Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6-chloro-3-nitro-pyridine-2-carboxylic acid amide (10.43 g, 51.75 mmol) is taken up in EtOH (250 mL), combined with ammonium chloride (1.384 g, 25.87 mmol) in water (250 mL) and heated to 60° C. At this temperature iron powder (8.67 g, 155.23 mmol) is added batchwise and the mixture is stirred for 1 h at 60° C. After cooling it is concentrated by rotary evaporation, filtered through silica gel, washed with DCM/MeOH (90/10 to 80/20), the resulting filtrate is evaporated down using the rotary evaporator and 3-amino-6-chloro-pyridine-2-carboxylic acid amide (HPLC-MS: tRet.=0.90 min; MS (M+H)+=172) is obtained.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1.[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[N:7]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1COCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3-methylmorpholino)-2-phenylquinoxaline-6-carboxylate (45 mg, 0.12 mmol, 1.00 equiv) in methanol (10 mL). Then a solution of sodium hydroxide (25 mg, 0.62 mmol, 5.00 equiv) in water (2 mL) was added. The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated in vacuo. The residue was diluted by 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aq. hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 40 mg (90%) of 3-(3-methylmorpholino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:2].[OH-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH:15](=[N:14][C:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)([CH2:27][CH:26]=[CH2:25])[C:4]([O:3][CH2:1][CH3:2])=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCBr
Reactant: CCOC(=O)C(N=Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC(N=Cc1ccccc1)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl(benzylidene-amino)-(3,4-dichlorophenyl)acetate (425 g) was dissolved in methylene chloride (1.8 L). 10N Aqueous sodium hydroxide (1.2 L), allyl bromide (158 mL), and tetrabutylammonium sulfate (41 g) were added to the resultant solution, followed by stirring at room temperature for one hour. The reaction mixture was subjected to partitioning. Water (1 L) was added to the aqueous layer, and then the mixture was extracted with methylene chloride. The thus-obtained organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (518 g). The title compound was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]([O:14][CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[C:11]([O:12][CH3:13])=[N:10][C:9]([O:14][CH3:15])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(OC)nc(OC)c1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC)nc(OC)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of the product of Example 29 (0.278 g, 1.31 mmol) in pyridine (2 mL) was added p-methoxybenzenesulfonyl chloride (0.28 g, 1.38 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with H2O. The mixture was extracted 3 times with ether. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo to provide 0.444 g (89%) of methyl 3-(4-methoxy-benzenesulfonylamino)-2,6-dimethoxy-isonicotinate as a solid. Electrospray Mass Spec: 382.8 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][S:8][CH2:9][C:10]([N:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[CH:34][C:35]2[CH:49]=[CH:48][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C.C(O)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[F:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C@H:34]([C:35]2[CH:49]=[CH:48][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])=[CH:37][CH:36]=2)[CH:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=2)[C:10](=[O:11])[N:12]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][O:14][C:13]2=[O:23])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=Nc2ccc(F)cc2)cc1
Reactant: COc1ccc(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CSC(C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@H](Nc2ccc(F)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
TiCl4 (1M in DCM, 7.2 ml, 7.2 mmol) was added to a solution of tetraisopropyl orthotitanate (0.71 ml 2.4 mmol) in DCM (40 ml) held at 0° C. under inert atmosphere. The mixture was stirred for 15 minutes, then (4S)-3-{[(4-methoxybenzyl)thio]acetyl}-4-phenyl-1,3-oxazolidin-2-one (3.4 g, 9.6 mmol) in dry DCM (20 ml) was added and the mixture was stirred for five minutes. Then tert-butyl (4-{[(4-fluorophenyl)imino]methyl}phenoxy)acetate (6.3 g, 19.0 mmol) in dry DCM (30 ml) was added and the mixture was given −40° C. and stirred for 20 minutes. Ethyl diisopropyl amine (3.3 ml, 19.0 mmol) was added and the mixture was stirred at −40° C. for 19 hours. The mixture was then given −78° C., added isopropanol (50 ml) and slowly given room temperature over night. Water (100 ml) was added and the mixture was stirred for 35 minutes at room temperature and then extracted twice with diethyl ether. The combined organic layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The crude product was dissolved in methanol and an off-white precipitate formed. Filtration and drying afforded 1.7 g (26%) of the title compound as an off-white solid. NMR (200 MHz): 1.5 (s, 9H), 3.65 (s, 1H), 3.8 (s, 3H), 4.1 (m, 1H), 4.4-4.6 (m, 4H), 5.0-5.2 (m, 2H), 5.4 (m, 1H), 6.4-6.6 (m, 2H), 6.7-7-4 (m, 15H).
Reaction SMILES: [K].[C:2]1([SH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Cl)[CH:11]=1>>[C:2]1([S:8][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1
Reactant: Sc1ccccc1
Agent: [K]
Product: c1ccc(Sc2cccc(Sc3ccccc3)c2)cc1

