Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:20][CH:19]=1)[CH:14]([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[CH2:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:36][CH:37]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:22][CH:23]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OCC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OCC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogen carbonate (2.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-isobutoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.30 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.55 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.07 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([CH:13]=[CH2:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>C(OCC)(=O)C.[Pt]>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([CH2:13][CH3:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=Cc1cc(Cl)cc(N)c1C(=O)OC
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)cc(N)c1C(=O)OC
Reaction time: 2 h
Yield: 93 %

Procedure:
A slurry of platinum on sulphide carbon (0.1 g) in ethyl acetate was added under nitrogen to a solution of the methyl 2-amino-4-chloro-6-vinylbenzoate (0.362 g) in ethyl acetate. This mixture was hydrogenated at 30 psi for 2 h. The catalyst was filtered off and the solvent removed in vacuo to leave the desired methyl 2-amino-4-chloro-6-ethylbenzoate as a yellow oil (0.34 g). δH (250 MHz, DMSO-d6) 1.08 (3H, t, J 7.5 Hz, CH2CH3), 2.60 (2H, q, J 7.5 Hz, CH2CH3), 3.81 (3H, s, CO2CH3), 5.85 (2H, s, NH2), 6.46 (1H, d, J 2.5 Hz, H-3 or H-5), 6.65 (1H, d, J 2.5 Hz, H-3 or H-5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](Br)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc([N+](=O)[O-])ccc21
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(C#C[Si](C)(C)C)c2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Yield: 45.1 %

Procedure:
3-Bromo 5-nitro-indazole-1-carboxylic acid tert-butyl ester (2 g, 5.8 mmol) was dissolved in dry DMF (30 mL) under nitrogen and triethylamine (1.6 mL, 1.6 mmol) added. Copper iodide (20 mg, 0.12 mmol), trimethylsilylacetylene (2.5 mL, 17.4 mmol) palladium bis-triphenylphosphine dichloride (84 mg, 0.12 mmol) and a further 1.6 mL of triethylamine were added and the mixture heated at 50° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was taken up in EtOAc and filtered through a plug of Celite®. The filtrate was washed with saturated ammonium chloride solution and dried over sodium sulfate then concentrated to a black foam. Purification by chromatography (silica, 1:1 petrol-EtOAc) gave the title compound as a black solid (940 mg, 45%); MS (ES+) m/e=360.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][CH3:9].[ClH:13].[CH2:14](O)[CH3:15]>>[ClH:13].[CH2:14]([O:11][C:10]([C:3]1[C:2]([NH2:1])=[C:6]([CH2:7][CH2:8][CH3:9])[S:5][CH:4]=1)=[O:12])[CH3:15]
Reactant: CCCc1scc(C(=O)O)c1N
Reactant: CCO
Agent: Cl
Product: CCCc1scc(C(=O)OCC)c1N

Procedure:
A sample of 1.50 g. (8.097 mmols) of 4-amino-5-propyl-3-thiophenecarboxylic acid was dissolved in 75 ml. absolute ethanol which had been previously saturated with gaseous hydrogen chloride. The resulting reaction was heated under reflux for 24 hours, cooled and evaporated to afford 1.43 g. (71%) of pure 4-amino-5-propyl-3-thiophenecarboxylic acid ethyl ester hydrochloride, m.p. 144° C. (dec.) after recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:3]1[C:2]([Cl:1])=[C:12]([Cl:13])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1CBr
Reaction time: 3 h
Yield: 112.1 %

