Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:11]([N:14]([CH2:27][CH2:28][CH3:29])[S:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:12][CH3:13]>>[CH2:27]([N:14]([CH2:11][CH2:12][CH3:13])[S:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:28][CH3:29]
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: NC1CCc2ccccc21
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)NC2CCc3ccccc32)cc1
Yield: 63 %

Procedure:
The title compound was prepared in 63% yield from (rac)-1-aminoindan (10.0 g, 75.2 mmole) and 4-(di-n-propylsulfamoyl) benzoyl chloride (16.3 g, 53.6 mmole, prepared from probenecid and SOCl2) via a procedure analogous to that described in Ex. 46, followed by crystallization from hexane:EtOAc, mp: 124-5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[Br:24])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=O.[CH3:25][NH2:26]>C1COCC1>[CH3:25][NH:26][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=2[Br:24])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: COC(=O)c1nc(Cc2cc(C(F)(F)F)ccc2Br)[nH]c(=O)c1O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Cc2cc(C(F)(F)F)ccc2Br)[nH]c(=O)c1O
Yield: 53 %

Procedure:
The compound was prepared according to the same procedure as in Example 21 using 2-(2-bromo-5-trifluoromethyl-benzyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.080 g; 0.197 mmol) and 2M methylamine solution in THF (1 ml). This provided the title product as an off-white solid (0.043 g; 53%). LCMS: m/z=427 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].CCN(C(C)C)C(C)C.[CH2:19](Br)[O:20][CH3:21]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:19][O:20][CH3:21]
Reactant: COCBr
Reactant: Oc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(F)cc1F
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 2,4-difluorophenol (11.0 g, 85 mmol) and DIPEA (15.5 mL, 89 mmol) in DCM (150 ml) at 0° C. under nitrogen was added MOM-Br (7.33 mL, 89 mmol) over 1 hr and the reaction mixture then maintained at RT for 16 hr. The resulting mixture was washed successively with water, aq 2M NaOH solution, water and brine, and was then dried (MgSO4) and evaporated in vacuo to afford 2,4-difluoro-1-(methoxymethoxy)benzene as a colourless oil (13.7 g, 88% yield). Rt 3.17 min (Method 1, basic, no ionization observed), which was used directly in the next step (below).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]#[CH:8])(=O)=O.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:16]1([C:22]2[CH2:27][CH2:26][N:25]([CH2:8][CH2:7][C:6]#[CH:5])[CH2:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCN1CC=C(c2ccccc2)CC1

Procedure:
A solution of 3-butynyl tosylate (25.0 g, 0.11 mol), 4-phenyl-1,2,3,6-tetrahydropyridine (21.8 g, 0.11 mol) and sodium bicarbonate (10.3 g, 0.12 mol) in 300 mL of dimethylformamide is heated at 80° C. for 18 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 200 mL of dichloromethane and 200 mL of water. The aqueous layer is extracted with 100 mL of dichloromethane and the combined organic layers are dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 25% ethyl acetate/75% hexane) to give the title compound as a yellow solid; mp 36.5°-37.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[N:8]([CH:11]([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)=[C:9]=[O:10]>ClCCl>[CH:11]([NH:8][C:9]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:10])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Product: O=C1CN(C(=O)NC(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of piperazin-2-one (100 mg, 1 mmol) was added (isocyanatomethylene)dibenzene (209 mg, 1 mmol) in dichloromethane (5 mL). The solution was stirred for 2 hours at room temperature and concentrated in vacuo. The residue was diluted with EtOAc and then washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (2:98 MeOH/DCM) to give desired compound N-benzhydryl-3-oxopiperazine-1-carboxamide (Compound 1) (232 mg, 75%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[OH:31].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][N:18]([CH3:20])[C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:31][C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[F:21])[CH:8]=2)=[O:12])[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Temperature: 190 °C
Yield: 70.5 %

