Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[NH:19][C@H:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:17]2[C:16](=[O:32])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1.CI.O>CN(C)C=O>[CH3:1][N:19]1[C@H:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:17]2[C:16](=[O:32])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=2)[C:10]1=[O:9]
Reactant: CC(C)[N-]C(C)C
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.8 M in tetrahydrofuran, 62 μL, 0.11 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL). Methyl iodide (8 μL, 0.13 mmol) is added and the mixture is stirred for 1 h. Water is added and the mixture is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 20 mg; ESI mass spectrum [M+H]+=504; Retention time HPLC: 1.04 min (Z017_S04).
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[N:6][C:7]=1[Cl:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 34 from 3-nitro-2,5,6-trichloropyridine (Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59,190. ) and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[Br:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Br-:14].[CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][N+:9]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)SC1=NCCN12
Reactant: BrCCc1ccccc1
Solvent: CC#N
Product: Cc1ccc2c(c1)SC1=[N+](CCc3ccccc3)CCN12
Product: [Br-]

Procedure:
A mixture of 3.8 parts of 2,3-dihydro-7-methylimidazo[2,1-b]benzothiazole, 11 parts of (2-bromoethyl)benzene and 40 parts of acetonitrile is stirred and refluxed for 8 hours. After cooling, the precipitated product is filtered off and dried, yielding 6 parts of 2,3-dihydro-7-methyl-1-(2-phenylethyl)imidazo[2,1-b]benzothiazolium bromide; mp. 150.6° C.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:23].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Product: O=C(N=c1ccn(-c2ccccc2)nc1)c1ccccc1
Yield: 37 %

Procedure:
6.0 (28.9 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 50 ml of benzoyl chloride were kept at 120° C. for 10 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from isopropanol. 3.3 g (37% of theory) of 4-benzoylimino-1,4-dihydro-1-phenylpyridazine hydrochloride were isolated as pale beige crystals of melting point 225°-226° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[OH-].[K+].[NH2:14]OS(O)(=O)=O>CN(C)C=O>[NH2:14][N:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: NOS(=O)(=O)O
Reactant: COc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc2c1ccn2N
Temperature: 20 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a mixture of 4-methoxyindole (1.26 g, 8.57 mmol), powdered potassium hydroxide (10.05 g, 0.179 mol) and dry dimethylformamide (20 mL) at 15° C. under argon was added, portionwise over 0.2 h, hydroxylamine-O-sulfonic acid. Internal temperature was kept ≦30° C. by external ice bath cooling. The mixture was stirred at 20° C. for 4 h, then was extracted with toluene (4×50 mL). The combined extracts were washed with water (4×50 mL) and brine (50 mL), then dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography of the residue on silica with 5-50% ether in hexane gradient elution gave 1-amino-4-methoxyindole (0.79 g, 56%). A mixture of 1-amino-4-methoxyindole (0.78 g, 4.8 mmol), nitrobenzene (3.4 g, 27.8 mmol), and methanolic HCl (3% w/w, 180 mL) was heated at reflux for 76 h, then cooled and partitioned between 10% aqueous NaOH (50 mL) and dichloromethane (3×30 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by chromatography on silica with 5-100% ether in hexane gradient elution. The resulting 5-methoxycinnoline (0.56 g, 3.5 mmol) was mixed with 48% aqueous HBr (35 mL) and the resulting solution heated at reflux for 18 h. The mixture was cooled, then evaporated in vacuo, and the residue dissolved in water (10 mL). Aqueous ammonia (d=0.880) was added until pH 6 was obtained, and the resulting mixture cooled to 0° C. The precipitated solid was collected by filtration and purified by charcoal-methanol treatment to give the title compound (0.37 g, 53%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl>O.CCO>[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1/[CH:17]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:11])[CH:4]=1)=[O:10]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2cccc(Cl)c2Cl)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a mixture of 1-(4-hydroxy-3-methylphenyl)ethanone (0.7 g, 4.66 mmol) (ICC, Indofine Chemical Company Inc.) and NaOH (0.36 g, 9.1 mmol) in 10 mL of 200 proof EtOH was added 2,3-dichlorobenzaldehyde (0.8 g, 4.66 mmol) (ACROS). The reaction mixture was stirred at rt for 18 h. Upon completion by LC/MS, 5 mL of H2O was added and the reaction mixture was acidified with conc. HCl to pH 5-6. The resulting precipitate was filtered, washed with water and dried to yield (E)-3-(2,3-dichlorophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one, (0.45 g, 31%). MS (EI) for C16H12C2O2, 308.3 (MH+).