Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[C:33]([O:35]C)[CH:32]=[CH:31][C:12]=3[C:13]=2[C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3].C(S)C>C(Cl)CCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:12]=3[C:13]=2[C:14](=[O:30])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)oc2cc(O)ccc12
Reaction time: 0.33 h

Procedure:
The title product was prepared by the demethylation of 2-(4-methoxyphenyl)-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-6-methoxybenzofuran, the product of Preparation 1a, supra. In a 250 ml three-neck round bottom flask were combined ethylene chloride (50 ml) and aluminum trichloride (9.60 g, 72 mmol) and ethanethiol (6.39 g, 103 mmol) to create a pale yellow liquid. To this liquid was then added the product of Example 1a(5.00 g, 10.3 mmol) in a gradual fashion. A red oil precipitated and the mixture was stirred for about 20 minutes. After cooling the reaction mixture in an ice bath 100 ml of tetrahydrofuran was added and the mixture was allowed to stir until all of the oil had gone into solution.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH:18]([C:23](C(OCC)=O)=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-:40].[Na+].Cl>CO>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH:18]([C:23]([OH:24])=[O:40])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)C(=O)OCC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of N-Cbz-L-Leu-L-Leu-DL-Nle-CO2Et (1.0 eq), as prepared in Example 5, in methanol at R.T. is added 1N NaOH (1.1 eq). The mixture is stirred for 6 h. The reaction mixture is cooled to 0° C., acidified with 1N HCl (pH=3) and extracted with EA. The organic extracts are washed with water, dried (MgSO4), filtered and concentrated to give a crude residue. Trituration with hexane and drying in vacuo gives the title compound, N-Cbz-L-Leu-L-Leu-DL-Nle-CO2H.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.ClCCl>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:16][C:17]=1[C:24]([F:25])([F:26])[F:27])[CH3:23]
Reactant: CCOc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F

Procedure:
N-Boc-(R)-2-(4-ethoxy-3-trifluoromethylbenzyl)morpholine, intermediate (a), was dissolved in TFA, (20% v/v solution in dichloromethane, 1.2 mL total) over 3 hrs. The reaction mixture was poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield the desired morpholine, example 10 as a yellow oil (17 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([NH:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: NCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)NCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-hydroxy-acetic acid and phenethylamine.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24].[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:23]#[N:24])[CH2:2][CH2:3][N:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (9.298 g, 38.4 mmol) and 2-chlorophenylacetonitrile (5.0 g, 32.0 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (2.82 g, 70.4 mmol) at 60° C. (7 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H2O (2×50 ml), and saturated aqueous NaCl (50 ml), dried (Na2SO4) and concentrated in vacuo. Trituration of the residue with 100% MeOH afforded 4-(2-chlorophenyl)-4-cyano-N-(1,1-dimethylethoxy) carbonyl piperidine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24]C(C)(C)C)=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
At room temperature, tert-butyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinate (1.4 g, 2.76 mmol) was dissolved in dichloromethane (20 mL). To the resulted solution, trifluoroacetic acid (20 mL) and triethylsilane (0.5 mL) were added. The resulted mixture was heated to 50° C. and stirred for 16 hours. The solvent was removed under reduced pressure, and water (50 mL) and ethyl acetate (70 mL) were added. The resulted mixture was separated and the organic phase was removed. The aqueous layer was filtered and the solid was washed with water (30 mL×2). The solid was dried under vacuum to give the title compound (1.1 g, purity 97%, yield 90%) as a light green solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1([CH3:28])[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])[C:15]=2[O:14]1>C(Cl)Cl>[CH:8]1([C:6]2[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:21]3[C:15]4[O:14][C:13]([CH3:28])([CH3:12])[CH2:17][C:16]=4[CH:18]=[CH:19][CH:20]=3)(=[O:23])=[O:24])=[O:27])[N:7]=2)[CH2:10][CH2:9]1
Reactant: Cc1cc(C2CC2)nc(N)n1
Reactant: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2O1
Solvent: ClCCl
Product: Cc1cc(C2CC2)nc(NC(=O)NS(=O)(=O)c2cccc3c2OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.47 g of 2-amino-4-cyclopropyl-6-methylpyrimidine in 15 ml of methylene chloride is added one g of the sulfonyl isocyanate prepared in Example 4. After stirring at room temperature overnight, the suspension is concentratd in vacuo, and the residue is triturated with 1-chlorobutane and filtered to give the subject compound.
