Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>ClCCl.CN(C)C=O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=4)[NH:9][N:8]=3)[CH2:5][CH2:6]2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n[nH]2)cc1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccc(CN2CCC(c3cc(-c4ccc(Cl)cc4)[nH]n3)CC2)cc1

Procedure:
A solution of 3-(4-piperidinyl)-5-(4-chlorophenyl)pyrazole (1.50 g), triethylamine (1.60 cm3) and 4-chlorobenzyl chloride (0.92 g) in 3:1 dichloromethane-dimethylformamide (20 cm3) was stirred at room temperature for 4.5 hours. Dichloromethane was removed by evaporation and the crude product was partitioned between water (25 cm3) and ethyl acetate (2×25 cm3). The combined organic extracts were washed with saturated brine (20 cm3), dried (MgSO4), filtered and evaporated to dryness to give an off-white solid. Recrystallisation from ethanol-water yielded the title compound as fine, white needles (0.575 g, 26%), m.p. 179°-181° C. (from EtOH/H2O); (Found: C, 65.19; H, 5.24; N, 10.86. C21H21N3Cl2 requires C, 65.29; H, 5.48; N, 10.88%.); δH (360 MHz; CDCl3) 1.71 (2H, apparent qd, J=12 and 3, 2×NCH2CHAHB), 1.84 (2H, apparent d, J=11, 2×NCH2CHAHB), 1.92 (2H, apparent t, J=11, 2×NCHAHB), 2.41-2.55 (1H, m, NCH2CH2CH), 2.84 (2H, apparent d, J=11, 2×NCHAHB), 3.44 (2H, s, NCH2Ar), 6.21 (1H, s, N=C--CH=C), 7.30-7.21 (6H, m, 6×ArH), 7.61 (2H, d J=8.1, 2×ArH) and 11.6-12.0 (1H, br s, NH); δC (90 MHz; CDCl3) 31.9 (t), 33.8 (d), 53.3 (t), 62.5 (t), 99.5 (d), 126.9 (d), 128.6 (d), 128.9 (d), 130.3 (d), 132.8 (s), 133.5 (s) and 136.8 (s). 3 quaternary carbons not observed; m/z (CI+ ; NH3) 386 (M+ +H; 30%), 262 (22), 228 (18), 210 (10), 196 (17), 179 (28), 162 (28), 154 (40), 142 (67), and 140 (100); m/z (CI- ; NH3) 420 (M- +Cl; 2%); 385 (M- ; 10), 259 (10), 178 (27) and 127 (20).
Reaction SMILES: C=O.C(N)(=O)C=C.[OH-].[Na+].[CH2:10]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])O.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH2:10][NH:12][C:13](=[O:16])[CH:14]=[CH2:15])[CH3:19]
Reactant: CNC
Reactant: C=CC(=O)NCO
Agent: C=CC(N)=O
Agent: C=O
Agent: [Na+]
Product: C=CC(=O)NCN(C)C
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Into a reaction vessel as employed in Example 1 is added 13.3 parts of paraformaldehyde and 62.9 parts of a 48.1% aqueous solution of acrylamide. The pH is adjusted with aqueous NaOH to 11.5 and the homogeneous mixture allowed to stand 24 hours at room temperature. The product, >90 mole percent converted N-methylolacrylamide, is acidified to a pH of 2 and to it is added 57.5 parts of a 40% dimethylamine aqueous solution acidified to a pH of 2. The resulting solution is heated 3 hours at 65° C. and yields about 50 mole percent of N-(dimethylaminomethyl)acrylamide.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]O>ClCCl>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: CN(C)CCO
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: ClCCl
Product: CN(C)CCOC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acid chloride, prepared from 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alphaoxobenzeneacetic acid (0.5 g) as described in Example 6, was dissolved in dichloromethane (10 mL) and added dropwise to a stirred, cold (<-50° C.) mixture of 2-(dimethylamino)ethanol (0.178 g) in dichloromethane (10 mL). The cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed once with saturated aqueous sodium bicarbonate, once with water, and the organic solution was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from diethyl ether-hexane provided pure 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid 2-(dimethylamino)ethyl ester as a colorless solid, mp 93°-94° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:23]O>C(OCC)(=O)C>[CH3:23][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: CO
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
3-Benzoyl-benzoic acid (5.12 g, 22.6 mmol) was stirred in methanol (45 mL) with conc. H2SO4 (2.0 mL) for 18 h at 60° C. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated to provide 3-benzoyl-benzoic acid methyl ester (5.4 g, 22.6 mmol) in quantitative yield as a yellow oil.
Reaction SMILES: [CH3:1]N(C=O)C.[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[CH:28]=[C:27]([OH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C.O>[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:26]=[C:27]([O:33][CH3:1])[CH:28]=[C:29]([CH2:31][OH:32])[CH:30]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 3 ml DMF solution containing 700 mg of {2-(3-hydroxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester there was added 440 mg of potassium carbonate and 0.15 ml of methyl iodide, and the mixture was stirred at room temperature for 17 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (544 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH2:10][C:11]1[S:12][C:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:15]=1>N1C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[CH2:3][S:4]([NH:10][C:11]1[S:12][C:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:15]=1)(=[O:6])=[O:5]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COc1ccc(-c2nc(N)sc2-c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(NS(=O)(=O)CC(F)(F)F)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
0.92 g of 2,2,2-trifluoroethanesulfonyl chloride was dropped into a solution of 1:56 g of 2-amino-4,5-bis(4-methoxyphenyl)thiazole in pyridine under stirring at room temperature in a nitrogen atmosphere, and the resulting mixture was stirred as such for 1 hour. Then the reaction mixture was poured into ice-water and the crystals thus precipitated were recovered by filtration and recrystallized from diethyl ether/ethyl acetate to give 0.80 g of 2-(2,2,2-trifluoroethanesulfonyl)amino-4,5-bis(4-methoxyphenyl)thiazole. The melting point of this product was from 259° to 261° C.
Reaction SMILES: CN1CCNCC1.[C@@H:8]12C(=O)[O:16][C:14](=[O:15])[C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2>O1CCOCC1>[CH:9]1([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:8]1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: CN1CCNCC1
Solvent: C1COCCO1
Product: O=C(O)C1CCCCC1
Reaction time: 1.25 h