Procedure:
The thiophenol derivative and the halogenated aromatic compound are reacted under the reaction conditions described above, subjected to distillation under a reduced pressure as it is or after filtration, to obtain a polyphenyl thioether crude product fraction. For example, by the reaction between a potassium salt of thiophenol and m-dichlorobenzene, a m-bis(phenylmercapto) benzene crude product can be obtained as a fraction at 220° C.-230° C./5 Torr.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][C:37]([OH:39])=[O:38]>>[Cl:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH2:36][C:37]([OH:39])=[O:38])=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C(O)CC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Yield: 47.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.72 g, 1.53 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.39 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[C:6]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](SC)=[N:18]3)=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].O>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>[CH3:3][O:4][C:5]1[C:6]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([OH:1])=[N:18]3)=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: OO
Reactant: COc1cccnc1-c1ccc2cnc(SC)nn12
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cccnc1-c1ccc2cnc(O)nn12
Temperature: 50 °C
Yield: 85.8 %

Procedure:
Sodium Tungstate Dihydrate (23.0 mg, 0.0698 mmol) and 50% Hydrogen Peroxide (50:50, Hydrogen peroxide:Water, 0.150 mL, 2.64 mmol) were added to 7-(3-Methoxy-pyridin-2-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.190 g, 0.698 mmol) in Methanol (10.0 mL) and Acetic acid (0.400 mL, 7.04 mmol). The mixture was stirred at 50° C. Formation of the sulfoxide was evident, followed by formation of the sulfone. After o.n., a 1:1 mixture of sulfoxide:sulfone was present. Additional 50% Hydrogen Peroxide (50:50, Hydrogen peroxide:Water, 0.150 mL, 2.64 mmol) was added. Further heating gave a ˜2:1 mixture. Aqueous workup (10% Na2S2O3, NaHCO3, water) and extract with DCM. The crude sulfone:sulfoxide mixture was hydrolyzed by dissolving in Tetrahydrofuran (6.0 mL) and adding 5.0 M of Sodium hydroxide in Water (0.500 mL, 2.50 mmol), then heating at 50° C. for 6 h. Work up by acidifying with Acetic acid to pH 5-6. Partition between DCM and water, extract with DCM using MeOH to solubilize the ppt that forms during extraction. Dry and conc. in vacuo to afford 7-(3-Methoxy-pyridin-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (145 mg, 85%).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][O:2][CH:3]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)c1ccoc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccccc1)c1ccoc1
Yield: 91.6 %

Procedure:
6.0 g of (3-furylcarbonyl)methylamine hydrochloride, 7.8 g of sodium bicarbonate and 5.7 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(1). 7.8 g of N-benzoyl-(3-furylcarbonyl)methylamine are thereby obtained. Yield: 91.8%
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5](Cl)[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1.O>CCO>[CH2:1]([O:3][C:4]([C:5]1[S:22][C:21]([C:20]2[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=2)=[N:23][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:15])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(Cl)C(=O)OCC
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC
Temperature: 75 °C
Reaction time: 5.5 h
Yield: 85.1 %