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[CH2:16][S:15][CH:14]2[N:11]([C:12](=[O:27])[CH:13]2[NH:17]C(=O)CC2C=CC=CC=2)[C:10]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:8][C:9]1[CH2:16][S:15][CH:14]2[N:11]([C:12](=[O:27])[CH:13]2[NH:17][C:3](=[O:4])[C:2]([Cl:7])([Cl:6])[Cl:1])[C:10]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:33])[Cl:34])=[O:29]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)C2SC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(Cl)(Cl)Cl)C2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trichloroacetyl chloride (1.04 cc.) is added, over the course of 30 minutes and with vigorous stirring, to a solution, cooled to -10°C, of 3-methyl-8-oxo-7-phenylacetamido-2-trichloroethoxycarbonyl-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (1.38 g) in pyridine (15 cc.). Thereafter, the mixture is stirred for 2 hours 30 minutes at a temperature of between -3° and -1°C. The mixture is then poured into water and crushed ice (100 cc.) and a maroon paste-like product settles out. After removing the liquid phase by decanting, this product is triturated in water (50 cc.) and is then taken up in ethyl acetate (200 cc.). The organic phase is washed with water (3 times 200 cc.), dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (12 mm Hg) at 30°C. The solid obtained is dissolved in benzene (20 cc.) and the solution obtained is chromatographed on a column of silica gel (20 g) (0.05-0.20 mm, pH neutral; diameter of the column: 1.5 cm, height: 20 cm). Elution is carried out successively with benzene (300 cc.), a mixture of benzene and ethyl acetate (99.5/0.5 by volume) (300 cc.) and a mixture of benzene and ethyl acetate (99/1 by volume) (600 cc.), collecting 25 cc. fractions. Fractions 6 to 36 are combined and concentrated to dryness under reduced pressure (12 mm Hg) at 30°C. 3-methyl-8-oxo-7-trichloroacetamido-2-trichloroethoxycarbonyl-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (450 mg) is obtained in the form of a light maroon solid, the characteristics of which are as Follows:RF = 0.63 [silica gel; chloroform/ethyl acetate (80/20 by volume)]
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[N:7]([CH:15]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12]O)[CH2:10][CH2:9]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+].C(Br)(Br)(Br)Br>CO>[N:37]([CH2:12][C@H:11]1[O:14][C@@H:8]([N:7]2[CH:15]=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])[CH2:9][CH2:10]1)=[N+:38]=[N-:39]
Reactant: CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCc1cn([C@H]2CC[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.8 %

Procedure:
A mixture of 350 mg of 2',3'-dideoxy-5-ethyluridine, 391 mg of triphenylphosphine, 475 mg of sodium azide and 496 mg of carbon tetrabromide was stirred at room temperature for 20 hours. 3 ml of methanol were added, the mixture was stirred for 1 hour and then evaporated. The residue was suspended in 30 ml of water and extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed with 20 ml of water and then evaporated. The residue was subjected to flash chromatography on a column of silica gel using ethyl acetate for the elution. The product was crystallized from a mixture of ethyl acetate and hexane to give 200 mg of 5'-azido-2',3',5'-trideoxy-5ethyluridine in the form of a white solid which was processed directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:32][CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: NCc1cccc(Cl)c1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)NCc2cccc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (17 mg, 0.054 mmol) and (3-chlorophenyl)methanamine (8.34 mg, 0.059 mmol) in THF (268 μL) was added PyBroP (27.5 mg, 0.059 mmol), DIEA (28.1 μL, 0.161 mmol) and HOBT (9.02 mg, 0.059 mmol). The reaction mixture was stirred overnight at room temperature. All volatile material was removed in vacuo and dissolved in DCM. The crude product dissolved in DCM was loaded to flash chromatography column (gradient EtOAc in heptane) providing 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(3-chlorobenzyl)-2-fluorobenzamide in 87% yield. LCMS (m/z): 441.1 (MH+), 0.79 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.74 (m, 1H), 7.63 (m, 2H), 7.35 (m, 4H), 6.14 (s, 1H), 4.48 (m, 2H), 3.92 (m, 2H), 3.43 (m, 2H), 1.73 (m, 4H).
