Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH:35]=[C:36]2[C:41](=[O:42])OC(C)(C)OC2=O)=[CH:30][CH:29]=1)#[N:27]>CCCCCC>[OH:42][C:41]1[C:30]2[C:31](=[CH:32][CH:33]=[C:28]([C:26]#[N:27])[CH:29]=2)[N:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C#N)cc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: N#Cc1ccc2nccc(O)c2c1
Temperature: 250 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of biphenyl (10 ml) and diphenyl ether (30 ml) was heated at 250° C. and 5-(4-cyanophenylamino)methylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (3.28 g) was added thereto. The mixture was stirred for 1 hr. The reaction mixture was cooled to 80° C. while stirring and hexane (100 ml) was added. The mixture was stirred in an ice bath for 0.5 hr. The resulting solid was collected by filtration and washed with hexane to give the object compound (1.86 g) as a yellow-brown powder.
Reaction SMILES: CS(O[C@H:6]1[C@H:10]([O:11][C:12]2[CH:13]=[N:14][C:15]([Br:18])=[CH:16][CH:17]=2)[CH2:9][O:8][CH2:7]1)(=O)=O.[CH3:19][CH:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:18][C:15]1[N:14]=[CH:13][C:12]([O:11][C@H:10]2[CH2:9][O:8][CH2:7][C@H:6]2[NH:25][S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])=[CH:17][CH:16]=1
Reactant: CC(C)S(N)(=O)=O
Reactant: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)S(=O)(=O)N[C@@H]1COC[C@@H]1Oc1ccc(Br)nc1

Procedure:
Trans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl methane sulfonate (591.7 mg, 1.75 mmol), propane-2-sulfonamide (647 mg, 5.25 mmol) and cesium carbonate (855 mg, 2.62 mmol) were combined in acetonitrile (8 mL) and subjected to microwave irradiation for 55 minutes at 150° C. The crude reaction mixture was combined with several similar reactions run under the same conditions (total starting material used: 1.527 g, 4.515 mmol) and shaken with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (Gradient: 5% to 40% ethyl acetate in heptane) to provide the title compound. Yield: 382 mg, 1.046 mmol, 23%. 1H NMR (400 MHz, CDCl3) δ 1.34 (d, J=6.8 Hz, 3H), 1.36 (d, J=6.8 Hz, 3H), 3.17 (septet, J=6.8 Hz, 1H), 3.74 (dd, J=9, 9 Hz, 1H), 3.94 (dd, J=10.9, 1.5 Hz, 1H), 4.14 (dd, J=8, 8 Hz, 1H), 4.19 (dd, J=10.9, 4.3 Hz, 1H), 4.27 (m, 1H), 4.84 (m, 1H), 5.66 (d, J=9.9 Hz, 1H), 7.20 (dd, J=8.8, 3.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 8.01 (d, J=3.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=O)[CH2:10][CH2:9][N:8]2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CCN(C(C)C)C(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13](=[C:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])[OH:15])[CH2:10][CH2:9][N:8]2[C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 116.7 %

Procedure:
Dichloromethane (200 mL) was added to 2-(4-chlorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.27 g, 13.7 mmol) (reference compound 51). The mixture was cooled with an ice bath. DMAP (2.008 g, 16.44 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.96 g, 20.54 mmol) and DIPEA (5.25 mL, 30.13 mmol) were added and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.25 g, 27.39 mmol) was added. The mixture was stirred at 0° C. for 15 min, then the mixture was warmed to room temperature and stirred overnight. The organic phase was washed with 1 M HCl and once with water. The organic layer was filtered through a phase separator and evaporated to yield crude methyl 2-(4-chlorobenzyl)-4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl)-piperidine-1-carboxylate (7.00 g, 117%). MS m/z 438, 440 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:21]([CH:23]1[CH2:25][CH2:24]1)#[CH:22]>CN(C=O)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:23]1([C:21]#[C:22][C:2]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[CH2:25][CH2:24]1
Reactant: C#CC1CC1
Reactant: COC(=O)c1nc(SC)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(SC)ncc1C#CC1CC1
Temperature: 80 °C
Yield: 86.2 %

