Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH2:13][CH2:12][C:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:29]=2[C:30]#[N:31])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([C:28]2[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][C:29]=2[C:30]#[N:31])[CH:3]=[C:4]([C:9]2[CH2:13][CH2:12][C:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[N:5]=1
Reactant: Cc1cc(Br)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)ccc2C#N)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)ccc2C#N)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Temperature: 120 °C
Yield: 32 %

Procedure:
To a solution of 2-(4-bromo-6-methyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 13) (180 mg, 0.5600 mmol) in 1,2-dimethoxyethane (3 mL) and water (1 mL) was added 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzonitrile (182.56 mg, 0.6100 mmol) and sodium carbonate (177.65 mg, 1.68 mmol). The reaction mixture was degassed with nitrogen and then treated with bis(triphenylphosphine)palladium (II) dichloride (19.61 mg, 0.0300 mmol). The reaction was heated in the microwave at 120° C. for 15 minutes. The reaction mixture was diluted with dichloromethane and water. After separation of the layers, the aqueous phase was re-extracted with dichloromethane and the combined organic phases passed through a hydrophobic frit. The solvent was evaporated and the residue purified by silica gel chromatography to afford 2-[2-methyl-6-(7-methyl-6-oxo-1,7-diazaspiro[4.4]non-1-en-2-yl)-4-pyridyl]-4-(trifluoromethyl)-benzonitrile (D14) as a colourless solid (74 mg);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>O1CCCC1>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)[CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: Clc1ccc(Cl)cc1
Reactant: C=CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution containing 294 g (2 mol) of 1,4-dichlorobenzene in 500 ml of anhydrous tetrahydrofuran was added dropwise over a period of about 110 minutes under nitrogen at 80° C. to a stirred suspension containing 48.6 g (2.0 mol) of magnesium turnings. The mixture was subsequently heated for 2 hours at 80°-84° C., then decanted from the excess magnesium, and the resultant solution of the Grignard compound was added dropwise over a period of 30 minutes at 80° C. to a stirred solution containing 194 g (1.8 mol) of 6-bromo-1-hexene (Fluka GmbH, 7910 Neu-Ulm) in 200 ml of tetrahydrofuran. The mixture was then stirred for 4 hours at 80° C. and then poured onto ice. After acidification with hydrochlcric acid, the mixture was extracted three times with a 1:1 mixture of diethyl ether/methyl tert-butyl ether, and the ether fractions were stirred thoroughly with activated charcoal and dried over sodium sulfate. The filtrate was evaporated, and the residue was fractionated. At a pressure of 13 hPa and a temperature of 116°-118° C., 156 g (corresponding to a yield of 40% of theory) of 4-(5-hexenyl)-1-chlorobenzene were obtained. 4-(8-Nonenyl)-1-chlorobenzene (b.p. 87° C. at 0.3 hPa), for example, can also be prepared in the same way.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N/C(/C#N)=[C:11](\[C:14](=[NH:18])OCC)/[C:12]#[N:13].Cl.[NH2:22][C:23]1C=CC=CC=1.[OH-].[Na+]>C(O)C>[NH2:18][C:14]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:23]=[N:22][C:11]=1[C:12]#[N:13]
Reactant: Nc1ccccc1
Reactant: CCOC(=N)/C(C#N)=C(\N)C#N
Reactant: NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ncn(Cc2ccccc2)c1N
Temperature: 10 °C

Procedure:
Benzylamine (2.86 ml, 26.3 mmol) was added dropwise to a solution of ethyl [(Z)-2-amino-1,2-dicyanovinyl]imidoformate (4.1 g, 25.0 mmol) and aniline hydrochloride (50 mg) in ethanol (80 ml), stirring at 10° C. and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was added dropwise to 1M sodium hydroxide (50 ml), stirring at 10° C. and the resultant suspension stirred at room temperature for 18 hours. The solid was collected by filtration, washed with water and dried in vacuo. The title compound was obtained as an off white solid (3.6 g, 18.2 mmol, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[C@@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CCC(C)=O>[CH3:19][C@@H:13]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccccc1F
Reactant: CCCCC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC[C@@H](C)Oc1ccccc1F
Reaction time: 14 h
Yield: 74.6 %

