Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10]([Cl:12])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].[I-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(Cl)Cl>[ClH:12].[C:19]([NH:23][CH:10]1[CH2:11][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Reactant: CC(C)(C)N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Product: Cl
Reaction time: 3 h

Procedure:
A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.30 g), t-butylamine (1.24 ml), a catalytic amount of sodium iodide and 18-crown-6 in methylene chloride (3 ml) was refluxed for 47 hours and cooled. The solvent was removed off in vacuo, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. To the residue were added ethyl acetate (5 ml) and 3N hydrochloric acid (2 ml) with cooling in an ice bath, and the mixture was stirred for 3 hours. The precipitate was collected by filtration, washed with ethyl acetate, water, ethyl acetate successively and dried to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (0.28 g).
Reaction SMILES: Br[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].CCN(C(C)C)C(C)C>ClC1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[C:18]([C:19]([O:21][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:20])=[CH:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=1
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: O=C1C=C(Br)C2CCC1C2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C

Procedure:
A mixture of 27 g of a 6.2% solution of 4-bromobicyclo[3.2.1]oct-3-en-2-one (Preparation Example P1) in chlorobenzene, 110 mg of ZnCl2, 2.34 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid and 1.2 g of Hünig's base is stirred at room temperature under a nitrogen atmosphere until a dark-brown solution is formed. The reaction mixture is then maintained under moderate reflux for 19 hours in an oil bath, with stirring. The mixture is then divided into 2 portions. To one portion there are added a further 1.12 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid, 0.06 g of ZnCl2 and 0.6 g of Hünig's base. The reaction mixture is then maintained under moderate reflux for 12 hours in an oil bath, with stirring. The solution is then washed twice with 0.1M hydrochloric acid (20 ml each time) and twice with water (20 ml each time). After drying the organic solution using magnesium sulfate and concentrating in vacuo, 3.9 g of 4-(2-methoxyethoxymethyl-6-trifluoromethyl-pyridin-3-ylcarbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one are obtained in the form of a brown oil.
Reaction SMILES: [CH2:1]([C:4]1([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]#[N:26])=[CH:15][CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].NN.C1COCC1>CCO.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([C:4]1([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]#[N:26])=[CH:15][CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C=CCC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Agent: [Cu+2]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(5-allyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-3-carbonitrile (35 mg, 0.103 mmol) in EtOH (2 mL) at ambient temperature is added H2NNH2/THF (1.0 M, 15 mL, 15 mmol) and saturated aqueous CuSO4 (0.1 mL). The reaction mixture is stirred at ambient temperature overnight. The mixture is concentrated and dissolved in EtOAc, which is washed with water, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 342 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm (HCl salt) 0.95 (t, J=7.2 Hz, 3 H), 1.21-1.33 (m, 2 H), 1.80-1.90 (m, 2 H), 1.90-2.02 (m, 1 H), 2.09-2.37 (m, 3 H), 2.59-2.68 (m, 1 H), 2.71-2.85 (m, 1 H), 6.81-6.88 (m, 1 H), 6.90-6.98 (m, 2 H), 7.19-7.25 (m, 1 H), 7.27-7.39 (m, 3 H), 7.43 (d, J=1.8 Hz, 1 H), 7.71 (dd, J=8.3, 2.0 Hz, 1 H), 8.10-8.18 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.[CH3:40][N:41](C)[CH2:42]CCN=C=NCC.CNC>C(OCC)(=O)C.O1CCCC1.CN(C)C=O>[CH3:40][N:41]([CH3:42])[C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (70 mg), 1H-1,2,3-benzotriazol-1-ol (33 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (46 mg) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 2 hr. 2M tetrahydrofuran solution (0.25 mL) of dimethylamine was added to this solution, and the mixture was stirred at room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate), and the obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (53 mg, yield: 30%) as colorless crystals. MS: 463 (MH+). melting point 153-154° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH:7]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[Br:22])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OCc1cccc(COC(C)=O)c1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(Br)c(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.7 %