Procedure:
A mixture of the amide 24 (1.44 g, 4.65 mmol), 2-fluoro-4-nitrophenol (2.21 g, 14.1 mmol) and K2CO3 (2.56 g, 18.5 mmol) in Ph2O (5.0 mL) was heated at 190° C. for 3 hrs. CHCl3 (100 mL) was added to the resultant dark brown mixture and then the mixture was extracted with 1M HCl. The aqueous phase was washed with CHCl3 and basified with NH4OH (pH 11). The resultant cloudy mixture was extracted with CHCl3 and the organic phase was collected, washed with water, dried over anhydrous Na2SO4 then concentrated under reduced pressure. The remaining yellow solid material was purified by flash chromatography, eluent CHCl3/MeOH (95:5, then 80:20) to afford title compound 25 as a white solid (1.41 g, 3.28 mmol, 71% yield). MS (m/z): 431.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[Cl:1])=[O:19]
Reactant: CCOC(=N)c1ccc(F)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccc(F)cc1Cl

Procedure:
starting from ethyl 2-chloro-4-fluorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2-chloro-4-fluorobenzimidate and therefrom with methylhydrazine there is obtained 3-(2-chloro-4-fluorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 67°-69° C.;
Reaction SMILES: [N+]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1)([O-])=O.[I:13]I>>[I:13][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1
Reactant: II
Reactant: O=[N+]([O-])c1n[nH]c2ccccc12
Product: Ic1n[nH]c2ccccc12

Procedure:
In step 1 of Scheme A, nitroindazole compound a is treated with iodine or iodine equivalent to form 3-iodo indazole compound b. The amine functionality at the 1-position may be protected (not shown) prior to carrying out this step, and then subsequently deprotected. In step 2 the iodoindazole b is reacted with aryl boronic acid c in the presence of suitable palladium catalyst to afford 3-aryl indazole d. Aryl boronic acid c may in certain embodiments be replaced with a corresponding heteroaryl boronic acid. In step 3 the nitro group on indazole compound d is reduced to yield amino-substituted indazole e. Indazole e in step 4 is then treated with arylsulfonyl chloride f to form the sulfonamide compound g, Compound g is a compound of formula Ia in accordance with the invention.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[Cl:19][CH:20]([F:23])[CH2:21]Cl>CO>[Cl:19][CH:20]([F:23])[CH2:21][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FC(Cl)CCl
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: CO
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1SCC(F)Cl
Reaction time: 24 h

Procedure:
A mixture of 217.8 g of the triethylamine salt of 2-mercaptophenylsulfonamide obtained in accordance with Example P6 and 101 g of 1,2-dichloro-1-fluoroethane in 950 ml of methanol is stirred in an autoclave for 24 hours at a temperature of from +65° C. to +70° C. and for a further 24 hours at from +95° C. to +100° C. The reaction mixture is then concentrated by evaporation and the residue is stirred with water. By extracting with ethyl acetate, washing with water, drying over sodium sulfate, concentrating by evaporation and purifying the residue by chromatography with methylene chloride, 99.5 g (49.2% of the theoretical yield) of 2-(2-chloro-2-fluoroethylthio)-phenylsulfonamide having a melting point of from +88° C. to +89° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH3:13])[C:3]=1[I:14].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:11])[CH3:10])=[C:4]([O:12][CH3:13])[C:3]=1[I:14]
Reactant: COc1c(C(C)=O)cc(Cl)c(Cl)c1I
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(Cl)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4,5-dichloro-3-iodo-2-methoxyphenyl)ethanone (4.1 g, 12 mmol) in methanol (59 mL) at 0° C. was treated with sodium tetrahydroborate (0.45 g, 12 mmol) and stirred at 0° C. for 1 h. The reaction mixture was quenched with water (50 mL) 0° C., and diluted with saturated sodium bicarbonate (50 mL) and ethyl acetate (100 mL). The aqueous layer was separated and extracted with additional ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL), dried with magnesium sulfate, filtered, and concentrated to give the desired product (quantitative). This material was used without further purification. LCMS for C9H8Cl2IO (M−OH)+: m/z=328.9, 330.9. Found: 328.9, 330.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH3:13])[N:3]=1.[CH3:31][OH:32]>C1COCC1>[CH3:31][O:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH3:13])[N:3]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc(Cl)c4ccccc4n3)CC2)cc1
Reactant: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc(OC)c4ccccc4n3)CC2)cc1
Temperature: 60 °C
Yield: 11.2 %