Procedure:
A reaction vessel was charged with 10 g of 2-fluorophenol, 25 g of (S)-1-methylhexyl tosylate, 20 g of potassium carbonate and 160 ml of MEK, and the mixture was refluxed with stirring for 14 hours (the disappearance of the starting materials was confirmed by TLC). The reaction liquid was poured into diluted hydrochloric acid and the mixture was extracted with benzene. The extract was washed with water and dried over Glauber's salt, and the solvents were distilled off. The residue was distilled under reduced pressure to obtain 14 g (74.5%) of (R) -2- (1-methylhexyl) oxyfluorobenzene.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([F:12])=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.[OH-].[Na+]>ClCCl>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=3)[CH2:11][CH:3]2[CH2:1][CH3:2])=[O:21])[CH:15]=1
Reactant: CCC1Cc2ccc(F)cc2N1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.5 g (10 mmol) 2-ethyl-6-fluoro-2,3-dihydro-1H-indol in 25 mL dichloromethane was added at 0° C. to 1.8 g (10 mmol) 6-chloro-pyrimidine-4-carboxylic acid chloride in 25 mL dichloromethane and then 10 mL (10 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 30 min at 0° C. and then for 1 h at RT. The organic phase was separated off and evaporated down. The residue was purified on silica gel.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: C1CCNC1
Product: O=[N+]([O-])c1cnc(N2CCCC2)nc1

Procedure:
Prepared essentially as described in Example 69a, using 2-chloro-5-nitro-pyrimidine and pyrrolidine. 1H NMR (DMSO-d6) δ 9.11 (s, 2H), 3.62 (m, 4H), 1.97 (m, 4H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([OH:23])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([O:40][CH2:41][C@H:42]2[CH2:46]OC(C)(C)[O:43]2)(=O)=O)=CC=1.Cl>C(#N)C.C(O)C.CO>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([O:23][CH2:46][C@H:42]([OH:43])[CH2:41][OH:40])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(O)ccc2-3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: CCO
Product: CCCc1ccc(-c2onc3c2CCc2cc(OC[C@H](O)CO)ccc2-3)cc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Example 9, 0.1 g, 0.327 mmol) in acetonitrile (2 mL) was added potassium carbonate (0.100 g, 0.720 mmol) and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (0.094 g, 0.327 mmol) at room temperature. The heterogeneous reaction mixture was heated at 120° C. in a microwave reactor for 1 h. Next, 2 mL of methanol was added followed by additional (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (100 mg). The contents were heated in the microwave reactor at 120° C. for 1 h. To the reaction mixture was added 1.0 mL of 2.5 M hydrochloric acid in ethanol at room temperature. The heterogeneous reaction mixture was stirred at room temperature for 1.5 h and concentrated under reduced pressure. Methanol (3 mL) was added followed by 3 drops of water and the contents were filtered. The pale yellow filtrate was subjected to Prep. HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the desired product were isolated and concentrated to yield (R)-3-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yloxy)propane-1,2-diol (0.016 g, 0.042 mmol, 13% yield) as a white solid. The compound had an HPLC retention time=3.73 min (condition C); LC/MS M+1=380.1; 1H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J=8.53 Hz, 1H) 7.69 (d, J=8.28 Hz, 2H) 7.31 (d, J=8.28 Hz, 2H) 6.85-6.92 (m, 2H) 4.08-4.15 (m, 3H) 3.74-3.91 (m, 2H) 2.96-3.05 (m, 4H) 2.55-2.68 (m, 3H) 1.97 (t, J=5.90 Hz, 1H) 1.68 (sxt, J=7.43 Hz, 2H) 0.97 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH2:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(N(CC)CC)C.[C:24](=[O:27])([O-])[O-].[K+].[K+].Br[C:31]1[C:32]([CH:37]([F:39])[F:38])=[N:33][N:34]([CH3:36])[CH:35]=1>C(#N)C.[Pd](Cl)Cl.CC(C)(CP(C1C=CC=CC=1)C1C=CC=CC=1)CP(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH:12][C:24]([C:31]2[C:32]([CH:37]([F:39])[F:38])=[N:33][N:34]([CH3:36])[CH:35]=2)=[O:27])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Nc1ccccc1-c1cc(F)c(F)c(F)c1
Reactant: Cn1cc(Br)c(C(F)F)n1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: CC(C)(CP(c1ccccc1)c1ccccc1)CP(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1cc(C(=O)Nc2ccccc2-c2cc(F)c(F)c(F)c2)c(C(F)F)n1
Temperature: 130 °C
Reaction time: 20 h
Yield: 57.5 %