Procedure:
To a suspension of m-xylylene glycol diacetate (28.4 g) and sodium acetate (55.2 g) dispersed in glacial acetic acid (130 ml) was added dropwise bromine (102.5 g) over 30 min at 15-20° C., and the mixture was stirred at 20-30° C for 13 hr. The reaction mixture was poured into 10% aqueous sodium sulfite solution (700 ml) in an ice bath. The mixture was stirred and extracted twice with ethyl acetate (250 ml). The ethyl acetate layer was washed 3 times with 10% aqueous sodium hydrogencarbonate solution (300 ml) and the solvent was evaporated to give an about 93:7 mixture (37.6 g, 97.6%) of 2,4-bis(acetoxymethyl)bromobenzene and 2,6-bis(acetoxymethyl)bromobenzene as a yellow oil. 2,4-bis(Acetoxymethyl)bromobenzene was isolated by preparative HPLC and used in the measurement.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([O:18][CH3:19])[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[C:10]2[Cl:31].[CH3:32][N:33]1[C:37]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:45]=2)=[O:39])=[CH:36][N:35]=[CH:34]1.[NH4+].[Cl-].C1[CH2:56][O:55]CC1>O>[Cl:31][C:10]1[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:38]([C:37]3[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=3)([C:40]3[CH:41]=[N:42][C:43]([C:46]([F:48])([F:47])[F:49])=[CH:44][CH:45]=3)[OH:39])[CH:8]=2)[N:13]=[C:12]([O:18][CH3:19])[C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.[C:56]([OH:55])([C:27]([F:28])([F:29])[F:30])=[O:39]
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1-c1ccc(OC(F)(F)F)cc1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Product: COc1nc2c(C)cc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1-c1ccc(OC(F)(F)F)cc1
Product: O=C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.0 mL, 3.202 mmol) was added to a −78° C. mixture of 6-bromo-4-chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline (1.1 g, 2.463 mmol, Intermediate 58, step d) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (0.691 g, 2.709 mmol, Intermediate 15, step c) in dry THF (25 mL) over a 2 min period. After complete addition stirring was continued at −78° C. for 10 min then the reaction was warmed up to 0° C. and stirred for 1 hour. Saturated NH4Cl was added and the reaction mixture slowly warmed to room temperature. Water was added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts was dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (DCM/10% MeOH in EtOAc) to provide product. Further purification using reverse phase HPLC provided the TFA salt of the title compound. MS (ESI) 623.1
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[CH2:25]([O:32][C:33]([C:35]12[CH2:42][CH2:41][C:38](C=O)([CH2:39][CH2:40]1)[CH2:37][CH2:36]2)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+].[C:47](OCC)(=O)C>C1COCC1>[CH2:25]([O:32][C:33]([C@:35]12[CH2:42][CH2:41][C@@:38]([CH:47]=[CH:5][C:3]([O:2][CH3:1])=[O:4])([CH2:37][CH2:36]1)[CH2:39][CH2:40]2)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=CC12CCC(C(=O)OCc3ccccc3)(CC1)CC2
Reactant: CCOC(C)=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C=C[C@]12CC[C@@](C(=O)OCc3ccccc3)(CC1)CC2
Reaction time: 0.17 h

Procedure:
Methyl (triphenylphosphoranylidene) acetate (60.2 g, 173 mmol) is added to a stirred solution of 4-formylbicyclo[2.2.2]octane-1-carboxylic acid benzyl ester (XIX, Example 94, 33.5 g, 123.2 mmol) in THF (550 ml). This mixture is then heated to gently reflux for 16 hr. The reaction mixture is cooled to 20-25° and to this is added saturated ammonium chloride (75 ml) and stirred for 10 minutes. Ethyl acetate (250 ml) and isomeric hexanes (300 ml) are added and stirred for 10 minutes. The resulting mixture is filtered through a plug of silica gel (850 g) with a thin layer of celite on the top. The solid is washed with ethyl acetate/hexane (1/1, 250 ml). The filtrates are combined and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 7.24, 6.81, 5.59, 5.01, 3.63, 1.81 and 1.48.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH2:29].[OH2:30].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].O>C(#N)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:27])(=[O:30])=[O:29])[N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CSc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Reactant: O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(S(C)(=O)=O)n1
Yield: 89.9 %