Procedure:
A mixture of ethyl 3,4-dichloro-2-methylbenzoate (34.0 g), N-bromosuccinimide (30.0 g) and carbon tetrachloride was irradiated with u.v. light in a photochemical reactor for 3 hours. The cooled mixture was filtered and the filtrate washed with water, dried (magnesium sulphate) and evaporated to give ethyl 2-bromomethyl-3,4-dichlorobenzoate (51.0 g) as an oil, NMR (CDCl3) 1.45 (t,3H), 4.4 (q,2H), 5.15 (s,2H), 7.7 (m,2H).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10])=[N+:2]=[N-:3].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[N:1]=[N+:2]=[N-:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=NC1CCCCC1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a solution of 2-azidocyclohexylalcohol (1 g, 7.1 mmol) in THF (10 mL), sodium hydride (284 mg, 7.1 mmol) was added. After 10 minutes, benzyl bromide (0.84 mL, 7.1 mmol) was added. The reaction mixture was partitioned between ethyl acetate and NaHCO3 (aq.). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting liquid on silica gel (hexane: ethyl acetate; 10:1) gave product (1.4 g, 85%). EI-MS m/z 232 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][OH:24])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(=O)CCC1=O.S([O-])(O)=O.[Na+]>CN(C)C=O>[Br:25][C:20]1[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)(=[O:12])=[O:13])=[N:16][CH:17]=[N:18][C:19]=1[O:21][CH2:22][CH2:23][OH:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(OCCO)ncn2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 4-tert-butyl-N-[6-(2-hydroxyethoxy)pyrimidin-4-yl)benzenesulfonamide (210 mg) in dimethylformamide (4 ml) is added N-bromosuccinimide (116 mg), and the mixture is stirred at room temperature for one hour. The mixture is treated with aqueous sodium hydrogen sulfite solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=40:1), and recrystallized from hexane/ethyl acetate to give N-[5-bromo-6-(2-hydroxyethoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (169 mg).
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[CH:40]1([CH2:43][O:44][C:45]2[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][C:50]=2[O:51][CH:52]([F:54])[F:53])[CH2:42][CH2:41]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:47]1[CH:48]=[CH:49][C:50]([O:51][CH:52]([F:54])[F:53])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:46]=1
Reactant: OB(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Yield: 45.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 0.40 g (1.1 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 0.55 g (2.1 mmol) of 3-cyclopropylmethoxy-4-difluoromethoxyphenylboronic acid obtained in the following Reference example 3-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 254 mg of the title compound was obtained as a white solid. (Yield: 46%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][C:14]1=[O:26].Cl.CC1N(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)C=C(OC2CCNCC2)C=1.Cl[C:54]1[N:59]=[CH:58][C:57]([CH2:60][CH2:61][CH3:62])=[CH:56][N:55]=1.ClC1N=CC(C2CC2)=CN=1>>[Cl:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:54]3[N:59]=[CH:58][C:57]([CH2:60][CH2:61][CH3:62])=[CH:56][N:55]=3)[CH2:22][CH2:21]2)=[CH:15][C:14]1=[O:26]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)c(Cl)c1
Reactant: CCCc1cnc(Cl)nc1
Agent: Cc1cc(OC2CCNCC2)cc(=O)n1-c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: Clc1ncc(C2CC2)cn1
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4Cl)c(=O)c3)CC2)nc1

Procedure:
Example 169 was prepared according to the procedures described in Example 168 and Example 162 substituting 1-(2-chloro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloride for 6-methyl-1-(4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloride and 2-chloro-5-propylpyrimidine for 2-chloro-5-cyclopropylpyrimidine in Step C. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (s, 2H), 8.16 (s, 1H), 7.99 (dd, J=8.25, 2.20 Hz, 1H), 7.62 (d, J=8.25 Hz, 1H), 7.06 (d, J=7.70 Hz, 1H), 6.10 (dd, J=7.70, 2.75 Hz, 1H), 6.05 (d, J=2.75 Hz, 1H), 4.55-4.64 (m, 1H), 4.23 (dd, J=11.55, 6.05 Hz, 2H), 3.59-3.69 (m, 2H), 3.14 (s, 3H), 2.43 (t, J=7.42 Hz, 2H), 2.11 (td, J=6.32, 3.30 Hz, 2 H), 1.88 (ddd, J=8.39, 4.40, 4.26 Hz, 2H), 1.55-1.61 (m, 2H), 0.96 (t, 3H). MS (ESI) 503 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:56]=2)[CH:51]=[CH:50]1
Reactant: Nc1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3cc[nH]c3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-6-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 58% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:13])[CH3:3].[S:14](N)(N)(=[O:16])=[O:15]>N1C=CC=CC=1>[F:12][C:11]1[C:6]2[CH2:5][N:4]([CH:2]([CH3:1])[CH3:3])[S:14](=[O:16])(=[O:15])[NH:13][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: NS(N)(=O)=O
Reactant: CC(C)NCc1c(N)cccc1F
Solvent: c1ccncc1
Product: CC(C)N1Cc2c(F)cccc2NS1(=O)=O
Temperature: 115 °C
Reaction time: 24 h