Procedure:
0.37 cm3 of N-methylpiperazine in solution in 5 cm3 of dioxane is added, under an argon atmosphere, to 0.50 g of (−)-trans-1,2-cyclohexanedicarboxylic anhydride in solution at −15° C. in 20 cm3 of dioxane. After 1.25 hours at 20° C., the reaction mixture is filtered, the solid is washed with 20 cm3 of diethyl ether, drained, and then dried under reduced pressure (2,7 kPa) at 20° C., to give 0.65 g of (1R,2R)-2-(4-methylpiperazin-1-yl)carbonyl]-1-cyclohexanecarboxylic acid in the form of a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][C@@H:4]([C:16]([NH2:18])=[O:17])[CH2:3]1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C>[C:12]([O:11][C:9]([NH:8][C@@H:7]1[CH2:6][CH2:5][C@@H:4]([C:16](=[O:17])[NH2:18])[CH2:3][C@@H:2]1[O:1][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@H]1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To (1R,3R,4R)-3-hydroxy-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid amide (e) (2.78 g, 10.8 mmol), para-nitrobenzoic acid (2.16 g, 12.9 mmol) and triphenylphosphine (3.38 g, 12.9 mmol) in dry THF (200 mL) and DMF (25 mL) under argon was added dropwise diisopropyl azodicarboxylate (2.5 mL, 12.9 mmol) at 0° C. After 5 min at 0° C. and 17 hours at room temperature, the mixture was concentrated in vacuo and the residue purified by flash column chromatography (silica gel, DCM/MeOH, 0-4%) to give a white solid (2.36 g, 5.8 mmol, 54%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[O:11][C@@H:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[O:11][C@@H:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21

