-3-chloropropane-1-sulfonamide.
Reaction SMILES: [OH:1][C@@H:2]([C@H:17]([OH:32])[C@H:18]([OH:31])[C@@H:19]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH2:20][OH:21])[C:3]([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:4].Cl.[CH2:34](O)[CH3:35]>>[OH:1][C@@H:2]([C@H:17]([OH:32])[C@H:18]([OH:31])[C@@H:19]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH2:25])[CH2:20][OH:21])[C:3]([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([O:10][CH2:34][CH3:35])=[O:9])=[O:4]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C[C@H](NC(=O)[C@@H](O)[C@H](O)[C@H](O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid (Compound 3) (500 mg) was added a 28% solution of hydrogen chloride in ethanol (200 ml) and the mixture was stirred at room temperature for 20 hours. After concentration, the residue was subjected to silica gel column chromatography and eluted with acetonitrile-water (5:1). The effective fractions were combined and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and neutralized with aqueous sodium hydrogencarbonate solution. The solution was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from chloroform-diethylether to afford the title compound (123 mg).
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H].O.N>C(O)(=O)C.[Pd]>[CH2:2]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCCC(O)c1ccc(CC(=O)OCC)cc1
Agent: [Pd]
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCc1ccc(CC(=O)OCC)cc1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To the solution of ethyl 4-(1-hydroxyundecyl)-phenylacetate (9.7 g, 0.029 mol) in acetic acid (50 ml) was added 10%-palladium on carbon. The reaction mixture was stirred for 18 hours under 1 atmospheric pressure of hydrogen and then poured onto the mixture of concentrated ammonia water (100 ml) and ice (100 g). The resultant precipitate was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain ethyl 4-undecylphenylacetate (3-w, 8.2 g, 88%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][NH:15][C:16](=O)[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16]([Cl:22])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cnc(OCc3ccccc3)cc12
Solvent: CN(C)C=O
Product: Clc1ncnc2cnc(OCc3ccccc3)cc12
Reaction time: 8 h

Procedure:
6-Chloro-3H-pyrido[3,4-d]pyrimidine-4-one (9.08 g, 50.0 mmol) was reacted with sodium hydride (60% dispersion on mineral oil, 8.14 g, 203.5 mmol) in benzyl alcohol at 150° C. for 18 hours. The mixture was partitioned between water and ether (water layer at pH14 from the excess sodium hydride) and the layers separated. The aqueous layer was further washed with ether, and then acidified to pH1 with dilute HCl, giving a cream precipitate. This was collected by filtration and dried at 60° C. in vacuo to give 6-benzyloxy-3H-pyrido[3,4-d]pyrimidin-4-one (10.59 g, 84%); δH [2H6]-DMSO 8.71 (1H,s), 7.79 (1H,s), 7.25-7.48 (6H,m), 5.40 (2H,s); m/z (M+1)+254. 6-Benzyloxy-3H-pyrido[3,4-d]pyrimidine-4-one (1.033 g, 4.08 mmol) was reacted with thionyl chloride (10 ml) and dimethyl formamide (2 drops) at reflux under a nitrogen atmosphere for 5 hours, and then left at room temperature overnight. The mixture was concentrated in vacuo, azeotroping twice with toluene to remove the excess thionyl chloride, to give 6-benzyloxy4-chloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 8.73 (1H,s), 8.10 (1H,s), 7.25-7.55 (6H,m), 5.41 (2H,s). 6-Benzyloxy-4-chloropyrido[3,4-d]pyrimidine (ca. half the above material, ca. 2 mmol) was reacted with 4-benzyloxyaniline (0.430 g, 2.25 mmol) in acetonitrile (10 ml) according to Procedure A for 5 hours. The resulting brown solid was 6-benzyloxy4-(4-benzyloxyanilino)pyrido[3,4-d]pyrimidine (0.621 g, 71%); δH [2H6]-DMSO 8.99 (1H,s), 8.73 (1H,s), 8.22 (1H,s), 7.71 (2H,d), 7.15-7.55 (10H,m), 7.10 (2H,d), 5.50 (2H,s), 5.13 (2H, s); m/z (M+1)+435.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]12([Si:17](Cl)(Cl)Cl)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>CCOCC>[C:7]12([SiH3:17])[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2
Reactant: Cl[Si](Cl)(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: [SiH3]C12CC3CC(CC(C3)C1)C2
Yield: 70.2 %

Procedure:
Lithium aluminum hydride (6.18 g) and dry ether (80 mL) were placed in a rb flask. Adamantyl trichlorosilane (50.8 g), dissolved in ether (50 mL) was added dropwise in the magnetically stirred flask at rt. The reaction was allowed to reflux for 24 h. The solution was filtered, evaporated, and 1 mL Et3N in 30 mL pentane was then added and the upper layer was carefully decanted. After evaporation, the crude reaction product was distilled, giving 22 g of adamantylsilane (70%, bp. 40 . . . 50° C./2 mbar). 1H NMR: 1.95 (15H), 3.68 (3H). 13C NMR: 20.63, 28.86, 37.99, 40.61. 29Si NMR: −43.55 (q, Si—H: 190 Hz). Purity was found to be 95.7% by GC.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][C:32]([OH:34])=[O:33])[CH:29]=2)[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:10]([CH2:11][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][C:32]([OH:34])=[O:33])[CH:29]=3)[CH:24]=[CH:23]2)=[CH:9][CH:8]=1.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][C:32]([OH:34])=[O:33])[CH:29]=2)[CH:24]=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(-c4ccccc4)cc3)c2c1

Procedure:
The titled compound (22 mg) as a light brown solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-phenylbenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (857 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 53 mg (yield 89%) of the title compound.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(NC2C=CC(C3C=CC(NC4C=CC=CC=4)=CC=3)=CC=2)C=CC=CC=1.[C-]#N.[K+].[C:37]([O:42][CH3:43])(=[O:41])[C:38]([CH3:40])=[CH2:39].CO>C(O)CO.CO>[C:1]([O:6][CH2:7][CH2:43][O:42][C:37](=[O:41])[C:38]([CH3:40])=[CH2:39])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Agent: [C-]#N
Agent: [K+]
Agent: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Solvent: OCCO
Solvent: CO
Product: C=C(C)C(=O)OCCOC(=O)C(=C)C

Procedure:
1200 g of methyl methacrylate (12 mole), 20 g of ethylene glycol and 0.65 g of N,N'-diphenyl benzidine (500 ppm) are added to a 2 liter round-bottomed flask. After the addition of 12.9 g of potassium cyanide (1%), a quantity of methanol equivalent to the ethylene glycol employed is taken off as methyl methacrylate/methanol-azeotrope while conducting air through at a temperature of 65° C. at the head of the column (approximately 1/2 hour). After that, an additional 73g of ethylene glycol are dosed in within 2 hours (total quantity of ethylene glycol 93g=1.5 mole). After altogether 4.5 hours of removing azeotrope, the trans-esterification is completed. After cooling of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. A residue of ethylene glycol dimethacrylate of 286 g = 96.5% results. The ethylene glycol dimethacrylate obtained in such a way can be used either without any further processing or optionally after destabilization.