Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC2N=C(C3C=CC(F)=NC=3)OC=2C=1.[CH3:19][N:20]([CH3:29])[C:21]1[N:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][N:22]=1.[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][C:32]=1O>>[CH3:19][N:20]([CH3:29])[C:21]1[N:22]=[CH:23][C:24]([C:27]2[O:28][C:32]3[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:39]=[CH:40][C:31]=3[N:30]=2)=[CH:25][N:26]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CN(C)c1ncc(C=O)cn1
Agent: COc1ccc2nc(-c3ccc(F)nc3)oc2c1
Product: COC(=O)c1ccc2nc(-c3cnc(N(C)C)nc3)oc2c1
Yield: 72.3 %

Procedure:
The synthesis was performed according to the procedure described for 5-(6-methoxy-1,3-benzoxazol-2-yl)-2-fluoropyridine starting with 180 mg of 2-dimethylamino-pyrimidine-5-carbaldehyde and 200 mg of methyl 4-amino-3-hydroxybenzoate to give 256.8 mg of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]OC=C)[CH:2]1[O:4][CH2:3]1.[OH2:13]>>[CH2:1]([O:5][CH:6]([OH:13])[CH2:7][CH2:8][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: C=COCCCCOCC1CO1
Reactant: O
Product: CCCC(O)OCC1CO1
Reaction time: 1 h
Yield: 99 %

Procedure:
5.0 g of paratoluenesulfonic acid and 140 g of pure water were charged in a 1 L four-necked separable flask, and a vacuum pump equipped with a stirrer, a thermometer, an air introduction tube and a cooling trap was installed. Under stirring, 500 g of the vinyloxybutyl glycidyl ether synthesized above was slowly added to the flask while the liquid temperature was adjusted so as to be kept at 40° C. After the addition was completed, the pressure was reduced to 20 kPa, and stirring was continued for 1 hour while dry air was introduced at 100 ml/min. The reaction solution was then analyzed by gas chromatography, and no peak of the vinyloxybutyl glycidyl ether was observed. However, since 5.2% of an acetal dimer was generated according to an analysis by liquid chromatography, 26 g of a 0.04% aqueous solution of paratoluenesulfonic acid was added, and an acetal decomposition reaction was conducted at a pressure of 5 kPa while the temperature was kept at 40° C. When the reactant was analyzed 1 hour after the reaction, the peak of the acetal dimer had almost disappeared, and thus the reaction was quenched. 2.1 g of sodium hydrogen carbonate was put into the solution in which the reaction had been completed to thereby neutralize the solution, and the water in the system was distilled off by concentration with a rotary evaporator, the water content in the system was confirmed to be 800 ppm or less, and the concentrated liquid was filtered to give the objective butanediol monoglycidyl ether with a purity of 92% and a yield of 99%. At this time, the butanediol contained in the obtained substance was 0.2%, and no acetal dimer was detected.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:27]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:27]=2)=[O:25])[CH:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(NC(=O)c2ccnc(N3CCOCC3)c2)c1
Product: COc1cc2ncnc(Nc3cccc(NC(=O)c4ccnc(N5CCOCC5)c4)c3)c2cc1OC
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6,7-dimethoxyquinazoline was reacted with N-(3-aminophenyl)-2-morpholinopyridine-4-carboxamide. The material so obtained was purified by column chromatography eluting with 96:3:1 methylene chloride/methanol/saturated aqueous ammonium hydroxide. The material so obtained was triturated under methylene chloride to give the title compound in 33% yield; NMR: 3.51 (m, 4H), 3.71 (m, 4H), 3.93 (s, 3H), 3.96 (s, 3H), 7.11 (d, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.35 (m. 1H), 7.44 (d, 1H), 7.57 (d, 1H), 7.86 (s, 1H), 8.23 (s, 1H), 8.29 (d, 1H), 8.46 (s, 1H), 9.49 (s, 1H), 10.34 (s, 1H); Mass: M+H+ 487.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([Cl:28])=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)nn2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylic acid (6.4 g) and thionyl chloride (30 ml) in tetrahydrofuran (60 ml) was refluxed for 1 hour and concentrated under reduced pressure, giving 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyridine (example E.32) (0.15 g, 0.42 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.101 g, 0.46 mmol) according to the general procedure VI. Obtained as a white solid (0.045 g, 29%). MS (ISP) 372.1 [(M+H)+] and 374 [(M+2+H)+]; mp 76-95° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([Mg]Br)[CH:10]([CH3:12])[CH3:11].CCOCC>O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.[Fe]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)C[Mg]Br
Agent: Cl[Ni]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Cc1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2,5-dibromopyridine (4.5 g, 19 mmol) in tetrahydrofuran (50 ml) was added [1,1′-bis (diphenylphosphino)ferrocene]dichloronickel (II) (103 mg, 0.19 mmol) and the resulting mixture was cooled to −10° C. A 2M solution of isobutylmagnesium bromide in ether (12.4 ml, 24.7 mmol) was added slowly and the mixture was stirred at −10 to 10° C. for 3.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in pentane to afford the 5-Bromo-2-(2-methylpropyl)pyridine compound as a volatile oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][C:13]1[N:18]=[C:17]([S:19][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:16]=[C:15]([OH:20])[CH:14]=1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
In a 100 mL round bottom flask, 2-(bromomethyl)-1,3,4-trichlorobenzene (550 mg, 2.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (250 mg, 2.0 mmol), and potassium carbonate (306 mg, 2.2 mmol) were mixed in DMF (10 mL). The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added. The mixture was filtered and washed with water and ethyl acetate to provide the title compound as a white solid (450 mg, 70% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.11 (s, 3H), 5.43 (s, 2H), 5.89 (s, 1H), 6.57 (br, 1H), 7.56 (d, 1H), 7.71 (d, 1H); M+ 318, 320.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[SiH4].[Cl-].[Na+]>CO>[CH3:1][O:2][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]
Reactant: CO[Si](CCl)(OC)OC
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [SiH4]
Solvent: CO
Product: COC[Si](OC)(OC)OC
Reaction time: 0.5 h