Procedure:
In an autoclave, 2-(3,4,5-trifluorophenyl)aniline (5.29 g, 23.7 mmol), triethylamine (1.20 g, 11.8 mmol), palladium chloride (86 mg, 0.47 mmol), anhydrous potassium carbonate (6.55 g, 47.4 mmol) and 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (313 mg, 0.71 mmol) were added to a solution of 4-bromo-3-difluoromethyl-1-methylpyrazole (5.00 g, 23.7 mmol) in acetonitrile (100 ml). The autoclave was flushed three times with 9 bar of nitrogen and then 3 times with 10 bar of carbon monoxide. The reaction mixture was stirred under a carbon monoxide pressure of 9 mbar at an external temperature of 130° C. for 20 h. The red-brown suspension obtained after cooling and venting was filtered, and the filtrate was freed from volatile components under reduced pressure. The residue was taken up in a mixture of tetrahydrofuran (60 ml) and methyl tert-butyl ether (MTBE, 60 ml), washed twice with hydrochloric acid (5% strength, in each case 40 ml) and once with water (30 ml), dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was triturated with diisopropyl ether (20 ml), and the solid was filtered off and dried under reduced pressure. 5.20 g (yield 54%) of N-(2-(3,4,5-trifluorophenyl)phenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide were isolated in a purity of 93%, according to HPLC analysis (Merck Chromolith SpeedROD RP-18e column, 50×4.6 mm; gradient: acetonitrile/water with 0.1% trifluoroacetic acid, 7 min from 10% to 95% acetonitrile).
Reaction SMILES: [OH-].[K+].[C:3]1([CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)O.[C:12]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)(=[O:14])[CH3:13].C(O)(=O)C>COCCO.C(OCC)(=O)C>[OH:7][C:6]1[CH:8]=[C:9]([OH:10])[C:11]2[CH:20]3[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:12](=[O:14])[CH2:13][C:3]=2[CH:5]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(=O)C1=CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COCCO
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(O)cc(O)c2C2CCCCC12
Temperature: 140 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere, there is added 50 g. (0.89) moles of potassium hydroxide in one liter of 2-methoxyethanol. Stirring is initiated and 100 g. (0.79 mole) of anhydrous phloroglucinol is added in three portions, followed by the addition of 100 g. (0.80 mole) of 1-acetyl-cyclohexene while maintaining the temperature at 50° C. The resulting solution is refluxed at 140° C. for 4 hours. After cooling there is then added gradually 53.6 g. of acetic acid while obtaining a pH of approximately 7. The solvent is then removed in vacuo, and the residue is further heated in an oil bath at 70° C., to obtain a viscous residue. The resulting residue is dissolved in ethyl acetate and water washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to obtain a brown solid. The resulting solid is recrystallized from ethyl acetate/cyclohexane to give 2,4-dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene; m.p. 220°-223° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]#[N:24].Cl>ClCCCl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:21]1[N:17]([CH3:16])[C:18]([CH2:22][C:23]#[N:24])=[CH:19][CH:20]=1)=[O:9]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 16.6 g. (0.125 mole) of aluminum chloride in 60 ml. 1,2-dichloroethane is added 26.2 g. (0.125 mole) of 2,4-dichlorobenzoyl chloride. The resulting solution is added slowly to a solution of 15 g. (0.125 mole) of 1-methylpyrrole- 2-acetonitrile in 60 ml. 1,2-dichloroethane while cooling externally with an ice bath. After the addition is complete, the mixture is stirred for 40 minutes at room temperature followed by heating at reflux for 3 minutes. It is then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated. The resulting red oily residue is chromatographed on a column packed with neutral alumina and eluted with benzene and ether. The first compound-bearing fractions upon evaporation yield a white solid, 5-(2',4'-dichlorobenzoyl)-1-methylpyrrole- 2-acetonitrile, which is purified by recrystallization from methanol, m.p. 129°-130°C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[N+:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])c3ccccc23)C1
Yield: 87.7 %

Procedure:
The compound was prepared from tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (3.56 g, 19 mmol) and 4-nitro-1-naphthol (3 g, 15.9 mmol). Yield: 5 g (88%) of the title compound as yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (d, J=7.03 Hz, 9H) 2.22-2.38 (m, 2H) 3.54-3.83 (m, 4H) 5.18 (br s, 1H) 6.74 (d, J=8.53 Hz, 1H) 7.56 (t, J=7.78 Hz, 1H) 7.71 (t, J=7.78 Hz, 1H) 8.29 (d, J=8.53 Hz, 1H) 8.33 (d, J=8.53 Hz, 1H) 8.72 (d, J=8.53 Hz, 1H). MS (ESI+) for C19H22N2O5 m/z 376.2 (M+NH4)+, 303.2 (M−tBu)+. HPLC 100%, RT=2.768 min (System A1, 10-97% MeCN over 3 min).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[F:14])(=[O:3])[CH3:2].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[F:14])=[O:3]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)CBr)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
N-(4-Acetyl-3-fluoro-phenyl)-acetamide (10.2 g, 51.2 mmol) is dissolved in 50 mL chloroform. At room temperature bromine (1.98 mL, 38.4 mmol) is added drop wise. The reaction mixture is stirred at room temperature for 1.5 hours. Subsequently the precipitated product is filtered off, washed first with chloroform and then with ethyl acetate to yield N-[4-(2-bromo-acetyl)-3-fluoro-phenyl]-acetamide (8.7 g, 43%); LCIMS at 254 nm; [M+H] 275; Rt 2.918 min)
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([O:15][CH2:16][CH2:17][OH:18])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[C:27]([C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])([Cl:37])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl>[C:38]([C:27]([N:11]1[C:12](=[O:13])[CH:14]([O:15][CH2:16][CH2:17][OH:18])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:10])([Cl:37])[C:28]([NH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:29])(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1NC(=O)N(Cc2ccccc2)C1OCCO
Reactant: CC(C)(C)C(=O)C(Cl)(Br)C(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C(Cl)(C(=O)Nc1ccccc1)N1C(=O)C(OCCO)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 80.4 %