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.C(O)C>O>[C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 123.2 %

Procedure:
The obtained phthalimide compound (13.7 g) and hydrazine monohydrate (2.5 g) are added to ethanol (34 ml) and the mixture is refluxed with stirring for 2 hours. After cooling, a small amount of water is added to the reaction mixture and the solvent is distilled off under reduced pressure. Chloroform (200 ml) is added to the residue and the insoluble substances are filtered off and washed twice with chloroform (each 50 ml). The filtrate and the washings are combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated to give the desired compound (12 g). Mass spectrum m/z: 320 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]3[N:21]=[CH:22][C:23]([CH:24]=O)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:19][CH2:20]3)[N:13]3[N:21]=[CH:22][C:23](/[CH:24]=[C:32]4/[C:30](=[O:31])[NH:29][C:27](=[O:28])[NH:26]/4)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NCC3CC3)cc(Nc3ccc(F)c(Cl)c3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NCC4CC4)cc(Nc4ccc(F)c(Cl)c4)nc23)N1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To 5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.09 mmol) in 1.0 mL of ethanol was added hydantoin (9 mg, 0.09 mmol) and piperidine (8 ul). The reaction was heated at 80° C. overnight, cooled to room temperature, filtered, and washed with ethanol to yield 20 mg (31% yield) (Z)-5-((5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino) pyrazolo[1,5-a]pyrimidin-3-yl) methylene)imidazolidine-2,4-dione as a yellow powder. LCMS (M+1=442)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17](O)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([O:32][Si](C)(C)C)=[C:29]([CH3:31])[CH3:30]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:29]([CH3:31])([CH3:30])[C:28]([O:27][CH3:26])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a stirred solution of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylethanol (290 mg, 0.87 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.7 mL, 3.5 mmol) in anhydrous dichloromethane (5 mL) was added titanium(IV) tetrachloride (1M solution in toluene, 1.9 mL, 1.9 mmol) dropwise at 0° C. under argon. The reaction mixture was stirred at 0° C. for 30 min and rt for 2 hr before being quenched by the slow addition of saturated aqueous sodium bicarbonate solution (15 mL). The mixture was filtered through a pad of celite that was then washed with dichloromethane (10 mL). The aqueous filtrate was reextracted with dichloromethane (10 mL). The combined dichloromethane layers were dried (Na2SO4), concentrated and purified by silica gel flash chromatography to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoate (216 mg, 0.52 mmol, 60% yield) as an oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[C@H:17]([CH3:21])[CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: C[C@@H]1CN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1S(=O)(=O)c1cccs1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A 100 mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-1-piperazinyl)phenyl)-2-propanol (0.950 g, 2.78 mmol), 5 mL of CH2Cl2, 2-thiophenesulfonyl chloride (0.583 g, 3.19 mmol, Sigma-Aldrich, St. Louis, Mo.), and triethylamine (0.580 mL, 4.16 mmol). After 1 h at room temperature, 0.010 g of DMAP was added. After an additional 30 min, the mixture was concentrated and purified via column chromatography (80 g of silica, 0 to 40% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.425 g) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ=7.70-7.46 (m, 4H), 7.12 (dd, J=3.7, 4.9 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 4.30 (m, 1H), 3.83 (td, J=3.0, 13.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.54-3.38 (m, 2H), 3.31 (s, 1H), 3.07 (dd, J=3.5, 12.3 Hz, 1H), 2.95 (dt, J=3.6, 11.6 Hz, 1H), 1.30 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 488.7 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.36 μM; GK-GKRP EC50 (LC MS/MS)=2.57 μM.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:17](=[O:33])[C:16]=1[C:34]#[N:35]>C1(C)C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[CH2:2][CH2:3]3)=[C:16]([C:34]#[N:35])[C:17]2=[O:33])=[CH:31][CH:30]=1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Solvent: Cc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 120 °C