Procedure:
Methyl [(2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-2-phenyl-3,4-dihydro-1,5-benzoxazepin-5(2H)yl]acetate (70a) (175 mg, 0.410 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (4 mL) and kept at ambient temperature for 30 min. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated and the residue used immediately in the next step.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C@@H:10]2[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]2[N:18]2[CH:25]=[C:24]([CH3:26])[C:22](=[O:23])[NH:21][C:19]2=[S:20])C(=O)C2=CC=CC=C12.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[CH:25]=[C:24]([CH3:26])[C:22](=[O:23])[NH:21][C:19]1=[S:20]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCN2C(=O)c3ccccc3C2=O)c(=S)[nH]c1=O
Agent: NN
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCN)c(=S)[nH]c1=O
Temperature: 62.5 °C
Reaction time: 14 h

Procedure:
2'-O-Phthalimidopropyl-5-methyl-2-thiouridine (5.0 g, 15.8 mmol) is dissolved in 100 ml methanol in a 500 ml flask. Hydrazine (2.02 g, 63.2 mmol) is added and the mixture is heated to reflux (60-65° C.) with stirring for 14 hours. The solvent is evaporated in vacuo and the residue is dissolved in dichloromethane (150 ml) and extracted twice with an equal volume NH4OH. The organic layer is evaporated to yield the crude product. NMR is used to assay product purity. The product is used in subsequent reactions without further purification.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:26]([CH3:28])[CH3:27])[C:11]2[C:12]([CH3:25])=[C:13]([CH:22]([CH3:24])[CH3:23])[C:14]3[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]=3[CH:21]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH:26]([N:10]([C:11]1[C:12]([CH3:25])=[C:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[O:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]=2[CH:21]=1)[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(N(c2cc3c(c(C(C)C)c2C)OCC3(C)C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(N(c2ccc(C(=O)O)cc2)C(C)C)cc2c(c1C(C)C)OCC2(C)C
Yield: 73.7 %

Procedure:
Following general procedure P and using 4-[isopropyl-(7-isopropyl-3,3,6-trimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid methyl ester (Compound 67, 0.037 g, 0.096 mmol) and 1.5 mL (7.5) of 5M sodium hydroxide in 5 mL of methanol, the title compound (0.027 g, 72%) was obtained, after flash column chromatography using 15% ethyl acetate in hexanes as the eluent, as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.87 (d, 2H, J=8.9 Hz), 6.59 (s, 1H), 6.42 (d, 2H, J=8.9 Hz), 4.34 (heptet, 1H, J=6.3 Hz), 4.24 (s, 2H), 3.19 (heptet, 1H, J=7.0 Hz), 1.36-1.26 (m, 15H), 0.99 (d, 3H, J=6.53 Hz).
Reaction SMILES: [Cl-].[C:2]1([PH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>[NH4+].[Cl-]>[C:9]1([P:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Diphenylphosphine chloride (5 mmol, 0.92 ml) was dissolved in TIM (25 ml). The solution was cooled to 0° C. 4-Methoxyphenyl magnesium bromide (6.5 mmol, 19 ml, 1.3 eq) was added dropwise to the solution over 20 minutes. The mixture was stirred for 3 hours. The mixture was allowed to warm to room temperature, and then stirred for another 5 hours after which saturated NH4Cl (20 ml) was added thereto to terminate the reaction. The inorganic salt was removed by suction filtration and the filtrate was extracted with dichloromethane (40 ml×3). The extract was dried over sodium sulfate and concentrated using an evaporator and an oil pump to give diphenyl-4-methoxyphenylphosphine.
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.CN1CCOCC1.CN(C(O[N:47]1N=[N:54][C:49]2C=CC=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN(C=O)C>[C:48]([CH2:49][NH:54][C:3](=[O:5])[CH:2]([OH:1])[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:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)#[N:47]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Yield: 75.9 %