Procedure:
51.5 g of 1-benzyl-5-(2-hydroxyethoxy)hydantoin and 20 g of triethylamine were dissolved in 500 ml of methylene chloride, and a solution of 34.8 g of α-bromo-α-pivaloyl-2-chloroacetanilide in 200 ml of methylene chloride was dropwise added thereto in about 1 hour. After completion of the dropwise addition, the solution was stirred for 2 hours. Then, the reaction solution was washed twice with 300 ml of dilute hydrochloric acid, and twice with 300 ml of water. After drying the reaction solution with sodium sulfate, it was concentrated and purified by silica gel chromatography to obtain 42.2 g of oily α-pivaloyl-α-(1-benzyl-5-(2-hydroxyethoxy)hydantoin-3-yl)-2-chloroacetanilide. (Yield: 84%)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[OH:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2[N+](=O)[O-])cc1
Yield: 93.1 %

Procedure:
38.6 g (0.20 mole) of 2.5-dichloro-3-nitropyridine, 41.2 g (0.21 mole) of methyl 2-(4-hydroxyphenoxy)propionate, 400 ml of acetonitrile, 35.9 g (0.26 mole) of potassium carbonate and 0.33 g (0.002 mole) of potassium iodide are heated for 13 hours to 80° C. The reaction mixture is filtered and the filter cake is washed with acetonitrile. The filtrate is concentrated by evaporation and the residue is taken up in 500 ml of methlyene chloride. After treating the solution with 15 g of activated carbon, it is filtered through a layer of silica gel and the filtrate is concentrated by evaporation. The residue is crystallised from a mixture of hexane and ethyl acetate, affording 65.7 g (93.1% of theory) of methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate with a melting point of 91°-92° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>CN(C=O)C>[NH2:8][C:5]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]([CH2:2][NH:1][S:31]([CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[N:7][N:6]=1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NCC1=NN=C(N)C1=NNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
A solution of 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (40 mg, 0.17 mmol) in anhydrous DMF (3 mL) was added to a 10 mL reaction vessel containing PS-DIEA (2.5 eq, 150 mg) and butane-1-sulfonyl chloride (1.1 eq, 0.19 mmol) suspended in anhydrous DMF (3 mL). The reaction mixture was stirred at ambient temperature under argon for approximately 16 hours before it was filtered, washed with DMF (3×5 mL) and concentrated under reduced pressure. The resulting yellow residue was recrystallized from ether to yield 13 mg (22%) of the title compound as a yellow powder. MS (m/z, ES+): 355 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:11][C:12](Cl)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[N:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(Cl)ccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2nccc(Cl)c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
3-amino-4-chloro-pyridin-2-ol (650 mg, 4.49 mmol) was dissolved in anhydrous N,N-dimethyl formamide (22 ml) under nitrogen atmosphere, and chloroacetyl chloride solution (0.394 ml, 4.94 mmol) was added thereto dropwise at room temperature and stirred for 30 minutes. Potassium carbonate (1.55 g, 11.24 mmol) was added thereto dropwise at room temperature, and the reaction mixture was heated to 1000 and stirred for 18 hours. The reaction mixture was cooled to room temperature and water was added to quench the reaction, and the organic layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was recrystallized from dichloromethane and diisopropyl ether to obtain white solid (608 mg, 73%).
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=O)=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44].[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:54]2[CH2:59][CH2:58][N:57]([C:41]3[N:40]([C:37]4[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[C:34]([F:33])=[CH:39][CH:38]=4)[CH:27]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]4[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)[CH2:56][CH2:55]2)=[CH:52][CH:53]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)/C=C/c1ccccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Product: COC(=O)CC1c2ccccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1ccc(F)c(C(F)(F)F)c1

Procedure:
Starting with 150 mg (0.34 mmol) of the iminophosphorane from Example 3A, 74 mg (0.34 mmol) of 4-fluoro-3-(trifluoromethyl)phenyl isocyanate and 61 mg (0.34 mmol) of N-(4-fluorophenyl)piperazine, the general procedure [E] and chromatographic purification (method 2) give 111 mg (54% of theory) of product.