Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([N:50]4[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Reactant: CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163,1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid (example 211) was reacted with N-methylpiperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O3 [(M+H)+] 733.3394, observed 733.3390.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]([NH:13][NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]1[O:25][C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3ccc([N+](=O)[O-])cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 66.9 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-nitrobenzohydrazide (8.5 g, 15.57 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (8.17 g, 31.13 mmol), iodine (7.90 g, 31.13 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 50 minutes and quenched with sat. aq. sodium thiosulfate (400 mL). The solution was extracted with CH2Cl2 (250 mL). The organic extract was washed with sat. aq. sodium thiosulfate (300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a light yellow solid (5.5 g, 67%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.37 (dm, J=9.0 Hz, 2H), 8.18 (dm, J=9.0 Hz, 2H), 7.36 (d, 8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 5.11 (d, J=9.2 Hz, 1H), 4.87 (dd, J=3.9, 8.8 Hz, 1H), 4.46 (dq, J=3.7, 6.3 Hz, 1H), 2.34 (s, 3H), 1.31 (d, J=6.3 Hz, 3H), 0.93 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1ccc(F)cc1
Product: O=C(Cl)CCCc1ccc(F)cc1
Yield: 101.4 %

Procedure:
A mixture of 4-(4-fluorophenyl)butyric acid (68.2 g, 0.37 mol) and thionyl chloride (155 g, 1.3 mol) was refluxed for 1.25 h. The mixture was concentrated in vacuo to give 75.3 g (100%) of 4-(4-fluorophenyl)butyryl chloride).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+].C>O>[CH2:2]([S:6]([O-:9])(=[O:8])=[O:7])[CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10].[Na+:10]
Reactant: O=S([O-])[O-]
Reactant: BrCCCBr
Agent: C
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCCS(=O)(=O)[O-]
Yield: 85.6 %

Procedure:
This compound was prepared by a modification of the method described in Stone, G. C. H. (1936) J. Am. Chem. Soc., 58:488. 1,3-Dibromopropane (40.4 g, 0.20 mol) was treated with sodium sulfite (60.3 g, 0.50 mol) in water at reflux temperature for 48 h. Inorganic salts (sodium bromide and sodium sulfite) were removed by successive treatment of the resultant reaction mixture with barium hydroxide and silver(I)oxide. The solution was then neutralized with Amberlite-120 (acid form) and decolorized with Norit-A. Barium ions were removed by treatment of the aqueous solution with Amberlite-120 (sodium form) ion-exchange resin. The solvent was removed on a rotary evaporator, and the crude product was recrystallized from water-ethanol several times to give the title compound (42.5 g). The small amount of trapped ethanol was removed by dissolving the crystals in a minimum amount of water and then concentrating the solution to dryness. The pure product was further dried under high vacuum at 56° C. for 24 h: mp>300° C.; 1H NMR (D2O), δ: 3.06-3.13 (m, 4H, H-1 and H-3), 2.13-2.29 (m, 2H, H-2); 13C NMR (D2O), δ: 52.3 (C-1 and C-3), 23.8 (C-2).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C)C=O.Cl>[ClH:35].[C:43]([NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1)(=[O:45])[CH3:44]
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-cis-N1-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N2-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (90 mg) was dissolved in N,N-dimethylformamide (3 ml), triethylamine (65 μl) and acetic anhydride (22 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and dichloromethane and a 0.3N aqueous solution of sodium hydroxide were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a colorless foamy substance. This product was suspended in 1N hydrochloric acid (0.3 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (73 mg) as a pale yellow foamy substance.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][C@@H:5]([NH:8]C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C([Cl:19])(=O)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[ClH:19].[NH2:8][C@@H:5]1[CH2:6][NH:7][C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(=O)NC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: N[C@H]1CCC(=O)NC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
N-((3S)-6-oxo(3-piperidyl))(tert-butoxy)carboxamide (3.9 mmol, 0.83 g) were dissolved in ethanol (10 mL) and cooled to 0° C. Acetyl chloride (2 mL) was added and the reaction was allowed to reach room temperature. The reaction was stirred for 1 hour after which the solvent was removed in vacuo to yield the title compound (725 mg, 99% yield) as the dihydrochloride salt. ES-MS: 115 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][N:29]([CH3:31])[CH3:30])=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1

