Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1.C(NC(C)C)(C)C.[Li].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=[O:30]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)[OH:30])=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1
Reactant: Clc1ccnc(Oc2ccccc2Cl)n1
Reactant: O=Cc1cccs1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.13 h

Procedure:
4-Chloro-2-(2-chloro-phenoxy)-pyrimidine (432 mg, 1.79 mmol) was dissolved in 10 mL of dry THF, and the reaction mixture was cooled to −78° C. under nitrogen. Lithium diisopropylamine (1.6 mL of 2M solution in THF) was added and the reaction mixture was stirred for eight minutes. Thiophene-2-carboxaldehyde (0.31 mL) was added, and the reaction mixture was stirred for 30 minutes at −78° C. The reaction was quenched by addition of 10 mL saturated aqueous ammonium chloride, and evaporated under reduced pressure to remove THF. Water (40 mL) and EtOAc (60 mL) were added, the organic phase was collected, and the aqueous phase was washed twice with 40 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC using 1.8% MeOH in methylene chloride to yield 98 mg of [4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanol. Mass Spec. M+H=354.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24]C(OCC)=O)[CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[OH-].[Na+]>C(O)C.CCOCC>[NH2:24][C:20]1[CH:19]=[C:18]([CH:16]([CH3:17])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:30])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)Nc1cc(C(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(c1ccnc(N)c1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of the product of Example 19 (0.80 g) in ethanol (30 ml) containing 40% sodium hydroxide solution (2.0 ml) was heated under reflux for 2 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with ethyl acetate. The combined organic extracts were dried (MgSO4) and evaporated to give a gum. The gum was dissolved in ether and the title compound, (0.45 g), crystallised on standing, m.p. 182°-185°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[CH3:1][C:2]([O:26][CH:21]([C:10]1[N:11]([CH3:20])[C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:22]([O:24][CH3:25])=[O:23])([CH3:7])[CH3:3]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-hydroxyacetate (858 mg, 2.442 mmol) in t-butyl acetate (20 mL) was treated with perchloric acid (0.147 mL, 2.442 mmol) and stirred at ambient temperature overnight. LCMS indicated only 45% conversion to the desired product. The mixture was made basic by adding 3N sodium hydroxide and then extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-50% ethyl acetate/hexanes gradient) to afford the desired product as a colorless residue (383 mg, 39%). LC/MS (m/z) ES+=408 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:31])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][NH:20]C(=O)OCC3C=CC=CC=3)[CH2:15]2)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:20][CH2:19][C@@H:16]1[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:31])[CH2:15]1
Reactant: O=C(NC[C@@H]1CCN(CCn2c(=O)ccc3ccc(F)cc32)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CCN(CCn2c(=O)ccc3ccc(F)cc32)C1
Reaction time: 2.5 h

Procedure:
To a solution of phenylmethyl ({(3S)-1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-3-pyrrolidinyl}methyl)carbamate (820 mg, 1.94 mmol) in MeOH (30 mL) was added 5% palladium on carbon (200 mg, 50% by weight with water). The mixture was hydrogenated at 15 psi for 2.5 h, filtered through a pad of Celite®, and concentrated to give a clear oil which darkened and solidified on standing (555 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[Br:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH2:33]Br)[CH:24]=1>CS(C)=O>[Br:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH2:33][N:8]2[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]3[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]2=3)[CH:24]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Br)cc1CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
(R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (200 mg, 0.882 mmol) (PREPARATION x2, 200 mg, 0.882 mmol) was dissolved in DMSO (5 mL). Sodium tert-butoxide (102 mg, 1.059 mmol) was then added to give a brown solution. After 5 minutes, methyl 4-bromo-2-(bromomethyl)benzoate (299 mg, 0.971 mmol) was added dropwise. The reaction was stirred overnight at room temperature, then quenched with aqueous saturated NH4Cl. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white foam (164 mg, 41%). ESI-MS m/z [M+H]+ calc'd for C18H18BrClN4O3, 453.04. found 453.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: FCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(OCCF)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
Thirty grams of ethyl 3-hydroxybenzoate, 14.9 g of 1-fluoro-2-chloroethane and 37.4 g of anhydrous potassium carbonate were added to 130 ml of dimethylformamide. With stirring, the reaction was carried out at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 32.6 g of crude ethyl 3-(2-fluoroethoxy)benzoate. The resulting crude ethyl 3-(2-fluoroethoxy)benzoate (32.6 g) was added at 40° to 45° C. to a solution of 6.0 g of lithium aluminum hydride in 200 ml of dry tetrahydrofuran, and the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was cooled to room temperature. Ethanol and water in this order were added to the mixture to decompose the unreacted lithium aluminum hydride. Water was then added, and the mixture was extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was removed to give 26.0 g of crude 3-(2-fluoroethoxy)benzyl alcohol This compound was chlorinated to give 30.0 g of 3-(2-fluoroethoxy)benzyl chloride.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH:8]([OH:18])[CH:9]([OH:17])[CH2:10][S:11]([CH2:14][CH2:15]Cl)(=[O:13])=[O:12])(=[O:6])=[O:5].C(N(CC)CC)C>CC(C)=O>[CH:14]([S:11]([CH2:10][CH:9]([OH:17])[CH:8]([OH:18])[CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])(=[O:13])=[O:12])=[CH2:15]
Reactant: O=S(=O)(CCCl)CC(O)C(O)CS(=O)(=O)CCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CS(=O)(=O)CC(O)C(O)CS(=O)(=O)C=C
Yield: 84.7 %

