Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[NH:11][NH:10][C:9]2=[O:14])=[C:6]([F:15])[C:5]([F:16])=[C:4]([F:17])[C:3]=1[F:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C>[F:15][C:6]1[C:7]([N:8]2[C:9](=[O:14])[N:10]=[N:11][C:12]2=[O:13])=[C:2]([F:1])[C:3]([F:18])=[C:4]([F:17])[C:5]=1[F:16]
Reactant: O=c1[nH][nH]c(=O)n1-c1c(F)c(F)c(F)c(F)c1F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1N=NC(=O)N1c1c(F)c(F)c(F)c(F)c1F
Reaction time: 0.33 h

Procedure:
A 50 ml, three-necked flask is fitted with a gas-dispersion tube, a drying tube and a stirrer. 4-(Pentafluorophenyl)-urazole, 0.5 g (1.8 mM) is dissolved in 25 ml of ethyl acetate. Anhydrous sodium sulfate, 3 g, is added to remove water present in NO2. The reaction mixture is cooled in an ice bath, and nitrogen dioxide added slowly for 20 minutes. The mixture is allowed to stir for 20 minutes. The Na2SO4 is removed by filtration and the ethyl acetate removed with the rotary evaporator to yield a red oil. The residual solvent is removed with a vacuum pump to yield a crystalline solid, 0.35 g, mp 88°-91° C. The product is further purified by sublimation, mp 94°-96° C.
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[K+].[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.C([O-])(O)=O.[Na+]>CC(OC)(C)C>[C:2]([O:5][C:10]([CH:7]1[CH2:9][CH2:8]1)=[O:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)C1CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
219.1 g (1913 mmol, 1 eq.) potassium tert-butylate were suspended in 2.5 L TBME and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-EtOH bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5% aq. NaHCO3 solution was added. The aqueous phase was separated and extracted with 500 ml TBME. The organic phases were washed with 500 ml half sat. aq. NaCl solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91% yield corrected for 8% residual TBME).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:22][C@@H:14]4[CH2:15][N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:17][C@@H:13]4[C@H:12]3[CH3:23])=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1.[Cu][C:29]#[N:30]>CN1CCCC1=O.C(OCC)(=O)C>[C:29]([C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:22][C@@H:14]4[CH2:15][N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:17][C@@H:13]4[C@H:12]3[CH3:23])=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1)#[N:30]
Reactant: N#C[Cu]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(C#N)cc12
Temperature: 220 °C
Yield: 56.8 %

Procedure:
A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 59 (70 mg, 0.153 mmol) and copper(I) cyanide (27.5 mg, 0.307 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated to 220° C. under microwave for 2 h. The resulting mixture was diluted with ethyl acetate (80 mL), washed with saturated NH4Cl, water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 60-100% ethyl acetate in hexanes, to give 6-cyano-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (35 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J=1.8 Hz, 1H), 8.37 (s, 1H), 7.61 (d, J=1.5 Hz, 1H), 4.24-4.01 (m, 1H), 3.26-3.11 (m, 2H), 3.05 (m, 1H), 2.93 (s, 3H), 2.93-2.83 (m, 1H), 2.61-2.54 (m, 1H), 2.36-2.17 (m, 1H), 1.93-1.82 (m, 1H), 1.70-1.55 (m, 1H), 1.36-1.25 (m, 1H), 1.10-1.02 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH2:45])(=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:45][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CCCCCCCCCC(N)=O
Product: CCCCCCCCCC(=O)NC(=O)c1ccc(C(C)(C)C)c(NC(=O)CC(CCCCC)c2ccc(OC)cc2OC)c1

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and decanamide, the title compound was obtained as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)(=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)Cl
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, a saturated sodium chloride solution 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated salt solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 1 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 300.6 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][S:11](=[O:14])[N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH2:22]>C(#N)C.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][S:11](=[O:22])(=[O:14])[N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(Br)c2)COS1=O
Reactant: O
Agent: Cl[Ru](Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(Br)c2)COS1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice water cooled solution of (4S)-tert-butyl 4-(3-bromo-5-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (34.6 g, 91 mmol) in acetonitrile (420 mL) under stirring was added NalO4 (29.2 g, 137 mmol), and ruthenium trichloride hydrate (0.359 g, 1.729 mmol), followed by water (320 ml). The reaction mixture was stirred at 0° C. for 2 hours. The mixture was diluted with EtOAc (500 ml), washed with brine (200 ml) twice, dried over Na2SO4, filtered and concentrated to afford the crude product, which was used directly at the next step. 40.3 grams of the crude product was obtained. LC-MS: (MW+Na): 419.9 m/z at 1.01 min.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[S:9][C:8]([S:10](NN)(=[O:12])=[O:11])=[CH:7][CH:6]=1.[Br:15]Br>CCCCCC>[Cl:4][C:5]1[S:9][C:8]([S:10]([Br:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: NNS(=O)(=O)c1ccc(Cl)s1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=S(=O)(Br)c1ccc(Cl)s1
Temperature: 2 °C
Yield: 50.2 %