Procedure:
Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (639 mg, 2.43 mmole) was dissolved in DMF (6 mL) and triethylamine (1.37 mL) was added. To the solution was added ethynylcyclopropane (287 uL, 3.40 mmole), followed by copper (I) iodide (22.4 mg 0.115 mmole) and bis(triphenylphosphine)palladium dichloride (85.4 mg 0.115 mmole). The reaction was placed under nitrogen at heated at 80° C. for 3.25 hours. The reaction was diluted with ethyl acetate (75 mL) and the solution was washed with water (25 mL). The organic layer was washed again with water (2×25 mL), brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-10% ethyl acetate in cyclohexanes to afford the title compound (520 mg, 86%). Taken on directly to the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8]C(=O)C)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>Cl>[F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([NH2:8])[CH:7]=1
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c(F)cc1N
Yield: 95.8 %

Procedure:
A suspension of 3.5 g of N-(5-fluoro-2-methyl-4-nitrophenyl)-acetamide in 5N hydrochloric acid was heated under reflux for 1 hour. After allowing to cool, the solution was neutralized with potassium carbonate, and extracted with 80 mL of ethylacetate. The organic layer was dried over anhydrous magnesium sulfate, allowed to pass through a silica gel pad, and then the solvent was distilled off under reduced pressure, to afford 2.69 g of the title compound as ocher crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3C)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1B(O)O.[CH2:13]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26](Br)=[CH:25][C:23]=2[CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:3]3[CH:4]=[CH:5][C:6]([CH:8]=[O:9])=[CH:7][C:2]=3[F:1])=[CH:25][C:23]=2[CH:24]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccc2oc(Cc3ccccc3)cc2c1
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccc3oc(Cc4ccccc4)cc3c2)c(F)c1

Procedure:
A solution of 2-fluoro-4-formylphenylboronic acid (58 mg, 0.348 mmol), 2-benzyl-5-bromobenzofuran (50 mg, 0.174 mmol), tetrakis(triphenylphosphine) palladium(0) (20 mg, 0.0174 mmol) and sodium carbonate (106 mg, 1.0 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 100° C. for 12 h. The mixture was partitioned between brine (20 mL) and EtOAc (20 mL). The organic layer was dried. Removal of solvents gave the residue which was purified by silica gel column chromatography (ISCO system, 30% dichloromethane in hexanes) to give the product as a off white solid: 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.61-7.75 (m, 5H), 7.27-7.51 (m, 7H), 6.45 (s, 1H), 4.14 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[O:12][CH2:13][CH:14]([OH:15])[CH2:16][O:7]1)[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: OCC(O)CO
Product: CCOc1ccccc1C1OCC(O)CO1

Procedure:
Using the method of Example 5e, 30 g 2-ethoxybenzaldehyde was reacted with 18.4 g glycerol to form 2-(2-ethoxyphenyl)-5-hydroxy-1,3-dioxane, crude b.p. 140°-148° C/10-5 mm.
Reaction SMILES: Cl.[Cl:2][CH:3]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]([CH3:22])[CH2:4]1.[Na].[CH3:24][OH:25]>>[ClH:2].[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]([CH3:22])[CH:3]([CH2:4][O:25][CH3:24])[CH2:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[CH:17]=1
Reactant: CO
Reactant: CN1CC(Cl)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: Cl
Agent: [Na]
Product: COCC1CN=C(c2ccccc2)c2cc(Cl)ccc2N1C

Procedure:
500 mg of 3,8-dichloro-1-methyl-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine hydrochloride were heated in a solution of 110 mg sodium in 70 ml methanol under reflux for 12 hours. After evaporation of the methanol in a vacuum the mass was further processed with water/chloroform and the chloroform solution was evaporated and concentrated in a vacuum. The residue was taken up in isopropanol and reacted with an ether solution of hydrogen chloride. There was obtained 7-chloro-1-methyl-2-methoxymethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride which product also was identical with the product obtained directly by reaction of N-methyl-N-(2-hydroxy-3-benzoylaminopropyl)-4'-chloroaniline in phosphoroxychloride at 120° C. and subsequent reaction with sodium and methanol as disclosed in Examples 4 and 8 of application Ser. No. 355 986; m.p. 198°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[OH:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(O)c(C=O)c1
Solvent: CC(=O)O
Product: COc1cc(C=O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a solution of 5-methoxysalicylaldehyde (22.52 g; 148 mmol) in acetic acid (120 ml) was added dropwise over 1 hour a mixture of fuming nitric acid (7.1 ml) in acetic acid (25 ml). After complete addition the mixture was stirred at room temperature for 5 hours. The precipitate was removed by filtration, washed with ethanol and dried to give the title compound (20.3 g, 69%) as a bright yellow solid.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[NH:34][C:35](=[O:43])OC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:35]([NH:34][C:27]3[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[F:25])=[O:43])[CH:11]=2)[C:35]([NH:34][C:27]2[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:43])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Nc1c(F)cc(F)cc1F)Oc1ccccc1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1c(F)cc(F)cc1F)N(Cc1cccc(CN(C(=O)Nc2c(F)cc(F)cc2F)C2CCCCCC2)c1)C1CCCCCC1
Yield: 64.1 %

