Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][CH:50]1[NH:54][CH2:53][C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])([OH:55])[CH2:51]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:54]3[CH:50]([CH3:49])[CH2:51][C:52]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[CH3:62])([OH:55])[CH2:53]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: Cc1ccccc1C1(O)CNC(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CC(O)(c3ccccc3C)CC2C)cc1Cl
Yield: 29.3 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 5-methyl-3-(2-methylphenyl)pyrrolidin-3-ol (8 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (5 mg). MS (ESI, pos. ion) m/z: calcd for C23H23ClN2O4: 426.1346, found 426.1350.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[N-:21]=[N+:22]=[N-:23].[Na+].CCOC(C)=O>CN(C=O)C>[N:21]([C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N=[N+]=[N-]
Temperature: 60 °C
Yield: 96 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (80 mg, 0.25 mmol, prepared according to Example 23, Step 12.2) and sodium azide (81 mg, 1.24 mmol) in DMF (1 mL) was stirred and heated at 60° C. for 3 h. The reaction mixture was cooled to RT, poured into AcOEt and washed successively with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (77.4 mg, 0.24 mmol, 95%) as a brownish solid, which was used in the next step without further purification. MS: 329 [M+1]+; HPLC: AtRet=2.56.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][NH:13][C:14](=[O:26])[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.ClCCl.[NH2:42][C@H:43]([C:50]([NH:52][C@H:53]([CH:58]=[N:59][NH:60][C:61]([NH2:63])=[O:62])[CH2:54][CH:55]([CH3:57])[CH3:56])=[O:51])[CH2:44][C:45]1[N:49]=[CH:48][NH:47][CH:46]=1>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([CH:8]([CH2:12][NH:13][C:14](=[O:26])[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9]([NH:42][C@H:43]([C:50]([NH:52][C@H:53]([CH:58]=[N:59][NH:60][C:61]([NH2:63])=[O:62])[CH2:54][CH:55]([CH3:57])[CH3:56])=[O:51])[CH2:44][C:45]1[N:49]=[CH:48][NH:47][CH:46]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(Cc1cccc2ccccc12)NCC(Cc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CNC(=O)Cc1cccc2ccccc12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
A mixture of 139 mg of (±)-2-benzyl-3-(1-naphthylacetamido)propionic acid and 65 mg of 1,1'-carbonyldiimidazole was added to 5 ml of dry dichloromethane, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was added to a solution of 261 mg of L-histidyl-L-leucinal semicarbazone.2p-toluenesulfonic acid salt and 0.11 ml of triethylamine in 3 ml of dry N,N-dimethylformamide, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 30 mg of N-[(±)-2-benzyl-3-(1-naphthylacetamido)propionyl]-L-histidyl-L-leucinal semicarbazone as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[N:25]=[C:24]([CH:26]5[CH2:29][C:28]([F:31])([F:30])[CH2:27]5)[O:23][N:22]=4)[CH:18]=[CH:17][C:16]=3[F:32])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[C:40](=[NH:43])([NH2:42])[CH3:41]>CS(C)=O>[F:30][C:28]1([F:31])[CH2:27][CH:26]([C:24]2[O:23][N:22]=[C:21]([C:19]3[CH:18]=[CH:17][C:16]([F:32])=[C:15]([NH:14][C:12]([C:9]4[N:7]5[CH:8]=[C:3]([C:1]6[NH:43][C:40]([CH3:41])=[N:42][N:2]=6)[CH:4]=[CH:5][C:6]5=[N:11][CH:10]=4)=[O:13])[CH:20]=3)[N:25]=2)[CH2:29]1
Reactant: N#Cc1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3F)n2c1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1nnc(-c2ccc3ncc(C(=O)Nc4cc(-c5noc(C6CC(F)(F)C6)n5)ccc4F)n3c2)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 6-cyano-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (42h) (15.0 mg, 0.034 mmol), CuBr (9.2 mg, 0.007 mmol), Cs2CO3(39 mg, 0.12 mmol), and acetimidamide hydrochloride (6.6 mg, 0.07 mmol) in DMSO (1 mL) was heated at 120° C. overnight. The reaction mixture was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-fluorophenyl)-6-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (F61). MS m/z 495.1 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].FC(F)(F)S(O[CH2:18][C:19]([F:31])([F:30])[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:30][C:19]([F:31])([C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])[CH2:18][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 17.9 %

