Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16]([NH:18][CH:19](P(OC)(OC)=O)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)=O.C(=O)=O.CN(C)C(N(C)C)=N>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6](/[CH:7]=[C:19](\[NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])/[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:9]=1
Reactant: COP(=O)(OC)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CN(C)C(=N)N(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N/C(=C\c1cc(Br)ccc1F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.0 g (30 mmol) of 5-bromo-2-fluorobenzaldehyde and 12.7 g (34 mmol) of benzyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate are introduced into 90 ml of THF and, while cooling with acetone/dry ice at −78° C., 3.91 g (34 mmol) of 1,1,3,3-tetramethylguanidine are added. After 4 h in the cold bath, the mixture is slowly warmed to RT and stirred at RT for a further 12 h. The solvent is distilled off in vacuo, and the crude product is taken up in ethyl acetate and washed once each with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The crude product is purified by chromatography (silica gel, cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[N:14][CH:13]([N:29]2C(=O)C3=CC=CC=C3C2=O)[C:12]1=[O:40].O.NN.C(OCC)(=O)C>C1COCC1>[NH2:29][CH:13]1[N:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:12]1=[O:40]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1nc2ccccc2s1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2nc3ccccc3s2)C1=O
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a suspension of (3RS)-1-(benzothiazol-2-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.30 g) in THF (50 ml) was added dropwise hydrazine monohydrate (0.12 g) under stirring at ambient temperature. The mixture was stirred for 2 hours at the same temperature and refluxed under stirring for 2 hours. The reaction mixture was cooled in an ice-bath. The resultant precipitates were filtered off atad washed with THF (30 ml). The filtrate and washing were combined and concentrated in vacuo to afford a crude product. The product was dissolved into ethyl acetate (150 ml) and extracted with 1N-HCl aqueous solution (3×25 ml). The aqueous layer was alkalined with sodium bicarbonate and extracted with ethyl acetate (2×100 ml). The extracts were dried over magnesium sulfate and filtered off by filtration. The filtrate was concentrated in vacuo to afford (3RS)-3-amino-1-(benzo-thiazol-2-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzo-diazepin-2-one as a colorless crystalline solid (110 mg). The compound was allowed to use in a next reaction step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11]C)[N:7]([CH3:13])[C@H:6]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:5]21[CH3:18].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[N:7]([CH3:13])[C@H:6]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:5]21[CH3:18]
Reactant: COc1cc2c(cc1Br)[C@]1(C)CCN(C)[C@@H]1N2C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CC[C@@]2(C)c3cc(Br)c(O)cc3N(C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-(±)-5-Bromo-1,2,3,3a,8,8a-hexahydro-6-methoxy-1,3a,8-trimethylpyrrolo[2,3-b]indole (11 g) was dissolved in dry DCM (200 ml) and added dropwise at 0° C to a stirred solution of BBr3 in DCM (300 ml). The mixture was warmed to room temperature and stirred overnight under nitrogen. The mixture was quenched with aq. Na2CO3 and aq. NaHCO3 until basic at 0° C. The organic layer was dried and evaporated to a foam (10 g). The IR, NMR and Mass Spectra confumed the purity and identity of this product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:21]([CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:21]([CH:26]3[CH2:27][CH2:28][N:29]([C:32](=[O:34])[CH3:33])[CH2:30][CH2:31]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.16 g, 0.67 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (0.1 g, 0.45 mmol), and cesium carbonate (0.22 g, 0.67 mmol) in DMSO (1.5 mL) was heated at 80° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 5% MeOH in EtOAc, to provide 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as off-white solid. MS (ESI, pos. ion) m/z: 442.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>C(#N)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(C=O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-3-methyl-benzaldehyde 52 (0.50 g, 3.67 mmol) is dissolved in 10 mL acetonitrile. Cesium carbonate (2.07 g, 6.35 mmol) and methyl bromoacetate (0.40 mL, 4.35 mmol) are added and the suspension is vigorously stirred at room temperature overnight. The suspension is poured into 1N aqueous HCl and extracted with EtOAc. Drying over MgSO4, filtration and concentration yielded (4-formyl-2-methyl-phenoxy)-acetic acid methyl ester 53: 1H-NMR (400 MHz, CDCl3) δ=9.86 (s, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.68 (dd, J=8.4, 1.6 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 2.34 (s, 3H). MS calculated for C11H13O4 (M+H+) 209.0, found 209.0.
Reaction SMILES: [Na+].[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2ncccc2N1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(C2=NS(=O)(=O)c3ncccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.9 %