Procedure:
A mixture of 0.82 g N,N'-dicycloheptyl-m-xylylenediamine, 1.26 g phenyl 2,4,6-trifluorophenylcarbamate and 50 ml toluene was heated under reflux for one hour. After cooling, the reaction mixture was washed twice with 50 ml of 1N-NaOH solution and then with sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure from the dried solution, and the residue was recrystallized from acetone, giving 1.02 g of 1,3-bis[[1-cycloheptyl-3-(2,4,6-trifluorophenyl)ureido]methyl]benzene.
Reaction SMILES: O.O.P([O-])(O)(O)=O.[Na+].[CH2:9]([O:16][C:17]1[C:18]([CH:27]=[O:28])=[CH:19][C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OO.Cl([O-])=[O:32].[Na+].Cl>C(OCC)(=O)C.O.C(#N)C>[CH2:9]([O:16][C:17]1[C:18]([C:27]([OH:32])=[O:28])=[CH:19][C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cc2c(cc1OCc1ccccc1)OCCO2
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=P([O-])(O)O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1cc2c(cc1OCc1ccccc1)OCCO2
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
A water (0.60 mL) solution of sodium dihydrogen phosphate dihydrate (0.50 g) was added to an acetonitrile (1.6 mL) suspension of the obtained 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (0.32 g), and a 30% hydrogen peroxide solution (0.20 mL) and a water (0.30 mL) solution of sodium chlorite (0.17 g) were sequentially added thereto under ice-cooling, followed by stirring at the same temperature for 15 minutes and then at room temperature for 1 hour and 30 minutes. The reaction mixture was adjusted to a pH of 1.4 with 1 mol/L hydrochloric acid, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.34 g of 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(Cc2ccc(N)c(N)c2)CC1