Procedure:
340 g (6.3 mol) of sodium methylate (95% strength) are dissolved in portions in 2.5 l of methanol in a laboratory reactor blanketed with nitrogen. During this procedure, the solution heats up to 65° C. Thereafter, 995 g (5.8 mol) of chloromethyltrimethoxysilane are added dropwise over 1.5 h and stirring is effected for a further 30 minutes at the boil. On addition of the silane, sodium chloride is precipitated spontaneously as the salt, but the suspension remains readily stirrable until the end of the metering. The precipitated sodium chloride is filtered off with suction and the methanol is removed under a partial vacuum at 40–50° C. The residue is purified by distillation (97–98° C. at 172 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>CO>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[Cl:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:35]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(Cl)c1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(Cl)c1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-(2-chloro-4-(diethylamino)benzoyl)benzoic acid (6.61 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (4.30 g.) and acetic anhydride (5 ml.) was allowed to stand overnight at room temperature, then diluted with methanol (10 ml.), affording 3-(2,4-bis(diethylamino)phenyl)-3-(2-chloro-4-(diethylamino)phenyl)phthalide (I: X=Y4 =(CH3CH2)2N, Y2 =Cl, Z4 =Z5 =Z6 =Z7 =H) (3.94 g., m.p. 141°-143° C.).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11](O)=[O:12])=O)=[CH:5][CH:4]=1.Br.O.[NH2:18][NH2:19]>O.C(O)C>[OH:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]2[CH2:9][CH2:10][C:11](=[O:12])[NH:18][N:19]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: Br
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(O)cc2)=NN1
Temperature: 110 °C
Yield: 41053.6 %

Procedure:
A mixture of 25.0g (0.120 mmol) of 3-(4-methoxybenzoyl)propionic acid and 175 ml of 48% HBr is heated under N2 at 110° C. for 5 hrs. After cooling, the mixture is diluted with an equal volume of water and exhaustively extracted with EtOAc (5×100 ml). The organic phase is washed with saturated NaCl, dried (MgSO4), filtered and the solvent removed to leave a white solid. After recrystallization from EtOAc, 16.8 g of 3-(4-hydroxybenzoyl)propionic acid, m.p. 157°-159° C., is obtained. Yield, 72. A mixture of 10.0 g (51.5 mmol) of the acid prepared above and 6.2 ml (128 mmol) of 98% hydrazine monohydrate in 172 ml of ethanol is heated at reflux overnight under N2. The resulting white solid is collected by suction filtration to give 9.37 g of 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone as a white powder, m.p. >300 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:24])[F:25])[C:9]=2[Cl:27])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (350 mg, 0.783 mmol) in N,N-dimethylformamide (12 ml) was added N-chlorosuccinimide (1.05 g, 7.83 mmol) at room temperature. After the mixture was stirred for 18 hr, 1.05 g of N-chlorosuccinimide was added. The resulting mixture was stirred for further 36 hr. 20 ml of saturated aqueous sodium thiosulfate and 50 ml of diethyl ether were added and the two-phase-mixture was stirred for 0.5 hr. The separated organic layer was washed with water (20 ml×3) and dried over magnesium sulfate. Removal of solvent gave a pale yellow gum, which was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (1:3) to afford 236 mg (63%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O: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][C:27]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(F)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(-c3ccc(F)cc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.02 (2H, m), 7.64 (4H, m), 7.59 (2H, m), 7.13 (2H, m), 6.89 (2H, d), 6.78 (2H, d), 4.16 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:7]([O:11][CH2:10][CH2:9][Br:30])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2OCCO2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCCBr)c1ccccc1