Procedure:
In a 1-liter, three-neck flask equipped with a magnetic stirrer, a thermometer, an an addition funnel were placed 300 ml of methylene chloride, 10.63 g (0.05 mol) of 5-chloro-2-thiophenesulfonyl hydrazine, and some crushed ice. The slurry was allowed to cool to 2° C., and 16.0 g (0.10 mol) of bromine was added dropwise with stirring at such a rate that the temperature did not exceed 10° C. After the addition was complete, the methylene chloride layer was separated, dried and the methylene chloride removed in vacuo, leaving a yellow-orange oil. The oil was dissolved in hexane and the resulting solution cooled to give 6.56 g of the title compound as slightly yellow crystals, mp 35°-37°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Nc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccccc2)cn1
Yield: 70 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using aniline instead of 3-methoxypropylamine, to the title compound (87 mg, 70%) which was obtained as an off white solid. MS: m/e=386.4[M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=O)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].CC(O)=O.[CH2:18]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:26]([N:25]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]1[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CC(=O)CC1CC
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Temperature: 0 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
A round-bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol, Preparation #DD.1) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added drop-wise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. and additional DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (1.5 L), followed by the portion-wise addition of solid sodium bicarbonate (175 g). The mixture was stirred for about 2 h and the organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified by silica gel chromatography using EtOAc/heptane as eluant (0-20% EtOAc in heptane). The solvent was removed under reduced pressure to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as a white solid: LC/MS (Table 2, Method a) Rt=3.26 min; MS m/z: 366 (M+H)+
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][CH:4]([CH3:16])[CH2:5][C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Na]>C(O)(=O)C>[CH3:3][CH:4]([CH3:16])[CH2:5][C:6]1[NH:2][N:1]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)C
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous hydrazine (3.58 g, 112 mmol) was added dropwise over a period of 30 minutes to a solution of ethyl 6-methyl-2,4-dioxoheptanoate, sodium salt (24.8 g, 112 mmol) in acetic acid (160 mL). The reaction was stirred overnight at ambient temperature, and then the solvent was removed under reduced pressure. The residue was dissolved in a mixture of diethyl ether and water, and solid sodium bicarbonate and sodium carbonate were added to adjust the mixture to pH 8. The aqueous layer was extracted twice with diethyl ether; the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (FLASH 65I cartridge, eluting with 50:50 ethyl acetate/hexanes) to provide 21.0 g of ethyl 5-(2-methylpropyl)-1H-pyrazole-3-carboxylate as a solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([Cl:17])=[C:5]([CH2:7][N:8]2C[C:12]3[CH:13]=[CH:14][S:15][C:11]=3[CH2:10][CH2:9]2)[CH:6]=1.S1C=CC=C1C1[O:25]C1.ClC1C=CC=CC=1CN>>[S:15]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:10]([OH:25])[CH2:9][NH:8][CH2:7][C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[Cl:17]
Reactant: Clc1ccccc1CN1CCc2sccc2C1
Reactant: c1csc(C2CO2)c1
Agent: NCc1ccccc1Cl
Product: OC(CNCc1ccccc1Cl)c1cccs1

Procedure:
Literature precedent for ticlopidine (J. P. Maffrand, R. Boigegrain, Heterocycles, 1979, 12, 1479; FR 2,424,278) shows that (2-thienyl)ethylene oxide 14 reacts with o-chlorobenzylamine to provide the desired N-(2-(2-thienyl)-2-hydroxyethyl)-o-chlorobenzylamine in low yield due to lack of regioselectivity in the epoxide ring opening (Scheme 5).
Reaction SMILES: [CH:1](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.CCCCCC.[CH:23]([C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH:36][C:37](=[O:49])[CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]1)([CH3:25])[CH3:24]>C(#N)C.CO>[CH:23]([C:26]1[C:31]([O:32][CH3:1])=[CH:30][CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH:36][C:37](=[O:49])[CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]1)([CH3:24])[CH3:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCCO)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCO)CC2)c1C(C)C
Reaction time: 96 h
Yield: 86.9 %

Procedure:
N,N-Diisopropylethylamine (513 mg, 3.97 mmol) and a solution of trimethylsilyl diazomethane in hexane (2.0 M, 2.0 ml, 3.97 mmol) were added to a solution of N-(2,6-diisopropyl-3-hydroxyphenyl)-2-[4-(3-hydroxypropyl) piperazin-1-yl]acetamide (500 mg, 1.32 mmol) in a mixed solvent of methanol (8 ml) and acetonitrile (12 ml) and the mixture was stirred for four days. After the reaction, the solvent was evaporated. The residue was made basic by adding an aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform methanol=10:1) to provide 449 mg (yield 87%) of N-(2,6-diisopropyl-3-methoxyphenyl)-2-[4-(3-hydroxypropyl) piperazin-1-yl]acetamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][OH:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][OH:11])[CH:3]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: OCc1ccc(Br)cc1CO
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2ccc(CO)c(CO)c2)cc1
Temperature: 80 °C