Procedure:
N-(1-methylethyl)-(2-amino-6-fluorophenyl)methylamine (0.3 g, 1.6 mmol) and sulphamide (5.08 g, 2.5 mmol) were suspended in 7 ml of dry pyridine and the mixture stirred at 115° C. for 24 hours in argon atmosphere. After cooling at room temperature the solvent was removed in vacuo and the residue dissolved in EtOAc (50 ml) and washed with 5N HCl (2×50 ml). Solvents removal afforded 5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1F)[C:11]#[N:12].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1>CS(C)=O.O>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=1[O:25][CH3:26])[C:11]#[N:12]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: COc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Cl)ccc1Oc1ccc(C#N)cc1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
Potassium carbonate (0.784 g, 5.68 mmol) and 3-bromo-4-fluorobenzonitrile (0.378 g, 1.89 mmol) was added to a solution of 4-chloro-2-methoxyphenol (0.300 g, 1.89 mmol) in DMSO (7 mL). The reaction was heated at 80° C. for 2 hours, then cooled and left stirring at room temperature for 18 hours. The reaction was diluted with water (70 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with 1M NaOH aqueous solution (50 mL), brine (2×70 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as an off-white solid (0.625 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C)C=O>[CH3:27][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1
Reactant: CN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCN(C)CC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.17 g, 0.39 mmol) in N,N-dimethylformamide (0.5 mL) was added N-methylpiperazine (0.44 mL, 3.92 mmol) and the reaction mixture was stirred at room temperature for 15 hours. N,N-dimethylformamide was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 60 mg (33.8%). MP 180-182° C. 1H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 7.89 (s, 2H), 6.73 (d, J=2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 3.88 (m, 5H), 3.84 (s, 3H), 2.68 (t, J=5.6 Hz, 2H), 2.50 (br s, 4H), 2.32 (br s, 4H), 2.30 (s, 6H), 2.15 (s, 3H). MS (ES+) m/z: 453.21 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:15])([CH3:14])[O:6][Si](C)(C)CCCN.O.O.O.O.O.[OH-].[CH3:22][N+:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:15])([CH3:14])[O-:6].[CH3:22][N+:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: C[Si](C)(CCCN)O[Si](C)(C)CCCN
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)([O-])CCCN