Procedure:
In a test tube containing of 4-Chloro-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (38.0 mg, 0.089 mmol) in THF (2 ml) was added MeOH (280.0 mg, 8.9 mmol). The reaction was heated at 60° C. for 0.5 hour. The solution was concentrated under reduced pressure. The residue was partitioned between water (2 ml) and dichloromethane (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was re-dissolvent in MeOH (2 ml) and purified by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 4-Methoxy-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (Yield 4.43 mg, 11.13%). MS m/z calc. 442.17, found (ESI); 443.4 (M+1)+. Retention time 2.40 minutes.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])[CH:15]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccnc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.6 %

Procedure:
A mixture of 4-nitro-phthalonitrile (3.46 g, 20 mmol), pyridin-3-ol (1.90 g, 20 mmol), K2CO3 (8.29 g, 60 mmol), and DMF (50 ml) was stirred at ambient temperature overnight. The reaction mixture was then combined with another batch of the same reaction performed on the same scale. Subsequently, the solid components were removed by filtration and the filtrate was concentrated in vacuo. To the residue was added water and the mixture was extracted with EtOAc. The organic phase was then washed with brine, dried, and evaporated in vacuo. The residue was recrystallized from EtOAc/MeOH to give 8.3 g of the title compound; 1H NMR (CDCl3): δ=8.56 to 8.59 (m, 1H), 8.45 to 8.47 (m, 1H), 7.76 (d, 1H), 7.42 to 7.44 (m, 2H), 7.22 to 7.32 (m, 2H).
Reaction SMILES: Cl.[CH:2]([NH:5][C@@H:6]([CH3:9])[CH2:7][OH:8])([CH3:4])[CH3:3].[C:10]1([CH2:16][C:17]([Cl:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[ClH:19].[CH:2]([NH:5][C@@H:6]([CH3:9])[CH2:7][O:8][C:17](=[O:18])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)N[C@@H](C)CO
Agent: Cl
Solvent: ClCCl
Product: CC(C)N[C@@H](C)COC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 10 g of (S)-2-isopropylamino-propan-1-ol hydrochloride in 300 ml of dichloromethane 10 ml of phenylacetic acid chloride are added. The reaction mixture is stirred at RT for about 15 h and then substantially concentrated under reduced pressure, and the highly viscous residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The resin-like residue is purified by silica gel chromatography, and the product fraction is separated off and concentrated. The residue is dissolved in 150 ml of 2-propanol and 25 ml 2 N HCl in water are added. The mixture is stirred for about 15 h and the resulting crystals are filtered off. This gives 10.9 g of the title compound. M. p. 114-118° C. (unsharp)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]2[O:20][C:21]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:22][C:18]=2[CH:17]=1>CO>[N:1]1([CH2:15][C:16]2[CH:28]=[CH:27][C:19]3[O:20][C:21]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:22][C:18]=3[CH:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Reactant: C1COCCN1
Solvent: CO
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc2cc(CN3CCOCC3)ccc2o1

Procedure:
A stirred solution of morpholine and triethylamine in methanol is treated with 5-bromomethyl-2-sulfamoylbenzo[b]furan to give the subject compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20].Cl>N1C=CC=CC=1>[CH3:17][N:18]([CH3:23])[S:19]([NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
To a solution of 1.0 g of 4-aminobenzanilide 4 dissolved in 10 ml of dried pyridine is added 1.01 g of dimethylaminosulfonyl chloride 5 at room temperature, and the mixture is stirred over-night. The reaction mixture is poured into ice-water, acidified with 6N hydrochloric acid, and extracted with a mixture of methylene chloride-methanol. The organic layer is extracted again with 10% sodium hydroxide solution. The alkaline layer is acidified with 6N hydrochloric acid; the precipitate is collected by filtration and recrystallized from methanol to give 864 mg of 4-[(dimethylaminosulfonyl)amino]benzanilide 6 as crystals, m.p. 213°-215° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([O:13][C:20](=[O:22])[CH3:21])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Solvent: c1ccncc1
Product: CCOC(=O)C1C(C(OC(C)=O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To 305 mg (0.944 mmol) of ethyl 2,2-dimethyl-3(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 2, 1 ml of pyridine and 1 ml of acetic anhydride, were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then purified by column chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 322 mg of ethyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3trifluoropropyl)cyclopropanecarboxylate (a mixture of two stereoisomers (55:45)) as a colorless oily substance.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:15][S:16]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 126.4 %

