Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][Br:9])[C:3]([O:5][CH3:6])=[O:4].[S:10]1C=CC=C1CC(O)=O.CCN(C(C)C)C(C)C.C1C[O:31][CH2:30][CH2:29]1>>[C:30]([S:10][CH:2]([CH2:7][CH2:8][Br:9])[C:3]([O:5][CH3:6])=[O:4])(=[O:31])[CH3:29]
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)C(Br)CCBr
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CCBr)SC(C)=O
Temperature: -20 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
10.0 g (38.4 mmol) of methyl 2,4-dibromobutanoate in 100 ml of dry THF at 20° C. was added drop wise the mixture of 2.75 ml (38.5 mmol) of thiolacetic acid in 8.5 ml (48.9 mmol) of DIPEA and 50 ml of dry THF in 1.5 hour. After stirring overnight at −20° C. then 0° C. for 2 hours under Ar, the mixture was concentrated, diluted with EtAc/Hexane, washed with 1.0 M NaH2PO4, dried over MgSO4, filtered, evaporated, and SiO2 chromatographic purification (1:12 to 1:10 EtAc/Hexane) to afford 9.5 g (96%) of the title compound. 1H NMR (CDCl3) 4.38 (1H, t, J=7.1 Hz), 3.74 (s, 3H), 3.40 (m, 2H), 2.57˜2.47 (m, 1H), 2.37 (s, 3H), 2.36˜2.21 (m, 1H); 13C NMR 193.24, 171.36, 53.15, 44.45, 34.67, 30.46, 29.46; MS m/z+276.9 (M+Na), 278.9 (M+2+Na)
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27](Cl)Cl.CCCCCC>>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH3:27])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: ClCCl
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4fluorophenyl)-5-pentylpyridine (Example 1) according to the procedures described in Example 101. 1H NMR (300 MHz, CDCl3): δ 7.10 (m, 4 H), 4.65 (dq, J=2.8, 6.6 Hz, 1 H), 3.75 (septet, J=6.6 Hz, 1 H), 3.20 (septet, J=6.6 Hz, 1 H), 2.19 (t, J =8.1 Hz, 2 H), 1.63 (d, J=2.6 Hz, 1 H), 1.40 (d, J=7.0 Hz, 3 H), 1.31 (m, 14 H), 1.11 (m, 4 H), 0.79 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C24H34FNO) 371, found 372 (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77; F, 5.11. Found: C, 77.59; H, 9.34; N, 3.75; F, 5.26. mp 99-101° C. Rf=0.2 (70% CH2Cl2/hexane).
Reaction SMILES: [BrH:1].[Br:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[NH2:10][C:11]([NH2:13])=[S:12]>CCO>[BrH:2].[BrH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:12][C:11](=[NH:10])[NH2:13]
Reactant: NC(N)=S
Reactant: Cc1[nH]cnc1CBr
Agent: Br
Solvent: CCO
Product: Cc1nc[nH]c1CSC(=N)N

Procedure:
A mixture of 12.8 g of 4-bromomethyl-5-methyl imidazole hydrobromide and 4 g. of thiourea in 200 ml. of EtOH is heated at reflux for 3 hr., cooled and the product is filtered off to give the title compound, m.p. 130°-132° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[C@H:9]([C:11]([O:13]C)=[O:12])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.O[Li:31].O>O>[Li+:31].[CH2:1]([N:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[C@H:9]([C:11]([O-:13])=[O:12])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]O
Reactant: COC(=O)[C@H](C)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H](C(=O)[O-])N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Product: [Li+]
Reaction time: 24 h

Procedure:
Methyl N-benzyl-N-(3-chloro-4-fluorophenyl)alaninate (2-1, 0.870 g, 2.704 mmol) in a 3:1:1 mixture of THF:MeOH:H2O (100 mL) was treated with LiOH hydrate (0.119 g, 2.974 mmol) then stirred 24 h. Upon completion, the reaction mixture was concentrated under vacuum to yield N-benzyl-N-(3-chloro-4-fluorophenyl)alanine lithium salt (2-2). MS 308.2 found, 308.7 (M+H+) required.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3](OCC)=[O:4].[O-:31][C:32]#[N:33].[K+]>C(O)CCC>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:2]2[O:1][C:32](=[O:31])[NH:33][C:3]2=[O:4])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC2OC(=O)NC2=O)cc1
Yield: 62.7 %

Procedure:
A mixture of ethyl 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (0.45 g), powdery potassium cyanate (0.24 g) and butanol (20 ml) was heated for 4 days under reflux. The solvent was distilled off under reduced pressure, and the residue was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:3) was obtained 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]-2,4-oxazolidinedione (0.28 g, 63%). The product was recrystallized from dichloromethane-ethanol to give colorless prisms, m.p.193-194° C.