Procedure:
2.0 g of 2-(3,3,3-trifluoropropyl)malononitrile and 4.7 g of 2,2,3,3,4,4,5,5,5-nonafluoropentyl trifluoromethanesulfonate were dissolved in 10 ml of N,N-dimethylformamide, 2.0 g of potassium carbonate was added, and the mixture was stirred at 60° C. for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.87 g of 2-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (5.3)).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: OCc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(CO)c3)C(C)(C)C2=O)cn1
Yield: 70 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (3-(bromomethyl)phenyl)methanol. Yield 70%, white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.47 (d, J=6.0 Hz, 2H), 4.54 (s, 2H), 5.15 (t, J=5.6 Hz, 1H) 5.2 (s, 2H), 7.25 (m, 3H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:25]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[CH2:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:16])[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC1CCNCC1
Reactant: O=C1COc2cc(F)ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3cc(F)ccc32)CC1
Yield: 46.6 %

Procedure:
4-(3-Chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (81MF763b) (0.40 g, 1.6 mmol), K2CO3 (0.44 g, 3.2 mmol), NaI (0.48 g, 3.2 mmol) and 4-butylpiperidine (0.24 g, 1.70 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (81MF763) (0.26 g, 46%). 1H NMR (CDCl3) δ.7.09-7.04 (m, 1H), 6.74-6.69 (m, 2H), 4.58 (s, 2H), 3.95 (t, J=7.2 Hz, 2H), 2.84 (d, J=11.2 Hz, 2H), 3.45 (t, J=6.8 Hz, 2H), 1.91-1.78 (m, 4H), 1.66 (d, J=9.2 Hz, 2H), 1.29-1.16 (m, 9H), 0.88 (t, 7.2 Hz, 3H); 13C NMR (CDCl3) δ163.6, 158.9 (d, J=243.7 Hz), 146.3 (d, J=11.5 Hz), 125.2 (d, J=3.0 Hz), 115.9 (d, J=9.7 Hz), 109.1 (d, J=22.8 Hz), 105.1 (d, J=26.1 Hz), 67.8, 55.9, 54.3, 39.9, 36.5, 36.0, 32.7, 29.2, 24.8, 23.1, 14.2.
Reaction SMILES: [F:1][C:2]([F:34])([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:33])([O:30]CC)[O:27]CC)[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].Br[Si](C)(C)C.O>ClCCl.CO>[F:34][C:2]([F:1])([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:27])([OH:33])[OH:30])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13]
Reactant: CCOP(=O)(CCCCCCCCCCCOC(F)(F)c1c(F)c(F)c(F)c(F)c1F)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=P(O)(O)CCCCCCCCCCCOC(F)(F)c1c(F)c(F)c(F)c(F)c1F
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A solution of diethyl 11-(perfluorobenzyloxy)undecylphosphonate (0.63 g, 1.3 mmol) in 15 mL of dry dichloromethane and 0.7 mL (5.3 mmol) bromotrimethylsilane was made. The system was sealed with a greased stopper and allowed to stir overnight. Volatiles were removed under reduced pressure to produce a viscous, brown oil, which was dissolved in 25 mL of a 4:1 methanol:water solution and allowed to stir for six hours. After removal of solvent under reduced pressure an off white solid formed, which was recrystallized from a minimal amount of acetonitrile to afford white crystals of 11-(perfluorobenzyloxy)undecylphosphonic acid (0.49 g, 92%). 1H NMR (399.9 MHz, DMSO-d6) δ 4.55 (s, 2H), 3.42 (t, J=6.4 Hz, 2H), 1.49-1.44 (m, 6H), 1.34-1.18 (m, 14H). 13C{1H} NMR (100.5 MHz, DMSO-d6) δ 104.5, 69.9, 58.8, 30.1, 29.9, 28.9, 28.8, 28.8, 28.7, 28.1, 26.8, 25.4, 22.648 (d, J=4.8 Hz). 31P{1H} NMR (161.91 MHz, DMSO-d6): δ 27.63. 19F NMR (376.3 MHz, DMSO-d6): δ −141.86 (m, 2F), −152.95 (m, 1F), −160.88 (m, 2F), from trifluoro acetic acid. Analysis calculated (found): C 50.00 (50.16), H 6.06 (6.23), F 21.97 (21.79). Exact mass calculated (found) for [M−H]−, m/z: 432.1489 (432.1487).
