Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:20][O:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[N:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:20][O:19][CH2:18]2)[C:13]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][C:28]([OH:30])([CH3:29])[CH3:31])[N:23]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(CC2COC2)C(=O)O)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2COC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 24 h
Yield: 39.2 %

Procedure:
A reaction of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-oxetan-3-yl-propionic acid (0.18 g, 0.56 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 0.1 g, 0.64 mmol), and triethyl amine (0.17 ml, 1.24 mmol) in methylene chloride (15 mL) was cooled to 0° C. To this solution was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.56 mmol). The reaction was allowed to warm to 25° C. and stirred for 24 h. After this time, the reaction was concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 3% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-oxetan-3-yl-propionamide (0.1 g, 40%) as a 1:1 enantiomeric reaction as a white gummy solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.01-2.15 (m, 1H, CH of CH2), 2.32-2.47 (m, 1H, CH of CH2), 2.75-2.91 (m, 1H, CH), 3.31 (s, 3H, SO2CH3), 3.69-3.79 (m, 1H, ArCHCO), 3.85 (s, 2H, NCH2), 4.16-4.30 (m, 2H, 2×OCH of 2×OCH2), 4.47-4.57 (m, 2H, 2×OCH of 2×OCH2), 4.65 (s, 1H, OH), 6.44 (d, J=2.4 Hz, 1H, Ar), 7.52 (d, J=2.4 Hz, 1H, Ar), 7.57 (dd, Jo=8.3 Hz, Jm=1.4 Hz, 1H, Ar), 7.70 (d, Jm=1.4 Hz, 1H, Ar), 8.00 (d, Jo=8.3 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: CNC(=O)O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(O)C=CC=CC=1.C(=O)([O-])N.CN=C=O.[C:27]([O-])(=O)[NH:28][C:29]([NH2:31])=[O:30].NC1C=CC=CC=1>>[CH3:27][NH:28][C:29]([NH:31][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:30]
Reactant: NC(=O)NC(=O)[O-]
Reactant: CNC(=O)Oc1ccccc1
Agent: CN=C=O
Agent: NC(=O)[O-]
Solvent: Nc1ccccc1
Solvent: Oc1ccccc1
Product: CNC(=O)Nc1ccccc1

Procedure:
Following pyrolysis the residual material in the flask had a composition of 25 mole percent phenyl N-methylcarbamate and 75 mole percent phenol. The flask was cooled, a vacuum applied and phenol was stripped at a pressure of 20 mm Hg. Recovered phenol was also chromatographically pure. The residual carbamate remaining after phenol was stripped was returned to the pyrolysis flask. After 3 cycles of pyrolysis and phenol stripping, analysis showed: 96% conversion to methyl isocyanate, 2% unconverted material and 2% conversion to the allophanate. The methyl isocyanate was identified by reaction with aniline to give 1-methyl-3-phenylurea melting at 149°-150.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4](=[O:7])[CH2:5][CH3:6].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:1][O:2][C:3](=[O:8])[C:4](=[O:7])[C:5]([CH3:6])=[CH:11][N:12]([CH3:13])[CH3:14]
Reactant: CCC(=O)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)C(=O)C(C)=CN(C)C
Reaction time: 8 h

Procedure:
Methyl-2-ketobutyrate (5 g, 43 mmol) was added at ambient temperature to dimethylformamide dimethyl acetal (5.13 g, 43 mmol, 5.72 ml). The solution was stirred overnight under nitrogen and then the volatile components were removed in vacuo at 40° C. The yellow residue was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=O)=[O:18].CC(C)=O.C([Li])CCC.CN(C)C=O>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:17]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1c(F)ccc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To 1-Benzyloxy-2,4-difluoro-benzene (525, 3.00 g, 13.6 mmol) in Tetrahydrofuran (48 mL) under an atmosphere of nitrogen and cooled with dry ice/acetone was added n-Butyllithium (1.60 M in hexane, 8.94 mL). After 20 minutes, N,N-dimethylformamide (1.46 mL, 0.0189 mol) was added to the reaction. After another 20 minutes, the flask was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, acidified to pH=1, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound as a yellow solid (526, 2.5 g, 74%).
Reaction SMILES: [C:1]([N:5]=[CH:6][N:7]=[CH:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Li].[Cl-].[Cr+2:15].[Cl-]>O1CCCC1.C1C=CC=CC=1>[C:1]([N:5]=[C:6]([Cr:15][C:6]([N:7]=[CH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][C:1]([CH3:2])([CH3:3])[CH3:4])[N:7]=[CH:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C=NC=NC(C)(C)C
Reactant: [Cr+2]
Agent: [Cl-]
Agent: [Li]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C=NC(=NC(C)(C)C)[Cr]C(N=CC(C)(C)C)=NC(C)(C)C
Reaction time: 6 h