Procedure:
11.4 g of 1,4-bis(chloroethylsulfonyl)-2,3-butanediol was dissolved in 300 ml of acetone and the same procedures as described in Synthesis Example 3 were followed using 6.8 g of triethylamine to obtain 7.6 g of white crystals.
Reaction SMILES: [C:1]([CH:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=O)[CH3:2].NC1NN=C(C2C=CC(OC3C=CC=CC=3)=CC=2)C=1C#N.NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C#N)=C3N=CC=2)C=CC=1.ClCCC(NC1C=C(C2[N:84]3[N:85]=[C:86]([C:91]4[CH:96]=[CH:95][C:94]([O:97][C:98]5[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=5)=[CH:93][CH:92]=4)[C:87]([C:88]([NH2:90])=[O:89])=[C:83]3[NH:82][CH2:81]C2)C=CC=1)=O>>[NH:6]1[CH2:5][CH:4]([CH:1]2[N:84]3[N:85]=[C:86]([C:91]4[CH:96]=[CH:95][C:94]([O:97][C:98]5[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=5)=[CH:93][CH:92]=4)[C:87]([C:88]([NH2:90])=[O:89])=[C:83]3[NH:82][CH2:81][CH2:2]2)[CH2:7]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2C1CNC1

Procedure:
The desired product was prepared from tert-butyl 3-acetylazetidine-1-carboxylate and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to the procedures for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to 5), compound 2 (step 1 and 2) and compound 38 (step 2), under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (DMSO-d6) δ 8.70 (br s, 1H), 8.44 (br s, 111), 7.50 (d, J=8.6 Hz, 2H), 7.45-7.40 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.4 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.72 (br s, 1H), 4.46-4.38 (m, 1H), 4.24-4.15 (m, 1H), 4.07-3.94 (m, 3H), 3.29-3.24 (m, 2H), 3.19-3.10 (m, 1H), 2.13-2.04 (m, 1H), 1.78-1.69 (m, 1H). MS (ESI) m/e [M+1]+ 390.0.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([CH2:18][P:19]([O:25]C(C)C)([O:21]C(C)C)=[O:20])=[CH:8][C@@H:9]([NH:15]C=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C(Cl)Cl.C[Si](C)(C)Br>C(O)C>[NH2:15][C@H:9]([CH:8]=[C:7]([CH2:18][P:19]([OH:25])([OH:21])=[O:20])[CH2:6][CH2:5][OH:4])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@@H](C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)[C@H](N)C=C(CCO)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
12.7 g (30.2 mmol) of ethyl 6-acetoxy-2(R)-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate are dissolved in 100 ml of abs. CH2Cl2 and 15.6 ml (120.8 mmol) of trimethylbromosilane are added to this solution at room temperature. The reaction mixture is allowed to stand for 24 hours at room temperature. After addition of 100 ml of abs. ethanol the reaction mixture is again allowed to stand for 24 hours at room temperature and then concentrated by evaporation. The residue is dissolved in ethanol and then a mixture of 100 ml of propylene oxide and 100 ml of ethanol is added dropwise. The suspension so obtained is stirred for 1 hour at 0° C. and then filtered with suction. The filter product is stirred overnight in ether and again filtered with suction. The filter product is dried, giving white crystals of ethyl 2(R)-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoate. Melting point: 170° C. (decomp.). ee=92%; αD =-45.6°± 1° (c=1.0 H2O).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5](=[O:20])[N:6]([CH:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]([O:11]C(C)(C)C)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5](=[O:20])[N:6]([CH:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CC(C)CC(C(=O)OC(C)(C)C)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
139 mg (purity 85%, 0.27 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 87 mg (84% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](F)[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=312.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 3,5-difluoro-pyridine.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:22])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:22][C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2ccccc21