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a 1 L RB flask equipped with magnetic stirring bar was added benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (25 g, 123 mmol) and CH2Cl2 (246 ml). The resulting solution was cooled in an ice bath to 0° C., whereupon mCPBA (42.5 g, 246 mmol) was added in three portions over ˜15 min. The resulting slurry was naturally warmed up to rt over 2 days. LCMS indicates a complete reaction. The reaction was worked up as follows: the heterogeneous mixture was cooled to −15° C. for 1 hour, filtered to remove the solid which was rinsed with cold DCM. The resulting filtrate was washed with 1N aq. NaOH (4×100 mL), water (100 mL) and brine, then dried with anhydrous sodium sulfate. DCM phase was concentrated to benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (24.5 g, 91% yield) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.44 (5 H, m), 5.08-5.21 (2 H, m), 3.90 (2 H, dd, J=19.70, 12.65 Hz), 3.65-3.77 (2 H, m), 3.42 (2 H, ddd, J=12.76, 6.16, 1.10 Hz); LCMS (Chromolith RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 2.41 min; MS (ES+) m/z: 242.0 (M+Na+);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:20]([OH:21])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)Nc1cc(Cl)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC(CC)n1c(O)nc2ncc(Cl)cc21
Temperature: 25 °C
Yield: 71 %

Procedure:
To a refluxing solution of 5-chloro-N3-(pentan-3-yl)pyridine-2,3-diamine (1.5 g, 7.0 mmol, 1.0 equiv) in THF (10 mL) was added CDI portionwise until starting material was consumed as judged by TLC (50% EtOAC/Hexanes; UV). Approximately 10 equiv of carbonyldiimidazole were required. The resulting reaction mixture was cooled to room temperature, and the excess carbonyldiimidazole was quenched by the careful addition of water. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with satd. aq. NaHCO3 twice, and brine once. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC provided 6-chloro-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol as a white solid (1.2 g, 71%). m/z=240.1 [M+H]+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]1[CH:15]=[CH:16][C:17]([F:30])=[C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH2:27][OH:28])[C:21]=2[CH3:29])[CH:19]=1)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:13][C:14]1[CH:15]=[CH:16][C:17]([F:30])=[C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH:27]=[O:28])[C:21]=2[CH3:29])[CH:19]=1)[CH3:12]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(CO)c2C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(F)c(-c2cc(C)nc(C=O)c2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a solution of oxalyl chloride (1.46 mL, 17.3 mmol) in DCM (50 mL) cooled to −78° C. was added dropwise, a solution of dimethyl sulfoxide (2.68 mL, 37.74 mmol) in DCM (5 mL). After addition, the solution was stirred for 15 mins. A solution of [4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]methanol (which may be prepared as described in Description 140) (4.33 g, 15.73 mmol) in DCM (10 mL) was then added dropwise over about 5 mins. The mixture was allowed to stir at −78° C. for 2 hrs. Triethylamine (8.74 mL, 62.91 mmol) was added dropwise giving a precipitate and this was allowed to warm to room temperature over one hour. The reaction mixture was washed with water and brine, dried over magnesium sulphate and evaporated. The crude residue was purified by silica gel chromatography (50 g SiO2) eluting with ethyl acetate in iso-hexane (0-40%). Evaporation of desired fractions gave 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbaldehyde (D141) (2.89 g, 10.574 mmol, 67.2% yield) as a yellow solid;
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH2:18])[S:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([C:29]2[S:30][CH:31]=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:29]2[S:30][CH:31]=[C:32]([C:34]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:14]3[S:13][C:10]4[C:9]([N:15]=3)=[CH:8][C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:12][N:11]=4)=[O:35])[N:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Solvent: O
Product: O=C(Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1)c1csc(-c2ccccc2)n1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 2-phenylthiazole-4-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol, dissolved in CH2Cl2, washed with dilute NaHCO3, concentrated and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C27H23N5OS2: 497.13. Found (M+H)+ m/z=498.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1>C(#N)C>[CH3:3][N:7]([CH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH2:6][C:5]#[CH:11]
Reactant: FC(F)(F)Oc1ccc2nc(CBr)sc2c1
Solvent: CC#N
Product: C#CCN(C)Cc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 193.7 %

Procedure:
2-(bromomethyl)-6-(trifluoromethoxy)benzo[d]thiazole (4.4 g, 0.0141 mol) and N-Me-propargylamine (2.4 g, 2.5 eq, 0.035 mol) were dissolved in acetonitrile (70 ml) and the reaction mixture was heated to reflux for 1 h. Then it was cooled, evaporated to dryness and the residue was partitioned between EtOAc and water (100 ml:100 ml), NH4OH was add (to give pH of 9-10) and the organic phase was separated, dried over Na2SO4, evaporated and the residue purified by chromatography (hexane-EtOAc) to give 4.1 g (97%) of N-methyl-N-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)methyl)prop-2-yn-1-amine. The free base (4.1 g) was dissolved in 100 ml Et2O and HCl/IPA (2N) was added (pH=1-2). The white suspension that was obtained was filtered and the collected solid was dried to give 2.7 g (mp=117-120° C.) which was identified to be the HCl salt of compound C. 1H-NMR (of the HCl salt of the title compound, DMSOd6) δ 8.38 (s, 1H, Ar), 8.20 (d, 1H, Ar), 7.58 (d, 1H, Ar), 4.86 (br s, 2H, C—CH2) 4.22 (br s, 2H, MeN-CH2—C), 3.88 (s, 1H, CH), 2.89 (s, 3H, NMe); 13C-NMR (DMSOd6) δ 163.38, 150.96, 145.83, 136.87, 124.36, 120.36, 120.08, 115.46, 81.22, 73.60, 53.50, 44.37; LCMS (ES-API for free base) 301.0 (M+H).