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, 50 mg, 0.116 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.102 mL, 0.927 mmol), 2-aminoacetonitrile, HCl (13.94 mg, 0.151 mmol), and HATU (66.1 mg, 0.174 mmol). This was stirred overnight before EtOAc was added. The EtOAc solution was washed with 1N HCl, sat NaHCO3, and brine. The organic layer was then dried with MgSO4 and concentrated to give N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (51 mg, 0.088 mmol, 76% yield): LCMS=470.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.23 (2 H, m), 7.65-7.76 (4 H, m), 7.53-7.64 (3 H, m), 5.21 (1 H, s), 4.19 (2 H, d, J=2.86 Hz). HPLC Peak RT=9.5 min (Analytical Method A).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:22][OH:23]>ClCCl>[Br:30][C:28]1[CH:27]=[CH:26][C:25]([F:31])=[C:24]([C@@:13]2([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])[C@H:14]([CH2:22][OH:23])[CH2:15][C@H:16]([CH:19]3[CH2:20][CH2:21]3)[O:17][CH2:18]2)[CH:29]=1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Benzoyl isothiocyanate (120 mg, 0.74 mmol) was added drop-wise to a solution of [(2R,4R,5S)-5-amino-5-(5-bromo-2-fluorophenyl)-2-cyclopropyltetrahydro-2H-pyran-4-yl]methanol (C56) (from the previous step, 225 mg, 50.78 mmol) in dichloromethane (25 mL) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1.5 hours, then was warmed to room temperature and stirred overnight before concentrating in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a solid. Yield: 127 mg, 26% over 2 steps LCMS m/z 454.3 [M+H+].
Reaction SMILES: [F-].C[N+](C)(C)C.[CH3:7][C:8]([S@@:11](/[N:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=1)=[O:12])([CH3:10])[CH3:9].C[Si](C)(C)[C:36]([F:39])([F:38])[F:37].[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH3:10][C:8]([S@@:11]([NH:13][CH:14]([C:15]1[N:16]=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[C:18]2=[N:19][CH:20]=1)[C:36]([F:39])([F:38])[F:37])=[O:12])([CH3:7])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=N/[S@@](=O)C(C)(C)C)cnc32)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(N[S@@](=O)C(C)(C)C)C(F)(F)F)cnc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a dry flask charged with 4 Å molecular sieves (5 g) and tetramethyl-ammonium fluoride (0.553 g, 5.93 mmol) was added THF (20 mL). The reaction mixture was stirred for about 30 min after which it was cooled to about −78° C. and a solution of (S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propane-2-sulfinamide (1.20 g, 2.97 mmol) in THF (10 mL) was added. After about 15 min trimethyl(trifluoromethyl)silane (0.877 mL, 5.93 mmol) was added to the reaction mixture. The mixture was allowed to warm to −35 to −45° C. After about 3 h, the reaction mixture was cooled to −78° C. and aqueous NH4Cl was added. The reaction mixture was allowed to warm to rt. EtOAc (30 mL) and brine (30 mL) were added. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concd in vacuo to provide crude (S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethyl)propane-2-sulfinamide (1.4 g, 99%) as a foamsulfonamide which was used without further purification. LC/MS (Table 1, Method a) Rt=2.49 min; MS m/z 475 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].I[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C(O)(C)(C)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: O
Product: COc1c(C(=O)NC2CCN(c3ccccc3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 30 %

Procedure:
A solution of the compound of Example 77 (200 mg, 0.42 mmol), iodobenzene (0.50 mL), tris(dibenzylideneacetone)dipalladium (0) (38 mg, 0.042 mmol), x-phos (40 mg, 0.085 mmol) and sodium tert-butoxide (102 mg, 1.1 mmol) in tert-butanol (4.0 mL) was stirred under microwave irradiation at 130° C. for 35 min. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=30/70-100/0) and recrystallized from ethyl acetate to give the title compound (70 mg, 30%) as a white solid.