Procedure:
To a solution of compound 1-3 (5.0 g, 13.7 mmol) in toluene (30 mL) was added DMFDMA (18.15 g, 68.4 mmol) and the mixture was heated at reflux for 4 hours. The TLC showed the starting material was disappeared. The mixture was cooled and the formed white solid was collected. After washed by PE, the solid was dried in vacuum to get the product 1.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:13][CH2:14][CH3:15])=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[CH2:14]([O:13][C:4]1[C:3]([CH2:2][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:6][N:5]=1)[CH3:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1onc(OCC)c1CBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1onc(OCC)c1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
A solusion of ethyl 4-bromomethyl-3-ethoxyisoxazole-5-carboxylate (5 g, 17.9 mmol) in DMF (85 mL) was added to a suspension of potassium phthalimid (3.6 g, 19,7 mmol) in DMF (125 mL) at 90° C. The resulting mixture was stirred at 90° C. for 40 min, then cooled and concentrated in vacuo. Water (250 mL) was added and the aqueous phase was extracted with diethylether (2×200 mL). The organic extracts were dried (MgSO4) and concentrated in vacuo to give a crude product which was recrystallized (EtOH) to yield the title compound (3.70 g, 60%): mp 93-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.Cl.CC#N>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NOC1CCCCO1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 187.7 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy) acrylamide (76 mg) in MeOH (1.3 mL) was added hydrogen chloride methanol reagent 10 (0.32 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (64.1 mg) as colorless powder.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:10]=4[C:11]=3[CH2:12][CH2:13][S:14][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[C:21]([Si:24]([CH3:26])([CH3:25])[O:19][C:16]1[CH:17]=[CH:18][C:9]2[NH:8][C:7]3[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:14][CH2:13][CH2:12][C:11]=3[C:10]=2[CH:15]=1)([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3

Procedure:
Following the procedure described in Example 80, using 6,7-Dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulen-9-ol (350 mg, 1.31 mmol) and TBSCl (225 mg, 1.50 mmol) as the starting material, the title compound was prepared as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:44]([NH2:48])(=[O:47])[CH:45]=[CH2:46]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([O:40][CH2:46][CH2:45][C:44]([NH2:48])=[O:47])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1
Reactant: C=CC(N)=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(OCCC(N)=O)CC1

Procedure:
In a manner similar to the method described in example 177, [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-(4-hydroxy-piperidin-1-yl)-methanone (example 101) was reacted with acrylamide (Promega) to give the title compound. HR-MS (ES, m/z) calculated for C37H46Cl2N5O4 [(M+H)+] 694.2922, observed 694.2918.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:41])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:42][CH:43]1[CH2:46][NH:45][CH2:44]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21]([N:45]4[CH2:46][CH:43]([F:42])[CH2:44]4)[N:20]=3)[C@H:13]2[CH3:41])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC1CNC1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 100 °C
Yield: 92.1 %

Procedure:
To (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-2-(methylsulfonyl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (175 mg, 0.265 mmol) in THF (1 mL) was added TEA (0.369 mL, 2.65 mmol) and 3-fluoroazetidine (236 mg, 2.120 mmol). The reaction was capped and heated at 100° C. for 10 min by microwave irradiation. The reaction was diluted with EtOAc, washed with sat. aqueous NaHCO3, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated before purification by column chromatography to afford (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({2-(3-fluoroazetidin-1-yl)-5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (160 mg, 0.244 mmol). LCMS calc.=655.2/657.2. found=655.4/657.4.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:27]1[C:28]2[C:35]([CH3:36])=[CH:34][S:33][C:29]=2[N:30]=[CH:31][N:32]=1>C(O)C>[O:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([NH:2][C:27]1[C:28]3[C:35]([CH3:36])=[CH:34][S:33][C:29]=3[N:30]=[CH:31][N:32]=1)[CH2:11]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: NC1Cc2ccc(Oc3ccccc3)cc2C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc2ncnc(NC3Cc4ccc(Oc5ccccc5)cc4C3)c12
Yield: 39.4 %