Yield: 96.8 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (234 mg, 1.19 mmol) was added to a solution of Compound 8 (170 mg, 0.54 mmol) in toluene (40 mL) and heated overnight at 120° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered to yield 247 mg (97%) of white solids. M.P. 258° C. 1H NMR (DMSO-d6): δ 3.69 (m, 4H), 3.94 (m, 4H), 5.47 (s, 2H), 7.16 (m, 3H), 7.28 (m, 3H), 7.43 (d, J=8.5 Hz, 1H), 7.50 (d, J=3.3 Hz, 1H), 7.64 (t, J=7.25, 2H), 7.81 (d, J=4.8 Hz, 1H) 7.95 (d, J=7.5 Hz, 1H). EIMS m/z 473 (M+1), 495 (M+23). Anal. (C26H21FN4O2S) C, H, N.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=1.[CH3:11][C:12]1([CH3:25])[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2OC)=[N:14][CH2:13]1>O1CCCC1>[CH3:11][C:12]1([CH3:25])[O:16][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=2)=[N:14][CH2:13]1
Reactant: Cc1ccc(Br)cc1F
Reactant: COc1ccccc1C1=NCC(C)(C)O1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C2=NCC(C)(C)O2)cc1F
Reaction time: 2 h

Procedure:
14.7 g (605.7 mol) of magnesium filings are initially introduced into 50 ml of analytical grade tetrahydrofuran under argon, and 117.7 g (623 mmol) of 4-bromo-2-fluoro-toluene in 500 ml of analytical grade tetrahydrofuran are added, while stirring. A clear solution forms at 35°-40° C. within 2 hours. A solution of 74.0 g (360.5 mmol) of the compound from Example II in 500 ml of analytical grade tetrahydrofuran is added dropwise at room temperature and the mixture is subsequently stirred at about 25° C. for 16 hours, initially with gentle cooling. The solvent is evaporated off and the crude product is subsequently rinsed in 600 ml of ethyl acetate and 800 ml of saturated ammonium chloride solution at 10° C., dried with sodium sulphate and evaporated in vacuo. For purification, the product is taken up in 600 ml of ether, any solid residue is filtered off with suction and the crude product is extracted into the aqueous phase by several extractions with 2M hydrochloric acid. This aqueous phase is covered with a layer of ether and brought to pH 13 with sodium hydroxide solution. After three extractions with ether, the product phase is dried with sodium sulphate and evaporated and the residual solvent is removed under a high vacuum.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][CH:9]1[CH2:14][NH:13][CH2:12][CH:11]([CH3:15])[NH:10]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:7][C:4]1[S:3][C:2]([N:13]2[CH2:12][CH:11]([CH3:15])[NH:10][CH:9]([CH3:8])[CH2:14]2)=[N:6][CH:5]=1
Reactant: CC1CNCC(C)N1
Reactant: Brc1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2ncc(Br)s2)CC(C)N1
Temperature: 60 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
A mixture of 2,5-dibromothiazole (29.5 g), 2,6-dimethyl piperazine (13.8 g), potassium carbonate (20.1 g) and dimethylformamide (150 mL) was stirred at 60° C. for 6 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound (21.5 g). Yield: 64%.
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:10][CH2:9][CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CCCCCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCOCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Into a reaction vessel, 3.29 g (22.5 mmol) of 2-hexyloxyethanol and 5.33 g (67.5 mmol) of pyridine were charged, and 4.72 g (24.7 mmol) of p-toluenesulfonic acid chloride was added thereto in an ice bath, which were then stirred for 1 hour and thereafter further stirred at room temperature for 3 hours. After the reaction was completed, 3N HCl was added to make the reaction mixture acidic, followed by extraction with toluene twice. The extract obtained was washed with water, and thereafter sodium sulfuric anhydride was added to effect drying. After the solvent was evaporated off, the resultant mixture was purified by silica gel chromatography (eluting solvent: toluene/ethyl acetate=10/1) to obtain 6.45 g (21.5 mmol) of 2-hexyloxyethyl p-toluenesulfonate. Yield: 95%.