Reaction SMILES: [C-:1]#[N:2].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[Co:13].[Co].[Cl-].[Zn+2:16].[Cl-]>O.C(O)(C)(C)C>[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[Co+3:13].[Co+3:13].[Zn+2:16].[Zn+2:16].[Zn+2:16]
Reactant: [Co]
Agent: [C-]#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)(C)O
Product: [Co+3]
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A one-liter round-bottom flask equipped with mechanical stirrer, addition funnel, and thermometer is charged with distilled water (604 g), potassium hexacyanocobaltate (14.8 g), and tert-butyl alcohol (78 g). The mixture is stirred until all of the cobalt salt dissolves. The resulting solution is heated to 30° C. A solution of zinc chloride in water (50 wt. % zinc chloride, 304 g of solution) is added over 50 min. with stirring. Stirring continues for another 30 min. at 30° C. The resulting white suspension is centrifuged. A wet cake of solids is isolated, and is resuspended with vigorous stirring in a solution of tert-butyl alcohol (204 g) and water (112 g). After all of the solids are completely suspended in the wash solution, the mixture is stirred for 30 min. The suspension is again centrifuged, and the wet solids are isolated. The solids are resuspended in 99.5% tert-butyl alcohol (288 g), centrifuged, and isolated as described above. The resulting paste contains about 24 wt. % zinc hexacyanocobaltate complex, the remainder being tert-butyl alcohol (about 64 wt. %), and water (about 12 wt. %). A sample of this paste catalyst is used "as is" as a catalyst for polyol synthesis. See Tables 1-5.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:30]1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:35](=[O:36])[CH2:34][C:32]1[NH:31][CH:30]=[N:29][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OCC1CC1
Product: O=C(Cc1cnc[nH]1)N1CCN(c2ccc(OC(F)F)c(OCC3CC3)c2)C[C@@H]1Cc1ccccc1
Yield: 35 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-piperazine and (1H-imidazol-4-yl)-acetic acid to afford the title compound as colorless solid (62 mg, 35%). LC/MS (Method B) 2.80 min, [M+1]+ 497.
Reaction SMILES: C(OC(NC(C1NC(C2C=CC=C3C=2N=C(NCC(F)(F)F)C(C)=N3)=CC=1C(OCC)=O)C)=O)(C)(C)C.Br[CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41].[C:59]([O:63][C:64]([NH:66][CH2:67][C:68](=[O:75])[CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:62])([CH3:61])[CH3:60].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCO>[C:59]([O:63][C:64]([NH:66][CH2:67][C:68](=[O:75])[CH:69]([CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41])[C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:61])([CH3:62])[CH3:60]
Reactant: CCOC(=O)CC(=O)CNC(=O)OC(C)(C)C
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)(C)C
Agent: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC(C)(C)C)nc12)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
This compound (873 mg, 34% yield) as a yellow foam was prepared according to the procedure described for intermediate 293b, using 2-bromo-1-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (605) (1.81 g, 5.11 mmol), ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (601) (1.50 g, 6.13 mmol) and K2CO3 (1.77 g, 12.77 mmol) in DMF (17 mL) was stirred at RT for 6 h, followed by the subsequent treatment of the resulting ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (296a) (1.43 g, 2.76 mmol, 54% yield, m/z (ESI, +ve) 519.2 (M+H)+) with NH4Oac (3.15 g, 40.9 mmol) in 12 mL of EtOH and AcOH (6 mL). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (dd, J=8.80, 5.67 Hz, 1H), 7.34 (dd, J=4.60, 2.45 Hz, 1H), 7.21 (dd, J=11.64, 8.90 Hz, 1H), 4.94 (s, 1H), 4.62 (d, J=5.87 Hz, 2H), 4.34 (q, J=7.24 Hz, 2H), 2.54 (s, 3H), 1.69 (s, 9H), 1.43 (s, 9H), 1.38-1.42 (m, 3H). 19F NMR (376 MHz, CDCl3) δ ppm −107.37 (s, 1F). m/z (ESI, +ve) 500.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)=[N+:17]=[N-:18].[O-]CC.[Na+].O>C(O)C>[CH:1]1([CH2:7][C:8]2[N:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)[N:17]=[N:18][C:9]=2[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC(=O)CC1CCCCC1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Ethyl 4-cyclohexyl-3-oxobutyrate (0.84 g, 3.96 mmol, 1.25 eq.) obtained in Example 102a) and 4-azido-N-ethylbenzamide (0.60 g, 3.15 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (298 mg, 3.96 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate-THF (4:1, 40 ml) and ethyl acetate (30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-yellow powder (1.04 g, 2.91 mmol, 92.4%).