Procedure:
A 250 ml three-neck round-bottom flask equipped with a magnetic stirrer, argon inlet, and condenser with drying tube was charged with 12.4 g (0.05 mol) of 1,3-bis(3-aminopropyl)tetramethyldisiloxane, 18.1 (88.12 mmol) of tetramethylammonium hydroxide pentahydrate, and 30 ml of tetrahydrofuran. The mixture was heated under reflux in an inert gas atmosphere for 5 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([N:13]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH3:14])(=[O:12])=[O:11].C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:23])C.Cl.CCOC(C)=O>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([N:13]([CH2:15][O:16][CH2:17][CH2:18][C:19]([OH:23])=[O:20])[CH3:14])(=[O:11])=[O:12]
Reactant: CN(COCCCO)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(COCCC(=O)O)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4,6-Trichloro-N-(3-hydroxypropoxymethyl)-N-methylbenzenesulfonamide (363 mg, 1 mmol), 2,2,6,6-tetramethylpiperidin-1-yloxy radical (38 mg, 0.245 mmol) and [bis(acetoxy)iodo]benzene (705 mg, 2.19 mmol) were dissolved in acetonitrile/water (1:1; 8 ml) and the solution was stirred at RT for 30 min. The reaction soln. was then cooled with ice, and 2 N hydrochloric acid (4 ml) and EtOAc (40 ml) were added. The phases were separated and the organic phase was washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml), dried with Na2SO4 and concentrated i. vac. The compound was taken up in 1 N sodium carbonate soln. (30 ml) and the mixture was extracted with EtOAc (3×20 ml). The aqueous phase was then adjusted to pH 3 with 2 N hydrochloric acid and extracted with EtOAc (3×20 ml). The combined organic phases were washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml), dried with Na2SO4 and concentrated i. vac. Yield: 310 mg (82%)
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[N:7][CH:8]=1)#N.BrC1C(C#N)=CC=[N:28][CH:27]=1>>[C:27]([C:8]1[N:7]=[CH:6][C:5]([C:9]#[C:10][CH:11]=[C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1)#[N:28]
Reactant: N#Cc1ccncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cncc(C#N)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2ccc(C#N)nc2)CC1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 45, but substituting 5-bromo-2-pyridincarbonitrile for 5-bromoisonicotinonitrile. Purification by flash chromatography (EtOAc—Petroleum Ether gradient from 5:95 to 40:60) afforded the title product.
Reaction SMILES: OC[C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.S(Cl)([Cl:20])=O.[CH:22](Cl)(Cl)[Cl:23]>>[ClH:20].[Cl:23][CH2:22][N:4]1[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7](=[O:9])[CH:8]=[CH:3]1
Reactant: O=c1cc(CO)[nH]cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: ClC(Cl)Cl
Product: Cl
Product: O=c1ccn(CCl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of 1,4-dihydro-2-(hydroxymethyl)5-(phenylmethoxy)-4-pyridinone (3 g, 12.99 mmole) in chloroform (15 ml) was cooled to 0° C. under argon and treated with thionyl chloride (6.1 ml, 83.62 mmole). Within several minutes, a homogeneous solution was obtained. After stirring an additional 5 minutes, a cream colored solid precipitated. The cooling bath was removed and the mixture was heated at reflux for 45 minutes. The mixture was cooled to 0° C. and the white suspended material was filtered, washed with chloroform and hexane and dried in vacuo. The yield of the title compound was 3.65 g.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:12])[NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([NH:4][N:5]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12]
Reactant: COC(=O)CBr
Reactant: CNC(=O)NNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CNC(=O)NN(CC(=O)OC)c1ccccc1
Yield: 77.9 %

Procedure:
A mixture of 4-methyl-1-phenylsemicarbazide (20.0 g), methyl bromoacetate (27.75 g) and diisopropylethylamine (23.2 ml) in toluene (200 ml) under nitrogen was heated at 90° to 100° for 25 h with stirring. Toluene (120 ml) was then distilled off at ca. 90° under reduced pressure. The mixture was cooled to <50° and diluted with water (120 ml) and ethyl acetate (200 ml). The organic phase was separated and washed with water (60 ml). The two aqueous phases were extracted sequentially with ethyl acetate (2×60 ml). The combined organic phases were filtered and concentrated to 80 ml at atmospheric pressure. Toluene (100 ml) was added and the solution was again concentrated to 80 ml. The concentrate was seeded at ca. 80° with an authentic sample of the title compound, and allowed to cool to ca. 20° overnight. The resultant solid was filtered off, washed with toluene (20 ml) followed by t-butyl methyl ether (20 ml), and dried in vacuo for 24 h to give the title compound (22.39 g), m.p. 122°-122.5°.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][N+:13]([O-:24])=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(Cc1ccncc1)OCC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cc1cc[n+]([O-])cc1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The starting material is prepared as follows: A mixture of 2.2 g of 4-(diethylphosphonomethyl)pyridine [Roczniki Chem. 38, (4), 625 (1964); Chem. Abst. 61, 10703], 2.2 g of m-chloroperbenzoic acid and 30 ml of chloroform is stirred at room temperature for 16 hours. The solvent is removed in vacuo and water is added. After washing the aqueous layer with ether, the water is removed in vacuo to afford 4-(diethylphosphonomethyl)pyridine-N-oxide.