Reaction SMILES: [Mg].Cl[C:3]1([F:18])[C:7]([F:9])(Cl)[O:6][C:5]([C:14]([F:17])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])[O:4]1>BrBr.O1CCCC1>[F:9][C:7]1[O:6][C:5]([C:14]([F:15])([F:16])[F:17])([C:10]([F:11])([F:13])[F:12])[O:4][C:3]=1[F:18]
Reactant: FC(F)(F)C1(C(F)(F)F)OC(F)(Cl)C(F)(Cl)O1
Agent: BrBr
Agent: [Mg]
Solvent: C1CCOC1
Product: FC1=C(F)OC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 28 °C
Yield: 57.2 %

Procedure:
A solution of bromine (3 g) and tetrahydrofuran (30 mL) was slowly added to a well stirred mixture of magnesium turnings (25 g) and tetrahydrofuran (365 mL) at 20° C. After the exothermic reaction stopped, the reaction mixture was cooled to 28° C. and 133 g of the 4,5-dichloro-perfluoro-2,2-dimethyl-1,3-dioxolane (89.9% trans and 10.1% cis) was slowly added. After an induction period an exothermic reaction was observed. The reaction mixture was distilled to remove all material boiling up to 65° C. The distillate was washed with ice water to give 58.9 g perfluoro-2,2-dimethyl-1,3-dioxole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(4-chlorophenyl)-2-(4-(methylsulfonamido)-1H-indazol-1-yl)butanoate (500 mg, 1.19 mmol) in dry THF (8 mL) was treated by NaH (95 mg, 2.38 mmol, 60% in oil) at 0° C. for 30 min, then was added (2-(chloromethoxy)ethyl)trimethylsilane (295 mg, 1.78 mmol) dropwise. The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=6/1) to afford the title compound as a pale yellow solid. LC/MS m/z=551.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:26])[CH:17]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:10][N:8]([CH3:9])[C:7]1[CH:6]=[CH:5][C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:26])[CH:17]=3)[N:12]=2)=[CH:3][C:2]=1[NH:1][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c(N)c3)n2)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c(NS(C)(=O)=O)c3)n2)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
Methyl 4-{5-[3-amino-4-(dimethylamino)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate was taken up in Pyridine (750 μL) and mesylchloride (40 μL; 0.46 mmol) was added and stirred at RT for 72 h. After the time, the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (DCM:MeOH from 100:0 to 90:10) to give the title compound as a yellow powder (150 mg; 88%, 2 steps). 1H NMR (DMSO-d6, 300 MHz) δ 9.07 (bs, 1H), 8.13-8.08 (m, 1H), 8.04-7.91 (m, 4H), 7.23 (d, J=8.7 Hz, 1H), 3.90 (s, 3H), 3.14 (s, 3H), 2.88 (s, 6H). LC/MS (Method B): 435.3 (M+H)+. HPLC (Method A) Rt. 4.33 min (purity: 94.4%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1.Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27].[H-].[Na+]>CN(C=O)C>[Cl:22][C:21]1[C:16]([S:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=3[N:6]=2)=[C:17]([C:26](=[O:28])[CH3:27])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(C(F)(F)F)ccc2s1
Yield: 86.6 %

Procedure:
The title compound was prepared using the method of example 258, starting with 5-trifluoromethyl-benzothiazole-2-thiol (239) (470 mg, 2.0 mmol), 1-(2,3-dichloro-5-nitro-phenyl)-ethanone (248) (466 mg, 2.0 mmol) and NaH (Aldrich, 60% suspension, 80 mg, 2.0 mmol) in DMF (20 mL). Compound 259 (750 mg, 87%) was obtained as a yellow solid.