Procedure:
The preferred aldehyde for the second route is benzaldehyde, especially when the glycol is ethylene glycol and the N-halogenated imide is N-bromosuccinimide. More specifically, 2-phenyl-1,3-dioxolane can be prepared by mixing benzaldehyde and ethylene glycol in a 1.0 to 1.2 mol ratio in an organic solvent containing a catalytic amount of an organic acid, such as p-toluenesulfonic acid. The mixture is heated and allowed to reflux for about an hour and a half, then treated with potassium carbonate, filtered, and distilled to produce 2-phenyl-1,3-dioxolane. The dioxolane is subsequently dissolved in carbon tetrachloride with an equimolar amount of N-bromosuccinimide and a catalytic amount of benzoyl peroxide. After heating under reflux conditions for up to 16 hours, cooling, and filtering, the mixture produces a filtrate that can be further concentrated to yield an ester, 2-bromoethyl benzoate. The ester so produced is used as an alkylating agent when reacted with a tertiary amine yielding a quaternary ammonium salt.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccn(Cc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
A suspension of 10 g (89 mmol) of uracil and 24.6 g of potassium carbonate in 350 mL DMF was stirred for 12 hours at room temperature, after which 16.5 mL (139 mmol) of benzyl bromide was added and the reaction allowed to continue for 2 days at room temperature. The undissolved residue was removed by filtration and the solvent removed from the filtrate under reduced pressure. 150 mL water was added to the residue and the mixture extracted 3 times with 100 mL methylene chloride. The collected methylene chloride fractions were washed with water, dried over MgSO4 and evaporated to dryness under reduced pressure. The residue was treated with a small amount of chloroform/methanol 40:1 from which 1-benzyluracil partially crystallizes. 2.6 g 1-benzyluracil was isolated by filtration and the rest was isolated by preparative column chromatography, using chloroform/methanol 40:1 giving a yield of 3.95 g (22%)(m.p. 168–170° C., Lit. 168–170° C., Kundu et al., J. Chem. Soc. Perkin Trans 1, 1985, 1295).
Reaction SMILES: C([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32](COCC[Si](C)(C)C)[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:18][C:19]#[N:20])[CH2:12][CH:11]1[F:43])(=O)C1C=CC=CC=1.[OH-].[Li+].[C:46](#[N:48])[CH3:47]>O.C(OCC)(=O)C>[C:19]([CH2:18][CH:17]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:15]2[CH:14]=[C:47]([CH:12]=[C:11]([F:43])[CH:10]=2)[C:46]#[N:48])[CH:11]([F:43])[CH2:12]1)#[N:20]
Reactant: CC#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(OC(=O)c5ccccc5)C(F)C4)c3)ncnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCC(CN1CCC(Oc2cc(F)cc(C#N)c2)C(F)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl benzoate (0.389 g, 0.644 mmol) (diastereomer 2) in acetonitrile (2.0 mL) and water (1.0 mL) was added lithium hydroxide (30.8 mg, 1.29 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product (0.322 g, 100%). The product was synthesized from diastereomer 1 using same procedure in 100% yield. LCMS (M+H)+: 500.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1/[CH:15]=[CH:16]/[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:12]([Cl:26])[CH:11]=[C:10]([Cl:27])[CH:9]=2)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:38][Si:39]([CH2:42][CH2:43][O:44][CH2:45]Cl)([CH3:41])[CH3:40]>CN(C=O)C.O>[C:19]1([NH:18][C:17](/[CH:16]=[CH:15]/[C:14]2[C:13]3[C:8](=[CH:9][C:10]([Cl:27])=[CH:11][C:12]=3[Cl:26])[N:7]([CH2:45][O:44][CH2:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C/C(=O)Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(/C=C/C(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a cooled (0°) solution of (E)-Ethyl-3-[2-(phenylcarbamoyl)ethenyl]-4,6-dichloroindole-2-carboxylate (300 mg) in dry DMF (25 ml) a solution of sodium bis-(trimethylsilyl)amide (1M;0.0814 ml) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes then cooled to 0°. Trimethylsilylethoxymethylchloride (185 mg) was added, and the reaction was stirred for one hour at room temperature. The resulting solution was poured in H2O (20 ml) and extracted with diethylether (15 ml×3). The organic layers were dried, concentrated under vacuum and the product isolated by chromatography on silica gel(CH/EA:83/15) to give the title compound (311 mg). Rf =0.35 CH/EA:85/15
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH3:12].[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)CC)C>C(O)(C)C>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH3:12]
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c(NCCO)n(C)c(=O)n(C)c1=O
Reaction time: 8 h

Procedure:
6-chloro-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione (3.4 g) was suspended in 30 ml of isopropanol, and the suspension was added with 1.26 ml of ethanolamine and 3.8 ml of triethylamine and then the resultant mixture was refluxed for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and thereafter crystals formed were collected by filtration, washed with water and then recrystallized using a water-ethanol solution (1:1, v/v), thereby 2.9 g of 6-(2-hydroxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione being obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11]C(C)([O-])C.[Na+].CI>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10]
Reactant: CC(C)(C)[O-]
Reactant: N#CCc1ccccc1I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C#N)c1ccccc1I
Reaction time: 3 h

Procedure:
2-(2-Iodophenyl)acetonitrile (3.0 g, 12 mmol) and sodium tert-butoxide (3.6 g, 37 mmol) were stirred in 20 mL of DMF, and MeI (0.77 mL, 12 mmol) was added dropwise. The reaction was then stirred for 3 hours. The solvent was removed under vacuum. The crude residue was purified by silica flash chromatography 0-15% EtOAc/hexanes.