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:9][CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12].N1C=CN=C1>CN(C=O)C>[Br:9][CH2:10][C@H:11]([O:12][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CBr)c1ccc2c(c1)COC(C)(C)O2
Temperature: 15 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Triethylsilyl chloride (205 g) was added dropwise to a stirred mixture of (1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350 g) and imidazole (108.5 g) in DMF (875 ml) at 5° C. Upon complete addition the mixture was warmed to 15° C. and stirred, at this temperature for 1 h. N-hexane (3500 ml) was then added to the mixture which was washed with water (3×1750 ml). The organic layer was dried over anhydrous MgSO4 before being filtered and concentrated under reduced pressure to give the title compound (488.6 g) as an oil, LC RT=7.97 min, δ (DMSO-d6) 7.18 (1H, d, J 8.2 Hz), 7.10 (1H, s), 6.75 (1H, d, J 8.2 Hz), 4.83 (1H, m), 4.78 (2H, d, J 6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1 Hz), 0.51 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=2[CH:12]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:37]2[S:36][C:35](=[O:40])[N:34]([CH2:33][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[C:38]2=[O:39])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=2[CH:12]=1
Reactant: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: O=C1CSC(=O)N1CCc1ccccn1
Product: COc1ccc(C=C2SC(=O)N(CCc3ccccn3)C2=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
5-[4-Methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-3-(2-pyridin-2-yl-ethyl)-thiazolidine-2,4-dione was prepared in a similar manner as described in Example 1 using 4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) benzaldehyde and 3-(2-pyridin-2-yl-ethyl)-thiazolidine-2,4-dione, mp 170–171° C., 1H NMR (300 MHz; DMSO-d6) 1.23 (s, 6 H); 1.28 (s, 6 H); 1.65 (s, 4 H); 2.02 (s, 3 H); 3.04 (t, J=7.1 Hz, 2 H); 3.81 (s, 3 H); 3.99 (t, J=7.1 Hz, 2 H); 7.04 (s, 1 H); 7.18–7.29 (m, 4 H); 7.36 (d, J=2.1 Hz, 1 H); 7.64 (dd, J1=9 Hz, J2=3.6 Hz, 1 H); 7.70 (t, J=3.7 Hz, 1 H); 7.91 (s, 1 H); 8.46 (d, J=4.0 Hz, 1 H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C([O:27][P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.C(#N)C>CCOC(C)=O>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[P:28](=[O:27])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: CCOP(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1

Procedure:
1-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (25 mg, 0.071 mmol), Cesium Fluoride (60 mg, 0.395 mmol), Ethoxydiphenylphosphane (68 mg, 0.287 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf: 0.4 (1:3 EtOAc:Pet Ether); Thick oil; 19.5 mg, 83%; 1H NMR (400 MHz, CDCl3, TMS) δ 8.28 (d, J=13.8 Hz, 1H), 7.95-7.84 (m, 3H), 7.79-7.40 (m, 13H); 13C NMR (100 MHz, CDCl3, TMS) δ 134.7 (d, J=2.3 Hz), 134.0 (d, J=9.3 Hz), 133.0, 132.3, 132.1 (d, J=10.0 Hz), 132.0 (d, J=1.5 Hz), 131.3 (d, J=243.5 Hz), 128.9, 128.5 (d, J=12.3 Hz), 128.4, 128.2, 127.4 (d, J=87.9 Hz), 126.8 (d, J=10.8 Hz); 31P NMR (162 MHz, CDCl3) δ 29.3; HRMS-ESI (m/z) calcd (C22H17OP+H)+: 329.1090. found: 329.1086; Known compound, Lit. Y. -L. Zhao, G. -J. Wu, Y. Li, L. -X. Gao, F.-S. Han, Chem. Eur. J. 2012, 18, 9622.