Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].C([Li])CCC.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>C1COCC1>[CH2:16]([O:15][C:14](=[O:18])[CH2:8][C:2]1[CH:3]=[CH:4][C:5]([CH3:7])=[CH:6][N:1]=1)[CH3:17]
Reactant: CCOC(=O)OCC
Reactant: Cc1ccc(C)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(C)cn1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-lutidine (540 mg, 5.05 mM) in 10 ml of THF at -10° C. was added 2.5M n-butyllithium solution (2.0 ml, 5.00 mM). The resulting mixture was stirred for 30 minutes while allowing the temperature to rise to 0° C. The reaction was cooled to -50° C. and diethyl carbonate (0.61 ml, 5.00 mM) was added and the reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4Cl solution and extracted into EtOAc. The resulting organic layer was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The residue was chromatographed on silica gel using 30% EtOAc/hexanes as the eluant to yield the title compound (43).
Reaction SMILES: N1C=CC=CC=1[C:7]1[C@@H:11]2[CH2:12][N:13]([C:15]3[C:24]([O:25][CH3:26])=[C:23]4[C:18]([C:19](=[O:33])[C:20]([C:30]([OH:32])=[O:31])=[CH:21][N:22]4[CH:27]4[CH2:29][CH2:28]4)=[CH:17][C:16]=3[F:34])[CH2:14][C@@H:10]2[O:9][N:8]=1.ON=C(Cl)[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:7]2[C@@H:11]3[CH2:12][N:13]([C:15]4[C:24]([O:25][CH3:26])=[C:23]5[C:18]([C:19](=[O:33])[C:20]([C:30]([OH:32])=[O:31])=[CH:21][N:22]5[CH:27]5[CH2:29][CH2:28]5)=[CH:17][C:16]=4[F:34])[CH2:14][C@@H:10]3[O:9][N:8]=2)[CH:39]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: COc1c(N2C[C@@H]3ON=C(c4ccccn4)[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: COc1c(N2C[C@@H]3ON=C(c4cccnc4)[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
The title compound was prepared in an analogous manner to acid 122, but using chloro oxime 2f. Acid 123 was isolated.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([Si:17]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=1)[CH3:16]>O1CCCC1>[OH:24][CH:23]([C:21]1[CH:22]=[C:18]([Si:17]([CH2:25][CH3:26])([CH2:15][CH3:16])[CH2:27][CH3:28])[O:19][CH:20]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dodecylmagnesium bromide (a 1M solution in tetrahydrofuran: 14.3 ml, 14.3 mmol) was added dropwise to a solution of 2-triethylsilyl-4-furaldehyde (2.0 g, 9.52 mmol) in THF (20 ml) at 0 degrees C under argon. After stirring at room temperature for 2 hours, the mixture was quenched with dilute HCl and extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 30% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=1)[CH:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:12][C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[CH:16]=[C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a mixture of 4-methoxyphenylboronic acid (1.57 g, 10.36 mmole) and tert-butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate (2.5 g, 8.6 mmole) in dichloromethane (75 mL) were added copper acetate (1.63 g, 8.6 mmole), triethyl amine (5.219 g, 51.6 mmol) and molecular sieves. The mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite pad. The filtrate was evaporated and purified by column chromatography to give the title compound (1.1 g, 32%). 1H NMR (500 MHz, CDCl3): δ ppm 7.26 (t, 1H), 6.99 (d, 2H), 6.89 (t, 3H), 6.79 (t, 2H), 6.29 (s, 1H), 3.80 (s, 3H), 3.48 (s, 2H), 3.38 (s, 2H), 2.42 (s, 2H), 2.29 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO.C(O)(=O)C.[Br:19]Br>>[Br:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[N:9]=[CH:8][NH:7][C:6]2=[O:12]
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2nc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
7-methylquinazolin-4(3H)-one (14.56 g, 91 mmol) was added to methanol (70 ml, 91 mmol) and glacial acetic acid (70 ml, 1212 mmol). The mixture was stirred at RT for 5 min followed by the slow addition of bromine (9.3 mL, 182 mmol). The reaction was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure and the resulting crude residue washed with aqueous sodium thiosulfate to remove excess bromine and HBr, then oven dried to give 6-bromo-7-methylquinazolin-4(3H)-one (18.35 g, 84% yield) as light yellow amorphous solid. MS (ESI, pos. ion) m/z: 239 [M+H]+
Reaction SMILES: [C:1]1(=[O:13])[O:10][C:8](=O)[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22]C)=[O:20])=[CH:17][CH:16]=1.CC1(C)CC(=O)OC(=O)C1>>[CH3:3][C:2]12[C:4]([CH3:5])([CH3:6])[CH:7]([CH2:11][CH2:12]1)[C:8](=[O:10])[N:14]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=1)[C:1]2=[O:13]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)C3CCC(C)(C2=O)C3(C)C)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and (+/−)-camphoric anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 333 (M+NH4)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15]>>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:4][CH2:3][CH2:2][O:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH:12]=[O:20]
Reactant: O=Cc1ccccc1O
Reactant: BrCCCOC1CCCCO1
Product: O=Cc1ccccc1OCCCOC1CCCCO1