Procedure:
The crude (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid sodium salt (˜0.928 mmol), (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.27 g, 0.928 mmol) and 047-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.494 g, 1.3 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (2 mL). The mixture was stirred at 25° C. for 1.5 h. Triethylamine (0.697 mL, 5 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with ethyl acetate (˜15 mL) and the product solidified. The solid was collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.03 g, 0.064 mmol, 6.9%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.92-1.05 (2H, m), 1.18-1.46 (4H, m), 2.26 (1H, d, J=3.1 Hz), 2.36 (1H, d, J=9.5 Hz), 2.45 (1H, d, J=3.0 Hz), 3.15 (1H, d, J=9.4 Hz), 4.13 (1H, d, J=15.6 Hz), 4.86 (1H, d, J=15.6 Hz), 7.01-7.05 (2H, m), 7.16-7.20 (2H, m), 7.39-7.42 (1H, m), 7.50 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 8.26 (1H, dd, J1=4.6 Hz, J2=1.5 Hz). LC-MS (ESI) calcd for C23H21FN4O4S 468.13, found 469.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[F:11][C:12]([F:14])([F:13])[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[OH:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.25 h
Yield: 117.9 %

Procedure:
2,4-Difluorobenzaldehyde (1.1 mL, 10.0 mmol) and (trifluoromethyl)trimethylsilane (1.77 mL, 12.0 mmol) were dissolved in THF (25 mL) and then cooled to 0° C. To this, 1M TBAF in THF (76 μL, 76 μmol) was added and the reaction mixture was allowed to warm to room temperature. After 3.25 h, 2.5M HCl (25 mL) was added. The reaction was stirred for 1 h and then extracted with ether. The organic layer was washed with brine and dried with Na2SO4. The solvent was removed under the reduced pressure to give 2,2,2-trifluoro-1-(2,4-difluoro-phenyl)ethanol (2.5 g) as a racemic mixture.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: CCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (700 mg, 2.48 mmol), 4-cyanobenzohydrazide (439 mg, 2.73 mmol) and anhydrous THF (20 mL) were placed in a 50 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (335 mg, 2.48 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (589 mg, 3.07 mmol) at −15° C. followed by triethylamine (0.43 mL, 3.07 mmol). The reaction mixture was maintained −15° C. and stirred for 1 h, after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h, the mixture was filtered under vacuum and the residue washed with THF (30 mL). The THF solution was concentrated to ca. 10 mL, whereupon EtOAc (200 mL) was added followed by extraction with 5% citric acid (3×100 mL). The phases were partitioned and the organic phase washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to furnish a light yellow solid (920 mg, 87% yield). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.80 (br s, 2H), 8.09 (d, J=8.6 Hz, 2H), 7.94 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 5.65 (d, J=6.7 Hz, 1H), 4.76 (br s, 1H), 4.43-4.35 (m, 1H), 4.15 (dd, J=3.7 Hz, 6.7 Hz, 1H), 2.94-2.79 (m, 2H) 1.38 (d, J=6.8 Hz, 3H) and 1.18 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C#N)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Fluoro-4-hydroxybenzonitrile (5.00 g, 36.5 mmoles) and allyl bromide (3.47 mL, 40.1 mmoles) in anhydrous DMF (40 mL) were treated with K2CO3 (10.0 g, 72.9 mmoles) and stirred overnight at 80° C. Reaction mixture cooled and diluted with ethyl acetate, washed with H2O (2×) and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound with no further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][Br:22]
Reactant: Cc1cccc(Cl)c1OCC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)COc1c(Cl)cccc1CBr

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-3-chlorotoluene (2.4 g, 11 mmol) from Step 1 above in CCl4 (40 mL) was added NBS (2.1 g, 11 mmol) and AIBN (1.8 g, 11 mmol). The mixture was refluxed for 8 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using hexanes as eluant. 2-(2,2,2-trifluoroethoxy)-3-chlorobenzyl bromide was obtained as an oil (HPLC retention time=22.3 min (method D)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:24])([CH2:21][CH:22]=[O:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:28])C.[OH-].[Na+]>[N+]([O-])([O-])=O.[Ag+].O>[CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:24])([CH2:21][C:22]([OH:28])=[O:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC=O)O2
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)O)O2
Reaction time: 2 h