Procedure:
A 100 mL Schlenk flask, equipped with a magnetic stir bar and a rubber septum, was charged with 1,4-di-tert-butyl-1,3-diazabutadiene (1.000 g, 5.94 mmol) and tetrahydrofuran (20 mL). To this stirred solution at ambient temperature was slowly added freshly cut lithium metal (0.042 g, 6.000 mmol) and the resultant dark brown solution was stirred for 6 h. This solution was then added dropwise by cannula over a 30 min period to a stirred suspension of anhydrous chromium(II) chloride (0.365 g, 2.970 mmol) in tetrahydrofuran (40 mL). The resultant deep purple solution was stirred for 6 h at ambient temperature. The volatile components were then removed under reduced pressure and the resultant dark purple powder was dissolved in toluene (50 mL). The solution was filtered through a 1-cm pad of Celite on a coarse glass frit, and toluene was then removed under reduced pressure. Dark purple crystals of 1 were obtained by sublimation at 85° C./0.05 Torr (0.442 g, 38%): mp 95-97° C.; IR (Nujol, cm−1) 1704 (w), 1628 (w), 1538 (w), 1246 (m), 1209 (s), 1132 (m), 1104 (m), 1034 (m); μeff=2.83 and 2.84 BM in the solid state and in benzene solution, respectively. Anal. Calcd for C20H40CrN4: C, 61.82; H, 10.38; N, 14.42. Found: C, 61.71; H, 10.06; N, 14.37.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]1(=O)[O:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:13]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: O=C1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2[nH]c(CCCCO)nc2c1
Temperature: 100 °C
Yield: 79.3 %

Procedure:
A mixture of 4-tert-butyl-benzene-1,2-diamine (1 g, 6.09 mmol) and valerolactone (0.67 g, 6.70 mmol, 1.1 eq.) in 4N HCl aq (5 ml) was sealed and heated for 2 h at 100° C. LCMS analysis shows remaining diamine. Completion was achieved using excess of valerolactone (˜1.3 ml, 2 eq.) heating at 100° for 4 h. The reaction was cooled to RT and basified to pH 12 with a saturated solution of Na2CO3. EtOAc (100 ml) was added and organic separated, washed with saturated solution of Na2CO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography over silica gel, eluted with DCM-MeOH from 2% to 5% gradually to yield 1.19 g (79%) of a beige solid; MS (ESI+) for C15H22N2O m/z 1 [M+H]+, 247.15; HPLC purity 100% (ret. time, 1.42 min). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.38 (9H, s), 1.65-1.75 (2H, m), 2.00 (2H, quin, J=7.17 Hz), 2.98 (2H, t, J=7.09 Hz), 3.72 (2H, t, J=5.99 Hz), 7.31 (1H, dd, J=8.51, 1.58 Hz), 7.48 (1H, d, J=8.20 Hz), 7.56 (1H, d, J=1.26 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][S-:17].[Na+]>CS(C)=O.O>[CH3:16][S:17][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15]
Reactant: C[S-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(3-bromopropyl)phthalimide (500 mg) in DMSO (8 mL) was added sodium thiomethoxide (144 mg) and the reaction stirred at room temperature for 16 h. Then with water (2 mL) was added and the mixture stirred at room temperature for 10 min. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(3-methylsulfanyl-propyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [NH:1]1[C:57](=[O:58])[C@H:48]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=2)[NH:47][C:45](=[O:46])[C@H:43]([CH3:44])[N:42]([CH3:59])[C:40](=[O:41])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:29](=[O:30])[C@H:25]([CH:26]([CH3:28])[CH3:27])[NH:24][C:22](=[O:23])[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[N:15](C(OCC2C=CC=CC=2)=O)[C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(O)=O>[Pd].CO>[NH:1]1[C:57](=[O:58])[C@H:48]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([OH:56])=[CH:54][CH:55]=2)[NH:47][C:45](=[O:46])[C@H:43]([CH3:44])[N:42]([CH3:59])[C:40](=[O:41])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:29](=[O:30])[C@H:25]([CH:26]([CH3:28])[CH3:27])[NH:24][C:22](=[O:23])[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:15][C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)[C@@H]1NC(=O)[C@H](CCCCN)N(C(=O)OCc2ccccc2)C(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc2ccccc2)NC1=O
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc2ccccc2)NC1=O
Reaction time: 2 h