Procedure:
Dissolve 2-chloro-3-oxo-pentanedioic acid diethyl ester (1370 g, 5.50 mol) in EtOH (8.5 L) and add 4-chloro-thiobenzamide (885 g, 5.00 mol). Heat the mixture to 75° C. and stir mechanically for 5.5 h. Cool the mixture to 45° C., then slowly add water (3.5 L) and stir overnight. Collect the yellow precipitate and wash the solids with 50% EtOH/water (4 L). Dry in an oven to obtain 1505 g (81%) of the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.90 (d, 2H, J=7.4), 7.41 (d, 2H, J=7.4), 4.34 (q, 2H, J=6.8), 4.24 (s, 2H), 4.19 (q, 2H, J=7.4), 1.36 (t, 3H, J=6.8), 1.27 (t, 3H, J=6.8).
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:11]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[O-2].[O-2].[Mn+4]>[C:24]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[O:17])[N:11]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[CH:10]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1cc(CO)n(Cc2ccco2)cc1OC(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: O=Cc1cc(=O)c(OC(c2ccccc2)c2ccccc2)cn1Cc1ccco1
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 2.700 g of 3-diphenylmethoxy-1-(2-furyl)methyl-6-hydroxymethyl-4-pyridone in 200 ml of methanol is added 15.00 g of active manganese dioxide at room temperature, and the mixture is stirred for 4 hours. After insolubles are removed by filtration, the filtrate is subjected to flash column chromatography on 120 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound (2.163 g) is obtained as colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CO)c1
Reaction time: 4 h

Procedure:
A solution of 2-bromo-5-methoxybenzoic acid (10.00 g, 43.3 mmol) in dry THF (40 ml) was treated with borane in THF (65 ml of 1.0M solution, 65 mmol) at room temperature under nitrogen. After stirring for 4 h, no starting material was detectable by tic. Excess borane was quenched by careful addition of water over 30 min, and the solvent was evaporated under reduced pressure. The residue was partitioned between ether and 5% Na2CO3. The ether layer was washed with 5% Na2CO3, water, and brine, and dried over MgSO4. Filtration and removal of solvent left a colorless oil which solidified (9.11 g, 97%); tlc (silica gel, CH2Cl2, Rf 0.25). This material was used without further purification.
Reaction SMILES: [NH:1]1[C:5]([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[N:8]=[N:7]2)=[CH:4][CH:3]=[N:2]1.Br[CH2:16][CH2:17][F:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:18][CH2:17][CH2:16][N:2]1[CH:3]=[CH:4][C:5]([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[N:8]=[N:7]2)=[N:1]1
Reactant: c1cc2c(cn1)nnn2-c1ccn[nH]1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FCCn1ccc(-n2nnc3cnccc32)n1
Yield: 99.3 %

Procedure:
To a solution of Intermediate 48 (50 mg, 0.269 mmol) in DMF (1 mL) was added 1-bromo-2-fluoroethane (41 mg, 0.322 mmol) and Cs2CO3 (263 mg, 0.806 mmol). The reaction was irradiated in a microwave apparatus for 10 min at 120° C. The resulting mixture was filtered, concentrated and purified by chromatography on silica gel eluted with 100% EtOAc to obtain the title compound (62 mg, 88%). MS (ESI) mass calcd. C10H9FN6, 232.1. m/z found, 233.0 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Cl:13][C:14](OC(Cl)(Cl)Cl)=[O:15]>O1CCCC1>[Cl:13][C:14]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To an ice-cooled solution of 6.5 g (40 retool) of N-hydroxyphthalimide in 200 mL dry tetrahydrofuran (THF) was added 10.0 mL (15.8 g, 80 mmole) of trichloromethyl chloroformate (diphosgene). The solution was then stirred for 6 hrs at room temperature. The solvent and excess trichloromethyl chloroformate were removed under reduced pressure to give a white crystalline solid, which was recrystallized from dry n-hexane to give colorless plates; m.p. 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15][S:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=3)(=[O:27])=[O:26])[CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: Nc1cccc(COCc2ccc(Cl)cc2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCc2ccc(Cl)cc2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.092g) as a light yellow gum (0.039 g). MS (ESI−): 472.8 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([CH2:13][CH3:14])=[N:7][C:6]=2[N:5]([CH3:15])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:15])[C:6]=4[N:7]=[C:8]3[CH2:13][CH3:14])=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 66.9 %