Procedure:
To a solution of 6.09 g. of (±)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetaldehyde in 280 ml. of ethanol was added a solution of 3.57 g. of silver nitrate in 42 ml. of H2O followed, dropwise over 0.5 hour, by a solution of 3.49 g. of sodium hydroxide in 100 ml. of H2O. The mixture was stirred at 23° for 2.0 hours, filtered, concentrated in vacuo, diluted with H2O, and extracted with ether. The aqueous solution was acidified with 1 N HCl and again extracted with ether. These latter extracts were washed with brine, dried over magnesium sulfate and stripped of solvents to give (±)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][C:43]1([O:46][C:47](=[O:49])[CH3:48])[CH2:45][CH2:44]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[C:47]([O:46][C:43]1([CH2:42][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:20][C:21]([C:23]5[C:24](=[O:36])[N:25]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:26]([CH3:29])[C:27]=5[CH3:28])=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:45][CH2:44]1)(=[O:49])[CH3:48]
Reactant: CC(=O)OC1(COS(C)(=O)=O)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OC1(COc2ccc3c(Oc4ccc(NC(=O)c5c(C)n(C)n(-c6ccccc6)c5=O)cc4F)ccnc3c2)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
To a mixture of compound N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-di-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (342 mg, 0.708 mmol) and (1-acetoxycyclopropyl)methyl methanesulfonate (1.77 mmol) in 5 mL of DMA was added Cs2CO3 (2.8 g, 8.85 mmol). After stirring at 40° C. for 1 day, the reaction mixture was concentrated in vacuo and the residue was chromatographed on a silica gel column (50:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a white solid (110 mg, 26%).
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:19]([P:1]([OH:2])[OH:3])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C=CCCCCCCCCCCCCCC
Reactant: O=[PH2]O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCP(O)O
Yield: 87.5 %

Procedure:
Example 6 is repeated with 66 g (0.5 mol) of phosphinic acid, 114.5 g (0.5 mol) of hexadecene, 23 mg of tris(dibenzylideneacetone)dipalladium and 32 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 500 g of tetrahydrofuran, passed through a column charged with Deloxan® THP II for purification and freed of solvent in a rotary evaporator. The residue is admixed with 500 g of completely ion-free water and stirred, and then filtered and the residue is washed with cold water and acetone to obtain 127 g (81% of theory) of hexadecylphosphonous acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([C:27]1[N:26]2[C:21]([CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[CH:22][CH:23]=[CH:24][C:25]2=[N:29][CH:28]=1)=[O:33]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2nccn12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 55 %

Procedure:
To a solution of 3.15 g (7.22 mmol) of 5-[N-tert-butoxycarbonyl-N-[3-(trifluoromethanesulfonamido)propan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 2.65 g (21.65 mmol) of 4-dimethylaminopyridine in 30 ml of chloroform was added dropwise, while stirring at room temperature for 3 minutes, 2.4 ml (21.65 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 15 hours under reflux. After completion of the reaction, the reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The solution was extracted with 150 ml of chloroform. The organic layer was washed with 250 ml of a saturated aqueous saline solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.31 g of the desired compound (54.8%, pale yellow liquid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC1CCCN(C)C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC1CCCN(C)C1
Yield: 91 %

Procedure:
A mixture of 6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)-3,4-dihydroquinazolin-4-one (2.72 g, 8.9 mmol), thionyl chloride (90 ml) and DMF (0.5 ml) was stirred and heated to reflux for 45 minutes. The mixture was evaporated and the residue was azeotroped with toluene. The residue was taken up in water and basified to pH8 by the addition of a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate (4×400 ml). The combined organic extracts were washed in turn with a saturated aqueous sodium hydrogen carbonate solution, water and brine, dried (MgSO4) and evaporated. The residue was dried overnight at 40° C. under vacuum to give 4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline (2.62 g, 91%) as a solid; NMR: (DMSOd6) 1.1 (m, 1H), 1.42-1.96 (m, 5H), 2.09 (m, 1H), 2.15 (s, 3H), 2.6 (d, 1H), 2.8 (d, 1H), 3.98 (s, 3H), 4.1 (d, 2H), 7.35 (s, 1H), 7.42 (s, 1H), 8.84 (s, 1H); Mass: M+H+ 322.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.N[C@@H](CCN1CC(OC2C=CC([F:48])=CC=2)C1)CO>>[F:48][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(F)cc2)C1
Reactant: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Product: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(F)cc2)C1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 83 except using (S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-ol in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.