Procedure:
The compound of example 669 (7 g, 32.25 mmol), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (9.63 g, 38.70 mmol) and [1,1-Bis(diphenylphosphino)-ferrocine]dichloropalladium(II), complex with dichloromethane (789 mg, 0.967 mmol) were taken in dry DMF under Argon atmosphere. Degassed 2M solution of sodium carbonate (8.54 g, 80.62 mmol) was added and the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled and the solvent was removed by distillation. The residue was taken in water and the aqueous mixture was extracted with ethyl acetate. The crude material obtained was purified using column chromatography (silicagel, 30% dichloromethane in petroleum ether) to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]([C:9]([C:15]([F:18])([F:17])[F:16])([C:11]([F:14])([F:13])[F:12])[OH:10])=[N:6][C:5]=1[C:19]1[CH:24]=[CH:23][C:22](SC)=[CH:21][CH:20]=1)[CH3:3].O[O:28][S:29]([O-:31])=O.[K+].S(OOS([O-])(=O)=O)(O)(=O)=O.[K+].[CH3:44]O>>[CH3:3][CH:2]([C:4]1[S:8][C:7]([C:9]([C:15]([F:17])([F:16])[F:18])([C:11]([F:13])([F:14])[F:12])[OH:10])=[N:6][C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([S:29]([CH3:44])(=[O:31])=[O:28])=[CH:23][CH:24]=1)[CH3:1]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ccc(-c2nc(C(O)(C(F)(F)F)C(F)(F)F)sc2C(C)C)cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)O
Agent: [K+]
Product: CC(C)c1sc(C(O)(C(F)(F)F)C(F)(F)F)nc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.90 g (14.2 mmol) of 5-(1-methylethyl)-4-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)thiazole-2-methanol in 200 ml of methanol at 25° C. was added 21.3 g (34.7 mmol) of Oxone® (potassium hydrogen persulfate) and the resulting suspension was stirred at 25° C. for 3 hours. The suspension was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate; and the solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was recrystallized from n-butyl chloride to provide 3.34 g of 5-(1-methylethyl)-4-(4-methylsulfonylphenyl)-α,α-bis(trifluoromethyl)thiazole-2-methanol as a yellow crystalline solid, m.p. 122°-123° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1)#[N:21]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[N:23][CH:24]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Product: N#Cc1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cn1
Yield: 46 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (196 mg) was reacted with 2-cyanopyridine-5-boronic acid pinacol ester as in General Procedure 4B to give the title compound as a yellow solid (46% yield). M.p.>200° C., LCMS: m/z=342.20 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.23 (2H, s), 5.27 (2H, s), 7.23 (1H, m), 7.32 (4H, m), 7.49 (2H, m), 8.03 (1H, d, J=8.3 Hz), 8.18 (2H, m), 8.95 (1H, d, J=2.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27](O)=[O:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[CH3:33][N:34]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CNCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCc1ccccn1)C(=O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (120 mg, 0.284 mmol) and 2-(2-methylaminoethyl)pyridine (0.047 ml, 0.341 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (58 mg, 0.426 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.568 mmol). After stirring the mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The resultant residue was purified by silica gel column chromatography (methylene chloride: MeOH, 15:1 elution), then treated with 4N hydrogen chloride in EtOAc (1ml) to give N-methyl-N-[2-(pyridin-2-yl)ethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (140.9 mg, 86%).
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:2]=[CH2:3].[OH-].[K+].Br[C:25](P(=O)(OCC)OCC)([F:27])[F:26]>C(#N)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH:25]([F:27])[F:26])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:2]=[CH2:3]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: C=CCc1c(O)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C=CCc1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-allyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (3.6 g, 12.53 mmol) was dissolved in acetonitrile (62.6 mL) and water (62.6 mL), then KOH (14.06 g, 251 mmol) was added and the solution was stirred until all the KOH went into solution. The resulting solution was then cooled to −78° C. (solution froze) and diethyl bromodifluoromethylphosphonate (4.45 mL, 25.06 mmol) was added. The reaction was removed from the dry ice bath and allowed to warm to room temperature. After 1 hour, EtOAc and water were added, and the resulting layers were separated. The aqueous layer was further extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (d, J=3.79 Hz, 1H) 7.08 (t, J=74.7 Hz, 1H) 6.96 (s, 1H) 6.76 (d, J=3.79 Hz, 1H) 5.89 (dd, J=16.93, 10.36 Hz, 1H) 4.91-5.05 (m, 2H) 3.57 (d, J=6.32 Hz, 2H) 1.59 (s, 9H). MS (ESI+) m/z 338.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:2]=2[F:1])=[O:19])=[CH:16][N:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: O=C(Nc1ccc(C(F)(F)F)cc1F)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(2-fluoro-4-trifluoromethyl-phenyl)-nicotinamide was prepared from 2-fluoro-4-trifluoromethyl aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C13H7N2OClF4 [M+H]+: 319.0256. Found: 319.0255.