Procedure:
By using 2-(3-bromopropoxy)tetrahydro-2H-pyran and salicylaldehyde, the title compound was obtained as colorless oil by similar procedures to those of Example 60b (yield: quantitative).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>ClC(Cl)C.C(N(CC)CC)C>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:14]=[O:15]
Reactant: COc1cccc(O)c1F
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc(C=O)c(O)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of 2-fluoro-3-methoxyphenol (22.0 g) and triethylamine (93.9 g) in dichloroethane (250 mL) was added magnesium chloride (71.7 g), and the mixture was stirred at 40° C. for 1 hr. To this mixture was added paraformaldehyde (46.5 g), and the mixture was stirred for 16 hr. The reaction solution was allowed to be cooled to room temperature, 1N hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (26.0 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (257 mg, 0.93 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (476 mg, 0.81 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) in Chloroform (15 mL). DIEA (0.808 mL, 4.63 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (225 mg, 34%): LC-MS (ES) m/z=507 (M+H)+
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)=[CH:26]1>ClCCl>[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([N:9]3[CH2:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[NH:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=4)=[O:35])=[CH:32][CH:31]=2)=[CH:26]1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(-c2ccsc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccsc2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine and 7 ml of N,N-diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(3-thienyl)benzoyl chloride in 30 ml of dichloromethane. The mixture is stirred 16 hours at room temperature and diluted with dichloromethane (50 ml). The solution is washed with 30 ml each of H2O, 2N HCl, saturated NaHCO3, water and dried (Na2SO4). The solvent is removed under vacuum and the residue purified by chromatography on silica gel with hexane-ethyl acetate as eluent to give a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6](B(O)O)[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].C(O)(=[O:17])C.OO>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6]([OH:17])[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Agent: OO
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(O)c1F
Reaction time: 65 h
Yield: 99 %

Procedure:
To a solution of 3-ethoxy-2,6-difluoro-phenylboronic acid (5.0 g, 0.025 mol) in tetrahydrofuran (80 mL) was added glacial acetic acid (30 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 4 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 3-ethoxy-2,6-difluoro-phenol (4.25 g, 99%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccnc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc[n+]([O-])c(Cl)c1
Yield: 90 %

Procedure:
2-Chloro-4-t-butylpyridine (5.0 g, 30 mmol) was dissolved in chloroform (75 mL), treated with MCPBA, ca. 75% (8.3 g, 36 mmol, 1.2 equivalents) and heated to reflux for 19 h. The mixture was stirred with sodium bisulfite solution until testing with starch-iodide paper indicated consumption of oxidant. The pH was adjusted to 7 with saturated aqueous NaHCO3 solution, the phases separated and the aqueous phase extracted once with CH2Cl2. The organic phases were pooled and washed twice with H2O, once with brine, dried (Na2SO4) and concentrated in vacuo to afford 2-chloro-4-t-butylpyridine-N-oxide (5.0 g, 90%), which crystallized to long white needles on standing.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:17]([NH2:21])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:21][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)C

Procedure:
In a DMF solution containing 2.0 g of Boc-Ile-OH, 0.82 ml of isobutylamine, 1.27 g of HOBt and 2.06 g of DCC were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture, after filtration, was treated similarly to that in Example 50 (Process 2),except for the crystallization solvent (hexane) to give 1.44 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][C:4]=1[CH:10]=O)[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(NCC)C>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[CH:10][C:4]1[NH:5][CH:6]=[C:7]([CH2:8][CH3:9])[C:3]=1[CH2:1][CH3:2])[CH3:19]
Reactant: CCc1c[nH]c(C=O)c1CC
Reactant: CCOC(=O)CC#N
Solvent: CCNCC
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1[nH]cc(CC)c1CC
Temperature: 25 °C