Reaction SMILES: [CH2:1]([Li])CCC.N#N.C(NC(C)C)(C)C.[NH:15]1[CH:19]=[N:18][C:17]([CH2:20][C:21]2([CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]2)[C:22]#[N:23])=[N:16]1.CI>O1CCCC1>[NH:15]1[CH:19]=[N:18][C:17]([CH:20]([C:21]2([CH:24]=[CH:25][CH:26]=[CH:27][CH2:28]2)[C:22]#[N:23])[CH3:1])=[N:16]1
Reactant: [Li]CCCC
Reactant: N#CC1(Cc2nc[nH]n2)C=CC=CC1
Agent: N#N
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CC(c1nc[nH]n1)C1(C#N)C=CC=CC1
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (25 mL of 2.1 M reagent in hexane, 0.0525 mole) is added dropwise in an N2 atmosphere to a solution of di-isopropylamine (5.6 g) in tetrahydrofuran (100 mL) which is maintained at -20°. This cold solution is then added dropwise to a solution of 4-[1-(1,2,4-triazolylmethyl)benzonitrile (9.10 g) in tetrahydrofuran (250 mL) which is maintained at -50° during addition and for 30 minutes subsequently. The reaction mixture is then cooled to -70° and 7.1 g (3.1 mL) of methyl iodide is added dropwise. The reaction is stirred at -70° for 30 minutes and then without external cooling for 10 hours. The reaction is quenched by addition of water (300 mL) and extracted with diethyl ether (3×100 mL). The combined ether extracts are extracted with 3 N hydrochloric acid (3×60 mL) and the acid extracts are made basic (pH 9) with 6 N sodium hydroxide. The crude product is extracted into ether (3×60 mL), and after drying (MgSO4) and solvent evaporation, 4-[1-(1-(1,2,4-triazolyl)ethyl]benzonitrile is obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(P(CCCC)CCCC)CCC.[CH:26]1([NH:29][C:30]([C:32]2[N:33]=[N:34][N:35]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[CH:43][CH:42]=3)[C:36]=2[CH2:37][CH2:38][CH2:39]O)=[O:31])[CH2:28][CH2:27]1.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:26]1([NH:29][C:30]([C:32]2[N:33]=[N:34][N:35]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:46]=3)[C:36]=2[CH2:37][CH2:38][CH2:39][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[O:31])[CH2:27][CH2:28]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOc2ccc(OC(F)(F)F)cc2)cc1
Yield: 64.3 %

Procedure:
To a solution of 4-(trifluoromethoxy)phenol (52 mg) in toluene (0.5 ml) was added a solution of tributylphosphine (51 mg) in toluene (0.5 ml) under stirring, a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (29 mg) in toluene (0.5 ml) and a solution of 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine in toluene (0.5 ml) were successively added, and the mixture was stirred at room temperature for 64 hr. The reaction mixture was filtered through a filter tube (Biospin column, Bio-Rad), and washed with 1 ml of ethyl acetate. The filtrates were combined, 1 ml of ethyl acetate and 1 ml of saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was vigorously stirred at room temperature for 30 min. The organic layer was recovered using Presep™ Dehydration (Wako Pure Chemical Industries, Ltd.) and concentrated to dryness. The residue was dissolved in DMSO (0.7 ml) and purified by preparative HPLC (Gilson, Inc., high-throughput purification system, column: YMC CombiPrep ODS-A S-5 μm, 50×20 mm, solvent: solution A; 0.1% formic acid aqueous solution, solution B; 0.1% formic acid acetonitrile solution, gradient cycle: 0 min (solution A/solution B=95/5), 1.00 min (solution A/solution B=95/5), 5.20 min (solution A/solution B=5/95), 6.40 min (solution A/solution B=5/95), 6.50 min (solution A/solution B=95/5), 6.60 min (solution A/solution B=95/5), flow rate: 25 ml/min, detection method: UV 220 nm) to give the title compound (27 mg) (LC/MS purity 100%, ESI+:518 [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[I:11]I>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[I:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH:7]=[O:8]
Reactant: II
Reactant: COc1ccc(C=O)cc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C=O)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate (0.92 g, 4.19 mmol) were mixed in dichloromethane (25 mL). Iodine (1.19 g, 4.7 mmol) was added in small portions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an aqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3×20 mL) followed by drying with MgSO4 and evaporation in vacuo afforded 0.94 g of 3-iodo-4-methoxybenzaldehyde.