Procedure:
using 2-amino-5-phenoxyindan hydrochloride (99 mg, 0.36 mmol), ethanol (3 ml), triethylamine (92 μl, 0.66 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (61 mg, 0.33 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (51 mg, 0.13 mmol) having the following physical properties:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].CN(C)CCN(C)C>>[CH3:18][N:17]([CH3:19])[CH:16]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=1)[C:10]#[N:11]
Reactant: COC(OC)N(C)C
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: CN(C)CCN(C)C
Product: CN(C)C=C(C#N)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 2-(3-(trifluoromethyl)phenyl)acetonitrile (4.55 g, 24.58 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (13.10 ml, 98 mmol), and N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.737 ml, 4.92 mmol) were heated to reflux for 5 h. After cooling to RT, the mixture was partitioned between saturated aqueous NH4Cl and EtOAc and extracted three times with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo. After absorbing on celite, the compound was purified by Isco (40 g silica, 10% to 70% EtOAc/hexanes) to give pure 3-(dimethylamino)-2-(3-(trifluoromethyl)phenyl)acrylonitrile (2.93 g, 50% yield).
Reaction SMILES: [C:1](SCC)(=[S:3])[CH3:2].[NH2:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10]1.C(N(CC)CC)C>CN(C=O)C>[F:28][C:17]1[CH:16]=[C:15]([N:11]2[CH2:10][C@H:9]([CH2:8][NH:7][C:1](=[S:3])[CH3:2])[O:13][C:12]2=[O:14])[CH:20]=[CH:19][C:18]=1[C:21]1[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: CCSC(C)=S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=S)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl dithioacetate (0.0708 ml, 0.747 mmol) is added to 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.200 g, 0.617 mmol) and triethylamine (0.0946 ml, 0.679 mmol) in DMF (3 ml) and is stirred at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give a white solid (0.21 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 3.59 (s, 2H), overlapping 3.84 (dd, J=6.6, 9.1, 2H) and 3.92 (t, J=4.7 Hz, 2H), 4.19 (t, J=9.1 Hz, 1H), 4.92-5.05 (m, 1H), 7.43 (dd, J=2.2, 8.5 Hz, 1H), 7.58 (dd, J=2.2, 14, 1H), 7.69 (t, J=8.5, 1H), 10.4 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 182-3; MS (m/z): [M+H]+=383.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2I)[CH:7]=1.[Br-].[CH:32]1([Zn+])[CH2:34][CH2:33]1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:32]2[CH2:34][CH2:33]2)[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(I)c34)CC2=O)cc1
Reactant: [Zn+]C1CC1
Agent: Cl
Agent: [Br-]
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(C5CC5)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-4-((R)-1-((6-chloro-3-iodopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (58 mg, 0.11 mmol) and [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (8.7 mg, 0.011 mmol) were added. After evacuating and backfilling with nitrogen, THF (1.1 mL) was added followed by cyclopropylzinc bromide (1.3 mL, 0.65 mmol, 0.5M solution in THF). The mixture was stirred at room temperature for 15 min. The reaction was diluted with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30-100% EtOAc in hexanes) to afford (R)-4-((R)-1-((6-chloro-3-cyclopropylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.
Reaction SMILES: C(O)(C)(C)C.[CH3:6][O:7][CH2:8][CH:9]([NH2:12])[CH2:10][CH3:11].Cl[C:14]1[C:15]([N+:25]([O-:27])=[O:26])=[C:16]([CH3:24])[C:17]([CH3:23])=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>C(Cl)(Cl)Cl>[CH3:6][O:7][CH2:8][CH:9]([NH:12][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[C:16]([CH3:24])[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:10][CH3:11]
Reactant: CCC(N)COC
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: CCC(COC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
(-)-2-Amino-1-butanol [100 grams, prepared according to D. Pitre and E. B. Grabitz, Chimia 23, 399 (1969)] was added in a dropwise manner to a stirred solution of tert-butanol (800 ml.) containing potassium tert-butoxide (126 grams). After warming this mixture to 70° C. to 80° C. for 2 hours, methyl iodide (175 grams) was added slowly at temperatures below 50° C. The suspension which formed was then stirred with refluxing overnight. After removal of the solid phase by filtration, the filtrate was fractionally distilled to give (-)-1-(methoxymethyl)propylamine contaminated with traces of tert-butanol, boiling point 125° C. to 147° C./760 mm. This amine was then allowed to react with 4-chloro-3,5-di-nitro-o-xylene, as described earlier, to give the desired product as a bright yellow solid with melting point 42.5° to 44° C., [α]D25° =137.6° (c 2.504, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([CH2:23]O)[CH2:21][OH:22].Cl.CN(C)CCCN=C=NCC.N(C(C)C)(C(C)C)CC>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][C:20]([CH2:21][OH:22])([N+:25]([O-:27])=[O:26])[CH2:19][OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])C(CO)(CO)CO
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc([C@H](C)C(=O)OCC(CO)(CO)[N+](=O)[O-])ccc2c1
Yield: 36.9 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), 2-hydroxymethyl-2-nitro-1,3-propanediol (2.89 g, 19.1 mmol), N,N-dimethylaminopyridine (DMAP, 0.88 g, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.86 g, 25.4 mmol) and NEt(i-Pr)2 (11 mL, 63.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between 3N HCl (100 mL) and CH2Cl2 (200 mL×2). The combined organic layer was back washed with water and brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (gradient from 1:2 to 1:1, Rf=0.1 in 1:2) to give the title compound as a white solid (2.48 g, 39% yield). Mp 124-126° C. 1H NMR (300 MHz, 10% CD3OD/CDCl3) δ 7.73-7.64 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.12 (m, 2H), 4.44 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 3.9-3.7 (m, 5H), 3.4 (br, 2H), 1.58 (d, J=7.2 Hz, 3H), 13C NMR (75 MHz, 10% CD3OD/CDCl3) δ 174.1, 157.4, 134.5, 133.5, 129.0, 128.6, 127.0, 125.7, 118.8, 105.4, 92.4, 61.2, 60.1, 55.0, 45.0, 17.7.