Yield: 17.2 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-chloro-quinolin-8-yl)-benzenesulfonamide (Intermediate 295) (370 mg, 1.10 mmol), t-butyl nitrite (171 mg, 1.66 mmol), AcOH (3.7 ml) and THF (3.7 ml) gave the title compound (60 mg, 17%) after purification by column chromatography with n-hexane/DCM (1:1) as the eluent.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][S:7]([O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:9])=[O:8].[CH2:32]1[NH:37][C:35](=[O:36])[NH:34][CH2:33]1.S(=O)(=O)(O)O>O1CCCC1.O.C(OCC)(=O)C.CN(C)C=O>[CH3:6][S:7]([O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:13]([C:29]([N:34]2[CH2:33][CH2:32][NH:37][C:35]2=[O:36])=[O:31])[CH2:12]1)(=[O:8])=[O:9]
Reactant: O=C1NCCN1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
To a mixture of N,N-dimethylformamide (0.6 ml) and tetrahydrofuran (1.2 ml) was added dropwise phosphorus oxychloride (0.58 ml) at -5° C. and the mixture was stirred at 5° C. for 5 minutes. To the mixture was added a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)proline (2.0 g) in tetrahydrofuran (20 ml) under ice-cooling. The solution was stirred at the same temperature for 30 minutes. To a solution were added ethylene urea (2.22 g) and concentrated sulfuric acid (0.035 ml), and the mixture was stirred at 45°-50° C. for 3 hours. Ethyl acetate (100 ml) and water (40 ml) was poured into the reaction mixture. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (1.98 g).
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([Li])CCC.[O:17]1[CH:19]([CH3:20])[CH2:18]1.B(F)(F)F.CCOCC>C1COCC1>[OH:17][CH:19]([CH3:20])[CH2:18][C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCCCOS(=O)(=O)C1CC1
Reactant: CC1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1(CC(C)O)CC1
Reaction time: 0.5 h

Procedure:
A solution of butyl cyclopropanesulfonate 2 (1.2 g, 6.7 mmol) in THF (24 mL) was cooled to −78° C. and n-butyllithium (1.6M in n-hexane, 5.0 mL, 8.1 mmol) was added within 5 min. The mixture was stirred for 30 min and epoxypropane derivative 1 or 8 (8.1 mmol) was added followed by addition of boron trifluoride diethyl etherate (0.84 mL, 6.7 mmol). The solution was stirred for 1 h at −78° C., the cooling bath was removed and stirring was continued for 2 additional hours. For aqueous work-up diluted hydrochloric acid (10%, 0.8 mL), water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was is concentrated at 40° C. to afford the corresponding butyl 1-[2-hydroxypropyl]cyclopropanesulfonate 3.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:44]([F:47])([F:46])[F:45])[O:30][N:29]=[C:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([C:41]([NH2:43])=[O:42])=[CH:33][CH:32]=3)[CH2:27]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:44]([F:46])([F:45])[F:47])[O:30][N:29]=[C:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([C:41]([N:43]=[S:2]([CH3:4])[CH3:1])=[O:42])=[CH:33][CH:32]=3)[CH2:27]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: CS(C)=O
Reactant: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(C)=NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of dimethylsulfoxide (38 mg) in dichloromethane (1 mL) at −60° C. was added trifluoroacetic anhydride (105 mg). After the reaction mixture was stirred for 10 minutes at −60° C., a solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxamide (75 mg, in 1.5 mL of dichloromethane and 0.4 mL of dimethylsulfoxide) was added. The reaction mixture was allowed to warm to −20° C. over 1 h, then quenched with water and extracted with dichloromethane. The combined organic extract was washed with aqueous 1.0 N of NaOH and brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (98:2 to 95:5) as eluent to afford the title product, a compound of the present invention, as semi-solid (70 mg, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([O:10][CH3:11])[CH:3]=1.CO[CH:14]([O:17][CH3:18])[O:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][O:17][CH:14]([O:15][CH3:16])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=1[O:10][CH3:11]
Reactant: COC(OC)OC
Reactant: COc1cc(Br)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(Br)ccc1C(OC)OC