Reaction SMILES: C(S[C:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[CH:9][CH:10]=2)[N:5]=1)C.O[O:29][S:30]([O-:32])=O.[K+].[CH2:34]1COC[CH2:35]1>O>[CH2:34]([S:30]([C:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]3)=[CH:9][CH:10]=2)[N:5]=1)(=[O:32])=[O:29])[CH3:35]
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CCSc1ncc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Agent: [K+]
Solvent: O
Product: CCS(=O)(=O)c1ncc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 4-(2-(ethylthio) quinazolin-7-yloxy)piperidine-1-carboxylate (1 eq) in THF (5 ml) was added a solution of oxone in water (5 ml) at 0° C. The reaction mixture was stirred for 30 min at 0° C. then warmed to room temperature and stirred for 4 h. The reaction was quenched with satd. sodium thiosulfate solution and basified with 1N NaOH. The product was extracted from basic layer with DCM. The DCM extracts were combined together, washed with brine and dried over sodium sulfate. The purification by flash column chromatography (70% EtOAc/Hexane) provide pure product in 60% yield. ES/MS m/z 422.0 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1>>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CNC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Product: CNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2o1

Procedure:
2-Chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to give, after purification by reverse HPLC, 293. MS (Q1) 379 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C(N)CN.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:24])([F:25])[F:26])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C(=O)NCC(F)(F)F)C(C)C)c3)c3cc(Cl)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: NCCN
Product: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 2-{[5-(5-chloro-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]amino}-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 1-1a (315 mg, 0.543 mmol) dissolved in a mixture of MeOH (3.0 ml) and THF (7 ml) was added ethylenediamine (0.183 ml, 2.72 mmol) followed by 1 M sodium hydroxide (1.086 ml, 1.086 mmol). The mixture was allowed to stir for ½ hr at room temperature. The reaction was quenched with 1N HCL (2.7 mL), concentrated to remove solvents and aqueous sodium bicarbonate (10 mL) added. The product was extracted into DCM, dried over sodium sulfate, concentrated and chromatographed on silica using 1-10% methanol/dichloromethane to give 135 mg desired product 1-1b as a foam. LRMS (ESI) m/z 426.1 [(M+H)+; calcd for C19H19ClF3N5O: 426.1].
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[C:31]1([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]1([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:4]3)[CH2:44][CH2:45]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 34 mg (0.084 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 19 mg (0.093 mmol) of 4-(3-phenylpropyl) piperidine in 2 mL of CH2Cl2 at rt was added 27 mg (0.13 mmol) of sodium triacetoxyborohydride. After stirring for 1 h, the reaction was diluted with 25 mL of CH2Cl2 and washed with 25 mL of sat'd NaHCO3. After separating the phases, the aqueous layer was extracted with 25 mL of CH2Cl2. The combined organic phases were washed with 50 mL of sat'd NaCl, dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 50:1 v/v CH2Cl2/MeOH to give 37 mg (74%) of the title compound: 1H NMR (500 MHz) δ 0.99-2.91 (32H), 3.20-3.27 (3H1), 5.19 (ABq, J=19.7, 2H), 7.17-7.43 (15H); NH3-CI-MS 593 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC1N(C)CC[NH+]1C.[OH:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([NH2:52])([CH2:45]3)[CH2:43]1)[CH2:49]2>ClCCl>[OH:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([NH:52][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[N:3]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:4]=4[CH3:10])=[O:9])([CH2:45]3)[CH2:43]1)[CH2:49]2
Reactant: Cc1nc(C(=O)O)c(C)n1-c1ccccc1
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Agent: CN1CC[NH+](C)C1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)NC23CC4CC(CC(O)(C4)C2)C3)c(C)n1-c1ccccc1
Yield: 67.1 %

Procedure:
To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.66 gram, 0.00306 mol) in dichloromethane (35 ml) was successively added diisopropylethylamine (DIPEA) (3.1 ml), CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate). (2.55 gram) and 3-hydroxyadamantane amine (0.612 gram, 0.00366 mol). The resulting mixture was reacted at 20° C. for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with 5% aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichoromethane/methanol=98/2 (v/v)) to give N-(3 hydroxyadamant-1-yl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (0.75 gram, 67% yield). Rf (silica gel/dichoromethane/methanol=98/2 (v/v))˜0.6. Melting point: 215-220° C.