Procedure:
A round bottom flask was charged with 2-isopropoxyethanol (0.5 mL, 4.34 mmol) and dichloromethane (21.68 mL) and was cooled to 0° C. Triethylamine (1.208 mL, 8.67 mmol) was added along with a tip of DMAP. Methanesulfonyl chloride (0.338 mL, 4.34 mmol) was added dropwise. The reaction mixture was slowly warmed to rt over 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and transferred to a separatory funnel The aqueous layer was extracted with dichloromethane (2×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 2-Isopropoxyethyl methanesulfonate (1 g) was isolated as a clear oil and was immediately used in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].C([Li])CCC.C[O:16][C:17]1[CH2:21][CH2:20][C:19](=O)[CH:18]=1>C1COCC1>[Cl:9][C:3]1[CH:4]=[C:5]([C:19]2[CH2:20][CH2:21][C:17](=[O:16])[CH:18]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(I)cc1Cl
Reactant: COC1=CC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C=C(c2ccc(Cl)c(Cl)c2)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A solution of 1,2-dichloro-4-iodobenzene (1.0 g, 3.66 mmol) in THF (50 mL) at −78° C. was treated with a solution of n-butyllithium (2.5 M in hexanes; 1.5 mL, 3.8 mmol) such that the reaction temperature remained ≦−78° C. After 15 min, a solution of 3-methoxy-2-cyclopenten-1-one (0.452 g, 3.96 mmol) in THF (20 mL) was added such that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over 2 h, quenched with a solution of 1N HCl and concentrated in vacuo to remove THF. A solution of 1N HCl (5 mL) was added, the solution was stirred for 30 min and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc/Heptanes as the eluting solvent to afford 0.3 g of target compound as a white powder (Yield 36%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.58-2.62 (m, 2 H) 2.97-3.03 (m, 2 H) 6.56 (t, 1 H) 7.45-7.55 (m, 2 H) 7.71 (d, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6]([C:18]([OH:20])=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[C:28]#[N:29]>CN(C)C=O.ClCCl>[C:28]([C:23]1[CH:24]=[N:25][N:26]([CH3:27])[C:22]=1[NH:21][C:18]([C:6]1[C:7]2[S:11][C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20])#[N:29]
Reactant: COc1ccc(C(=O)O)c2sc(N3CCOCC3)nc12
Reactant: Cn1ncc(C#N)c1N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCOCC3)nc12
Yield: 11.4 %

Procedure:
Starting with 4-methoxy-2-(morpholin-4-yl)benzothiazole-7-carboxylic acid (0.13 g) oxalyl chloride (0.10 ml), dichloromethane (10 ml) and dimethylformamide (1 drop), followed by 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (0.11 g), sodium hexamethyldisilylamine (1.0M in tetrahydrofuran, 0.88 ml) and dichloromethane (10 ml). Purification by flash chromatography (eluent ethyl acetate) yielded the title compound as an off-white solid (0.02 g). TLC Rf 0.45 (ethyl acetate); Mpt 299-300° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([C:26]([OH:28])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=[O:13])=[O:12].C(N(C(C)C)C(C)C)C.O[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][O:27][C:26](=[O:28])[C@@H:15]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:41]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc2ccccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](COC(=O)[C@@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc3ccccc3c2)C1
Reaction time: 15 h
Yield: 66.7 %

Procedure:
A solution of 1.0 g of N-2-naphthylsulfonyl-(D)-tryptophan in 20 ml of DMF is treated with 0.5 ml of ethyldiisopropylamine. After the addition of 0.6 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate (Example 3c) and 1.1 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate the reaction mixture is stirred for 15 hours. The solvent is evaporated and the residue is taken up in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated. Chromatography over silica gel with ethyl acetate gives 1.0 g of N-(2-naphthylsulfonyl)-D-tryptophan (S)-l-t-butyoxycarbonyl-3-piperidinylmethyl ester.