Procedure:
To a solution of 4-bromo-2-methoxybenzaldehyde (5.2 g, 24.2 mmol) in methanol (20 ml) and trimethylorthoformate (14 ml, 5.5 eq.) was added p-toluenesulfonic acid (46 mg, 0.01 eq.) and the mixture was refluxed for 3 hr. Potassium carbonate (125 mg, 0.03 eq.) and silicagel was added, the solvent was removed under reduced pressure and the solid residue packed into a loading column and purified by MPLC (hexanes-ethylacetate 40-80% gradient). MS (EI+): 262, 260 (1/1, M+, 10%); 231, 229 (1/1, 90%); 215, 213 (1/1, 10%); 199, 170, 150, 118, 92, 75, 45 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH:9]([CH2:15][C:16]2[O:20][N:19]=[C:18]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:28])[CH:9]([CH2:15][C:16]2[O:20][N:19]=[C:18]([O:21][C:22]([F:26])([F:27])[CH:23]([F:25])[F:24])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cc(OC(F)(F)C(F)F)no1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cc(OC(F)(F)C(F)F)no1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionate (1.402 g, 3.425 mmol) in methanol (30 ml) was added 1N aqueous sodium hydroxide solution (6.85 ml, 6.85 mmol), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was concentrated and diluted with water. The reaction solution was acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionic acid as a colorless liquid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:35][CH2:36][CH2:37][C:38](=[O:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C(CCCI)c1ccccc1
Reactant: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a solution of methyl 3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.12 g, 0.33 mmol) and potassium carbonate (0.091 g, 0.66 mmol) in N,N-dimethylformamide (3 mL), was added 4-iodo-1-phenylbutan-1-one (0.09 g, 0.33 mmol). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water and brine. The organic phase was dried over MgSO4, filtered, and isolated by Biotage flash chromatography (1-8% methanol/dichloromethane) to obtain the title compound (0.11 g, 65%); 1H NMR (DMSO-d6): δ 1.75 (d, 2H, J=10.8 Hz), 1.83 (t, 2H, J=7.2 Hz), 2.35-2.41 (m, 4H), 2.67-2.74 (m, 4H), 3.04 (t, 2H, J=7.2 Hz), 3.88 (s, 3H), 5.19 (s, 2H), 6.87 (t, 1H, J=7.6 Hz), 7.02 (d, 2H, J=8 Hz), 7.24 (t, 2H, J=8.4 Hz), 7.52 (t, 2H, J=7.2 Hz), 7.57-7.65 (m, 2H), 7.79 (dt, 1H, J=8 and 1.2 Hz), 7.90-7.99 (m, 3H), 8.58 (t, 1H, J=1.6 Hz); MS for C31H33N3O4 m/z 512.3 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CCO.O>[C:17]1([C:14]2[O:13][C:12]([CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:11][CH2:10]3)=[N:16][N:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CN1CCC(c2nnc(-c3ccccc3)o2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCC(c2nnc(-c3ccccc3)o2)CC1
Reaction time: 4 h

Procedure:
To a stirred solution of [4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-piperidin-1-yl]-acetic acid ethyl ester in EtOH was added NaOH (36.6 mg, 0.916 mmol, 2 eq) in water (0.421 mL). The mixture was stirred for 4 h and the cloudy suspension was treated dropwise with 2.3 mL of 1N HCl until pH ˜7. The solvent was evaporated in vacuo to yield the title compound in quantitative yield used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=7.58 Hz, 2H) 7.56-7.64 (m, 3H) 2.92-3.08 (m, 5H) 2.29-2.42 (m, 2H) 2.01-2.12 (m, 2H) 1.80-1.96 (m, 2H). MS (m/z, MH+): 288.3.