Procedure:
To a solution of 1,3-dimethyl-8-ethylxanthine (416 mg) in DMF (10 ml) were added potassium carbonate (332 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) and the mixture was stirred at room temperature for 21 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized (ethyl acetate-ether) to provide the title compound as white powder (584 mg, 67%). 1H-NMR (CDCl3) δ: 1.30(3H,t,J=7.6Hz), 2.72(2H,q,J=7.6Hz), 3.40(3H,s), 3.61(3H,s), 5.64(2H,s), 7.21-7.80(8H,m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][Br:31])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a heterogeneous, refluxing solution of 2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (590 mg, 1.65 mmol) and carbon tetrachloride (24 mL) was quickly added N-bromosuccinimide (yield: 308 mg, 1.73 mmol) followed by benzoyl peroxide (12 mg, 0.05 mmol). After 1 hour the reaction had only run to near 50% completion. Additional benzoyl peroxide (12 mg, 0.05 mmol) was added, and the reaction checked after another 1 hour. The reaction was still not complete, and so more benzoyl peroxide (4 mg, 0.017 mmol) was added. After 30 minutes, the reaction was completed. The mixture was cooled to 23° C. and diluted with ethyl acetate. The acetate solution was washed with saturated NaHCO3, water, and brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 4:1) to provide the product (yield: 530 mg, 74%). 1H NMR (300 MHz, CDCl3) δ 3.16 (s, 3H), 4.34 (s, 2H), 7.20 (dd, J=8.8, 8.8 Hz, 2H), 7.67-7.74 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.17 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 437 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][NH2:5].C(O[C:10](=O)[C:11]([F:14])([F:13])[F:12])C>C1(C)C(C)=CC=CC=1>[F:12][C:11]([F:14])([F:13])[C:10]1[NH:1][CH2:2][CH:3]([OH:6])[CH2:4][N:5]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCC(O)CN
Solvent: Cc1ccccc1C
Product: OC1CN=C(C(F)(F)F)NC1
Yield: 112.5 %

Procedure:
1,3-Diamino-2-hydroxypropane (10 g, 111 mmol) and ethyltrifluoroacetate (13.5 ml, 114 mmol) were dissolved in xylene (85 ml) and refluxed overnight in a Dean-Stark apparatus. The solvents were evaporated in vacuo to give a dark viscous oil 21 g identified by 300 MHz nmr as product.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12]CC)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18]>C(OCC)(=O)C>[OH:12][C:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]2[C:15](=[O:23])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=[C:2]2[N:11]=1
Reactant: COC(=O)c1ccccc1N
Reactant: CCOc1nc(Cl)nc2ccccc12
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2nc2nc(O)c3ccccc3n12
Temperature: 25 °C

Procedure:
To the 2-chloro-4-ethoxy-quinazoline (500 mg, 2.40 mmol) in a boiling tube was added methyl anthranilate (372 μL, 2.88 mmol). The mixture was heated with a hot air gun (approx. 400 deg C.) for 15 minutes before cooling to room temperature. The resulting crude product was suspended in ethyl acetate (10 mL) and heated to boiling. The mixture was then cooled and the pure off-white product isolated by filtration (257 mg).