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:4][CH:3]([N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11])[C:2]#[CH:1]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)N1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a solution of but-3-yn-2-ol (13.3 g, 0.19 mol), phthalimide (28.5 g, 0.19 mol) and triphenylphosphine (76.0 g, 0.28 mol) in tetrahydrofuran was added diethyl azodicarboxylate (123.8 g, 0.28 mol, 310 mL of 40% toluene solution) drop wise at room temperature. The reaction mixture was stirred for 16 h. Solvent was removed and the residue was treated with 600 mL mixture of ether and hexane (1:1). The precipitate was filtered off and the filtrate was concentrated to give 90 g of the crude. The crude was then purified on silica gel eluting with 15% ethyl acetate in hexane to give 24 g of the title compound as a white solid (63% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.72 (d, J=6.99 Hz, 3H) 2.35 (d, J=2.21 Hz, 1H) 5.22 (dt, J=14.34, 7.35, 2.57 Hz, 1H) 7.68-7.78 (m, 2H) 7.82-7.90 (m, 2H), MS (ESI), M/Z: 200.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH2:32][CH3:33])[CH:24]=2)=[CH:18][C:17]=1[CH3:35].C(O)(=O)C>CC(N(C)C)=O>[CH3:30][O:29][C:26]1[N:27]=[N:28][C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:35])[CH:18]=2)=[CH:24][C:25]=1[C:31]1[NH:4][C:3]2[C:2]([C:32]=1[CH3:33])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCC(=O)c1cc(-c2cc(C)c(O)c(C)c2)nnc1OC
Reactant: Nc1ccccc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1C
Temperature: 140 °C

Procedure:
73.4 μl of 2-chloroaniline and 21 mg of anhydrous magnesium sulfate are suspended in 3 ml dimethylacetamide. 100 mg of 1-[6-(4-Hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-propan-1-one and 31.4 mg acetic acid are added and the reaction is degassed with argon. 96 mg of tripotassium phosphate and 35.7 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 16 h. The solution is filtered. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 35 mg.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[C:20]([F:23])(F)[F:21].C1COCC1>C(Cl)Cl>[F:21][C:20]1([F:23])[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate 11B (280 mg, 1.16 mmol), Nat (112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF (10 mL). The tube was sealed, and then the mixture was stirred at 80° C. overnight. The resulting mixture was diluted with DCM, filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which was used for next step without further purification. LC-MS: m/z 292.3 (M+H)+
Reaction SMILES: Cl.[OH-:2].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11]>CC(C)=O.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:2])=[O:11]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C(=O)O
Reaction time: 1 h

Procedure:
2.5 g of hydrochloride were dissolved in 25 ml of acetone and 0.8 g of NaOH in 20 ml of water. To this solution, there were added 2 g of 5-chloro-2-methoxy-benzoyl chloride in 20 ml of acetone and the whole was stirred for 1 hour. Then, water and dilute hydrochloric acid were added and the product was recrystallized from methanol. The 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-5-chloro-2-methoxy-benzoic acid so obtained was found to melt at 171°-173° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:9][C:8](=O)[CH2:7][CH2:6][CH2:5][C:4]([CH3:12])([CH3:11])[P:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][C:22]([CH:28]([CH3:30])[CH3:29])=[CH:21][C:20]=1[CH:31]([CH3:33])[CH3:32].C(O)COCCO.O.NN.[OH-].[K+]>>[CH3:34][C:2]1([CH3:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([CH3:11])([CH3:12])[P:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([CH:31]([CH3:32])[CH3:33])=[CH:21][C:22]([CH:28]([CH3:30])[CH3:29])=[CH:23][C:24]=1[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCC(=O)CC2(C)C)c(C(C)C)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCCCC2(C)C)c(C(C)C)c1
Temperature: 210 °C
Reaction time: 7 h
Yield: 41.1 %

Procedure:
A round bottom flask was charged with 2,2,8,8-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphocan-4-one (1.25 g, 2.61 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Nitrogen-sparged diethylene glycol (13.7 mL, 144 mmol, 55 equiv) was added, and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The mixture was charged with hydrazine hydrate (1.16 mL, 13.1 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (733 mg, 13.1 mmol, 5 equiv). The mixture was immersed in an oil bath at 160° C. under a nitrogen atmosphere. The temperature of the bath was gradually increased to 210° C. over 30 minutes and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen overnight. The Claisen adapter was washed with ethyl acetate (30 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with ethyl acetate (3×20 mL), and the combined organic fractions were washed once with water (50 mL) and aqueous saturated sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The purified product was triturated from hot methanol and collected by filtration to afford the title compound as a white solid (499 mg, 92 area % by HPLC, 41% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-7.87 (m, 1H), 7.33-7.26 (m, 2H), 7.23-7.17 (m, 1H), 6.97 (s, 2H), 3.00-2.85 (m, 1H), 2.61-2.44 (m, 2H), 1.91-1.61 (m, 5H), 1.61-1.41 (m, 5H), 1.39 (d, J=2.5 Hz, 6H), 1.31 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.8 Hz, 6H), 0.98 (d, J=6.7 Hz, 6H), 0.74 (d, J=15.0 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.2 (d, J=35 Hz), 147.1, 145.8, 137.3, 136.8 (d, J=8 Hz), 136.6 (d, J=21 Hz), 132.0 (d, J=7 Hz), 126.9, 124.6, 119.8, 43.8 (d, J=18 Hz), 36.3 (d, J=30 Hz), 34.3, 31.1, 31.0 (d, J=18 Hz), 28.3 (d, J=4 Hz), 26.8 (d, J=11 Hz), 26.7, 24.4, 23.1 (d, J=2 Hz), 22.4 (d, J=6 Hz). 31P NMR (CDCl3, 202 MHz) δ ppm 10.5 (s). HRMS (TOF-ESI+) calcd for [M, C32H49P]+ 464.3572. Found 464.3584.
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:29].[Na+].Br[CH2:32][CH2:33][CH2:34][N:35]=[C:36]=[O:37]>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:35]([CH2:34][CH2:33][CH2:32][I:29])[C:36]2=[O:37])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=NCCCBr
Reactant: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3CCCI)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 21, step 3) was reacted with sodium iodide and 3-bromopropylisocyanate to give the title compound as a light yellow foam. MS: 610.6 ([M+H]+)
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][OH:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][O:28][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(CO)CC3)c2-c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-methanol (Example 1, Compound E, 2.0 g) in dichloromethane (30 mL) is added sequentially pyridine (0.60 mL), methanesulfonyl chloride (0.55 mL), and 4-dimethylaminopyridine (0.06 g) at 0° C. under a nitrogen atmosphere. The mixture is stirred at 0° C. for 30 minutes and is warmed to room temperature. The mixture is stirred at room temperature for four hours and is then diluted with dichloromethane (30 mL.) The mixture is washed 0.5 N hydrochloric acid solution and with brine solution. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography to afford the synthetic intermediate methanesulfonic acid 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropylmethyl ester (2.35 g.)
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7](C(O)=O)=[CH:8][NH:9]2)=[CH:4][C:3]=1[CH3:16].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCCC>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]=[CH:8][NH:9]2)=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc2c(=O)c(C(=O)O)c[nH]c2cc1I
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc2c(=O)cc[nH]c2cc1I
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
Under vigorous stirring, 7-iodo-6-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (6.50 g, 19.8 mmol) was added portionwise to Dowtherm® A (120 mL) at 250° C., then the mixture was stirred for another 90 min. After cooling, heptane (170 mL) was added, and the precipitate was collected by filtration. The crude material was triturated in hexane/ethyl acetate (1:1) to afford the title compound (5.12 g, 91%). Off-white solid, ISP-MS: m/e=286.1 ([M+H]+).