Procedure:
The 3,4-diethyl-2-formylpyrrole (14.1 g, 93.1 mmol) was dissolved in 200 mL of dry ethanol, and ethyl cyanoacetate (20 mL, 137.9 mmol) and diethylamine (20 mL, 193.3 mmol) were added to the solution. The reaction mixture was heated to reflux under an inert atmosphere and stirred under reflux for 2 hours, after which it was cooled to room temperature and then placed in an ice bath. The resulting dark suspension was filtered through a medium filter, and the light brown solids were washed with cold ethanol. The collected filtrates were concentrated under reduced pressure, precipitating more solids. The thick suspension was filtered, and the combined solids were separated and purified to give 2-cyano-3-(3,4-diethyl -1H-pyrrol-2-yl) acrylic acid ethyl ester, a compound of formula 201 in which R1 and R2 are both ethyl.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]1[C:21]2=[N:22][CH:23]=[C:24]([CH:26]=[CH2:27])[CH:25]=[C:20]2[CH:19]=[CH:18]1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:24]3[CH:25]=[C:20]4[CH:19]=[CH:18][N:17]([CH3:16])[C:21]4=[N:22][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc2c(ccn2C)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnc3c(ccn3C)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:13][O:14][CH3:15])[CH2:11][F:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]([N:13]([O:14][CH3:15])[C:30]([C:29]2[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=2)=[O:31])[CH2:11][F:12])=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(CF)CCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(CF)CCc1ccc(Cl)cc1
Temperature: 24 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To a stirred solution of N-[3-(4-chlorophenyl)-1-fluoromethyl-propyl]-O-methyl-hydroxylamine (60 mg; 0.26 mmol), prepared as described in example P8c and triethylamine (0.05 ml; 0.31 mmol) in dichloromethane (1 ml) under nitrogen was added drop wise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (51 mg; 0.26 mmol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen. The mixture was washed with 1M sodium hydroxide (20 ml), 1M hydrochloric acid (20 ml) and brine (20 ml). Organics were dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 70:30) to afford 67 mg (66% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [3-(4-chloro-phenyl)-1-fluoromethyl-propyl]-methoxy-amide as a clear oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:5]
Reactant: C[C@H](O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (S)-(+)-1-amino-2-propanol (7.84 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.8 min) to provide 2-hydroxy-N—((S)-2-hydroxypropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (19 mg, 0.031 mmol, 44.7% yield) as a mixture of diastereomers: LCMS=489.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.35 Hz), 7.54-7.74 (7 H, m), 5.15 (1 H, s), 3.80-3.92 (1 H, m), 3.12-3.42 (2 H, m), 1.13 (3 H, d, J=4.83 Hz); HPLC peak RT=8.6 min (Method A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([O:14][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OC(C)(C)C)CC1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OC(C)(C)C)CC1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (1-20 g) in dichloromethane (50 mL) at 0° C., triethylamine (0.61 mL) and methanesulfonyl chloride (0.31 mL) were added and the mixture stirred overnight at room temperature. The resulting solution was evaporated under reduced pressure and purified on Biotage Horizon® system (silica, gradient 10-20% ethyl acetate in dichloromethane) to yield the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:20](=[O:21])[C:19]1[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: OCCCCCCCCCCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
11.4 g (45.4 mmol) 11-bromo-1-undecanol, 11.0 g (47.7 mmol) 3,5-dinitrobenzoyl chloride, 54 mg 4-dimethylaminopyridine were dissolved in 94 ml dichloromethane. The solution was subsequently cooled to 0° C. and then 18.3 ml (227 mmol) Pyridine was added dropwise, in the course of 25 minutes. After 4.5 hours at 0° C. the reaction mixture was partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using Toluene yielded 18.1 g (90%) 3,5-Dinitrobenzoic acid 11-bromoundecyl ester as yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[S:6][CH:7]=1)#[CH:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)#[CH:2]
Reactant: C#Cc1csc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#Cc1csc(CO)c1
Temperature: 0 °C
Yield: 60 %

Procedure:
To a solution of 4-ethynylthiophene-2-carboxaldehyde (1.5 g, 11 mmol) that was obtained in Example 9 (9b) in methanol (30 ml) was added sodium borohydride (0.49 g, 13 mmol) at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 15 minutes. After cooling the reaction mixture to 0° C., water (100 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9 to 3:7) as the eluent to afford the title compound (0.88 g) in a yield of 60% as a brown oily product.