Procedure:
A suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-4-yl]methyl}pyridin-2(1H)-one 0.28 g, 0.0006 mol), and magnesium monoperoxyphthalate hexahydrate 90.6 g, 0.0012 mol) in acetonitrile (8.0 ml) and water (2.0 ml) was stirred at room temperature for 16 h. The resulting clear solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and water (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to afford the title compound (0.27 g, 90%) as a pale yellow substance: 1H NMR (CD3OD/400 MHz) δ 8.91 (d, 1H, J=5.2 Hz), 7.63 (d over m, 2H, J=5.2 Hz), 7.03 (m, 2H), 6.58 (s, 1H), 5.54 (s, 2H), 5.33 (s, 2H), 3.28 (s, 3H), and 2.49 (s, 3H); 19F NMR (CD3OD/400 MHz) δ−111.58 (m), −115.98 (m);ES-HRMS m/z 500.0113 (M+H C19H17N3O4BrSF2 requires 500.0086).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[CH2:12][CH2:13][CH:14]=1.Cl>C1COCC1>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[CH2:15][N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:27])=[O:5])[C:10]1=[O:26]
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC=C(CCC(=O)O)C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
11 mg of LiOH.H2O solution (0.26 mmol) was added to 0.75 ml of THF solution containing 58 mg of 3-[1-(2,4-dimethoxy benzyl)-2-oxo-1,2,5,6-tetrahydro pyridine-3-yl]-propionic acid methyl ester (d) (0.17 mmol) in a dropwise manner at 0° C. After the reaction mixture was stirred for 2 hrs at 0° C. and for 1 hr at room temperature, 5% HCl was added to the mixture to pH 2. Then the mixture was extracted three times with 10 ml of ethyl acetate, the organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with methanol/chloroform (1:10) solvent mixture as an eluant to give 44 mg of the title compound (f1) (yield: 80%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[C:19]([S:27][CH2:28][CH2:29][OH:30])=[C:18]2[CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[C:19]([S:27][CH2:28][CH:29]=[O:30])=[C:18]2[CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:39][CH:40]=1
Reactant: COC(=O)C(C)(C)Cc1c(SCCO)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1c(SCC=O)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of oxalyl chloride (579 mg, 4.56 mmol) in CH2Cl2 (15 mL) at -70° C. there was slowly added DMSO (711 mg, 9.12 mmol). The mixture was stirred for 3 minutes, then at -70° C. there was slowly added a solution of the alcohol from Step 5 (1.7 g, 3.8 mmol) in CH2Cl2 (15 mL). The resulting mixture was stirred at -70° C. for 20 minutes, then there was slowly added Et3N (1.92 g, 19 mmol). The mixture was stirred in the cold for a further 5 minutes, then it was allowed to warm up to room temperature. After dilution with Et2O (200 mL) the mixture was washed twice with 1N HCl, then with H2O (3×), dried and evaporated to a residue which was chromatographed on silica gel, eluting with a 1:1 mixture of hexane and EtOAc, to afford the title compound as a thick oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]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.C(N(CC)CC)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 72.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid (143 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (75 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 24 h. At this time, the reaction was diluted with methylene chloride (5 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (133 mg, 72%) as a white solid: mp 170-172° C.; EI-HRMS m/e calcd for C21H24N2O2S (M+) 368.1558, found 368.1556.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].O.[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28]#[N:29])=[C:11]([CH3:30])[O:10][N:9]=1>CS(C)=O>[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28](=[N:2][OH:3])[NH2:29])=[C:11]([CH3:30])[O:10][N:9]=1
Reactant: NO
Reactant: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C(N)=NO
Temperature: 65 °C
Yield: 24 %

Procedure:
A neutral 2 M solution of hydroxylamine hydrochloride and NaOH in water (0.5 mL, 1.0 mmol) was added to 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (5.4 mg, 0.017 mmol) in DMSO (0.5 mL) and stirred at 65° C. over night. Crude LCMS on the reaction mixture show 41% product, 38% amide and 21% starting material. Purification using preparative HPLC gave E5 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carboximidamide (1.42 mg, 24%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 356.2 (M+H), 354.21 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.11 m 2H, 6.85 m 2H, 2.77 nm 2H, 2.11 s 3H, 1.88 s 3H, 1.75 m 2H, 0.98 t (7.5 Hz) 3H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[CH:23]=[N:22][CH:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:30][CH:29]=2)[C:32]1=[O:36])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(Cn2cncn2)cc1
Product: C[C@@H](n1ccn(-c2ccc(Cn3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 17).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[F:23])=[CH:7][C:3]=1[C:4](O)=[O:5].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.C(OC([N:50]1[CH2:55][CH2:54][CH:53]([S:56]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[N:71]=[CH:70][C:69]([NH2:72])=[CH:68][N:67]=3)=[CH:61][CH:60]=2)(=[O:58])=[O:57])[CH2:52][CH2:51]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=2[F:23])=[CH:7][C:3]=1[C:4]([NH:72][C:69]1[CH:70]=[N:71][C:66]([NH:65][C:62]2[CH:63]=[CH:64][C:59]([S:56]([CH:53]3[CH2:54][CH2:55][NH:50][CH2:51][CH2:52]3)(=[O:57])=[O:58])=[CH:60][CH:61]=2)=[N:67][CH:68]=1)=[O:5]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.7 %

Procedure:
Intermediate 18 (Example 26) (0.159 g, 0.44 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were diluted with DCM (4 mL) and treated with TFA (0.2 mL). After 2 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.017 g, 6%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[S:20]1[CH2:25][CH2:24][CH2:23][S:22][CH:21]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[H-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]([O:11][C:10]([NH:9][CH2:8][C:7]1[CH:17]=[C:3]([CH:4]=[CH:5][C:6]=1[O:18][CH3:19])[CH2:2][C:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:20][CH2:25][CH2:24][CH2:23][S:22]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1SCCCS1
Reactant: COc1ccc(CBr)cc1CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Cc2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)SCCCS1
Reaction time: 8 h

Procedure:
1.76 g of t-butyl N-[5-(bromomethyl)-2-methoxybenzyl]carbamate and 0.76 ml of ethyl 1,3-dithian-2-carboxylate were dissolved in anhydrous N,N-dimethylformamide. A solution of 220 mg of 60% sodium hydride in 18 ml of toluene was added under ice-cooling, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 1.70 g of the title compound from the 3:1 hexane-ethyl acetate fraction.