Procedure:
1-(3,4-dinitrobenzyl)-4-methylpiperazine (1 g) was dissolved in DMF:MeOH (1:1, 20 mil) and agitated with 10% Pd/C (50 mg) under an atmosphere of H2 for 6 hours. The mixture was then filtered and evaporated to give a dark solid which was used immediately without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30]([OH:32])=O)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.Cl.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[F:56][C:57]([F:61])([F:60])[CH2:58][NH:59][C:30]([CH:28]1[CH2:29][N:26]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH2:12][C:11]([C:17]4[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=4)([C:13]([F:15])([F:16])[F:14])[O:10][N:9]=3)=[CH:7][C:2]=2[Cl:1])[CH2:27]1)=[O:32]
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
To a stirred solution of 1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.190 mmol) in dry DMF (3 mL) was added EDCl.HCl (0.055 g, 0.280 mmol), DIPEA (0.049 g, 0.380 mmol) and 2,2,2-trifluoro-ethylamine hydrochloride (0.026 g, 0.190 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL), white solid was precipitated out, and solid was filtered, dried. Solid was purified by preparative TLC to afford off white solid (0.045 g, 41%). 1H-NMR (400 MHz, CDCl3) δ: 3.38-3.42 (m, 1H), 3.60 (d, 1H, J=17.08 Hz), 3.93-4.03 (m, 3H), 4.26-4.36 (m, 4H), 5.95 (t, 1H), 6.49 (d, 1H, J=8.52 Hz), 7.42 (dd, 1H, J1=8.56 Hz, J2=1.88 Hz), 7.47 (d, 1H, J=1.84 Hz), 7.62 (s, 2H); LC-MS (m/z): [M−H] 605.40.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[OH:24][CH2:25][C:26]1[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:10]([O:24][CH2:25][C:26]1[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1[nH]cccc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
At RT, 0.65 g (9.59 mmol) of imidazole, 2.42 g (8.79 mmol) of t-butyldiphenylchlorosilane and 0.10 g (0.80 mmol) of DMAP are added to 1.00 g (7.99 mmol) of the compound from Example 2A in 19 ml of DMF, and the mixture is stirred for 18 h. 180 ml of water are then added, and the mixture is kept at 0° C. for 3 h. After filtration, the residue obtained is purified by chromatography on silica gel (ethyl acetate/ethyldimethylamine 1000:1). This gives 801 mg (27% of theory) of the desired compound.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:17][O:18]C(=O)C)[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=O)C.N>Cl.C(O)C.O1CCCC1>[OH:4][CH2:5][CH:6]([CH2:17][OH:18])[CH2:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(CCC(COC(C)=O)COC(C)=O)OCC
Agent: Cl
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(CO)CO)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
Diethyl 4-acetoxy-3-(acetoxymethyl)butylphosphonate (4.6 g, 14.18 mmol) was dissolved in hydrochloric acid/ethanol solution (14 ml, 2.2M) and the reaction mixture was stirred at 80° C. for 90 minutes. It was then cooled to 5° C., neutralized with aqueous ammonia solution and diluted with tetrahydrofuran. The resulting ammonium hydrochloride was filtered off, washed with tetrahydrofuran and the combined filtrates concentrated to an oil which was chromatographed on silica gel (eluting with 94:6 CHCl3 :EtOH) to give the title compound (2.1 g, 62%). 1H NMR δH ](CD3)2SO] 1.22 (6H, t, 7=7Hz, (OCH2CH3)2), 1.46 (3H, m, CH2CH) 1.72 (2H, m, PCH2), 3.35 (4H, m, 2xH2OH), 3.5-3.75 (2H, br.s, D2O exchangeable, 2xOH), 3.96 (4H, m, (OCH2CH3)2). Found: C,44.79: H,8.93%. C9H21O5P 0.2 H2O requires: C,44.43; H,8.86.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@H:31]([N:33]([CH3:38])[C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@H:31]([N:33]([CH3:38])[C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: ClCc1ccccn1
Reactant: C[C@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Agent: Cl
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 8 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide to give the title compound in 8% yield; NMR spectrum (DMSO-d6) 1.19 (d, 3H), 2.79 (s, 3H), 3.87-4.26 (m, 3H), 4.38-4.48 (m, 2H), 5.11-5.22 (m, 1H), 5.29 (s, 2H), 7.18-7.25 (m, 2H), 7.32-7.38 (m, 2H), 7.48 (d, 1H), 7.58 (d, 1H), 7.72 (t, 1H), 7.87 (t, 1H), 7.94 (d, 1H), 8.44 (s, 1H), 8.59 (d, 1H), 9.58 (s, 1H); Mass spectrum MH+ 508.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][CH:15]=[C:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=5[CH:19]=4)[N:17]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C([Si](C)(C)[O:37][CH2:38][CH:39]=O)(C)(C)C.Cl>O1CCOCC1>[CH3:28][C:24]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]2[CH:19]=[C:18]([C:16]3[N:17]=[C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH:4]5[CH2:5][CH2:6][N:1]([CH2:39][CH2:38][OH:37])[CH2:2][CH2:3]5)[CH2:8][CH2:9]4)[S:14][CH:15]=3)[CH:27]=[CH:26][C:25]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(C5CCNCC5)CC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(C5CCN(CCO)CC5)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 50 mg (0.11 mmol) of 1-piperidin-4-yl-4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine and 24 mg (0.13 mmol) of (tertbutyldimethylsilanyloxy)acetaldehyde. The protecting group was cleaved off as already described using a 4N HCl solution in dioxane. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=1.[H-].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(F)c(O)cc1F
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
To a mixture of 4-amino-2,5-difluorophenol (100 mg, 0.64 mmol), and 4-chloropicolinamide (110 mg, 0.71 mmol) in DMF (2 mL) was added NaH (80 mg, 1.3 mmol, 60% dispersed in mineral oil). The reaction mixture was microwaved at 120° C. for 1.5 hours, then cooled to rt, diluted with water (20 mL), and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (80 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography with (EtOAc/PE (v/v)=4/1) to afford the title compound as a brown solid (52 mg, 26%).