Procedure:
A dry mixture of 20.3 mg of the product of Example 12 or 13 and 4.4 mg of 10% palladium on carbon are combined with 1.5 ml of a 5:95 mixture on a volume basis of 88% formic acid and methanol. The mixture is stirred for 2 hours and filtered through Celite which had been prewashed with 5% formic acid and methanol followed by washing with two 1 ml portions of methanol. The filtrate is freeze-dried affording a residue of 17 mg of "Cyclo(D-Trp-Lys-Val-Phe-N-Me-Ala-Tyr)."
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: CCOC(=O)CN
Reactant: COc1cc(I)c(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cc(OC)c(OC)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a stirred solution of 2-iodo-4,5-dimethoxybenzoic acid (24.6 g, 80 mmol), ethyl 2-aminoacetate hydrochloride (11 g, 88 mmol), EDCl (17 g, 88 mmol) and HOBt (14 g, 88 mmol) in dry DCM (500 mL) was added Et3N (55 mL, 400 mmol) dropwise at rt. The resulting mixture was stirred at room temperature overnight then the reaction was quenched with water, and thoroughly extracted with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using petroleum ether/ethyl acetate 3:1 (v:v) as eluent to give ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate (29 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([N+:25]([O-])=O)[CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:23])[F:24])=[C:17]([NH2:25])[CH:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C=C\c2ccc(OC(F)F)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(/C=C\c2ccc(OC(F)F)c(N)c2)cc(OC)c1OC
Temperature: 50 °C
Yield: 68.5 %

Procedure:
4.1 grams (10.8 mmol) of (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3′-nitro-4′-difluoromethoxy-phenyl)ethene was dissolved in 10 ml of acetone/water (V/V, 2:1). The mixture was heated to 50°C., and was stirred to dissolve all the solid. 18.8 grams of sodium thiosulphate was added and the reaction mixture was heated to reflux for 6 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. The organic layer was separated, and the water layer was extracted with 50 ml×4 of ethyl acetate. The organic layer was combined and was washed with saturated brine, and then was dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporator partially and then cooled to get crude product. The crude product was recrystallized from petroleum ether to give 2.6 grams of yellowish crystalline solid in a yield of 68.6%. 1H-NMR (ppm) δ: 7.08 (d, 1H, 2′-H), 6.92 (dd, 1H, 6′-H), 6.76 (d, 1H, 5′-H), 6.62 (s, 2H, 2,6-H), 6.49 (d, 1H, 1a-H), 6.43 (d, 1H, 1a′-H), 6.28 (t, 1H, J2H-F=72 Hz, —CHF2), 5.13 (broad, 2H, NH2), 3.86 (s, 3H, 4-OCH3), 3.70 (s, 6H, 3,5-OCH3).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:10]=1
Reactant: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzaldehyde (3.00 g) in tetrahydrofuran (30 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.36 g) at 0° C. After stirring at room temperature for 1 hr., water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxyphenyl)methanol as colorless crystals (2.91 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:13]([NH:23][C:24](=[O:37])[CH2:25][C:26]3[C:30]4=[N:31][C:32]([O:35]C)=[CH:33][CH:34]=[C:29]4[NH:28][CH:27]=3)[CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)=[CH:11][N:12]=2)=[CH:4][CH:3]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:13]([NH:23][C:24](=[O:37])[CH2:25][C:26]3[C:30]4=[N:31][C:32]([OH:35])=[CH:33][CH:34]=[C:29]4[NH:28][CH:27]=3)[CH2:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[C:19]([F:21])[CH:20]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2[nH]cc(CC(=O)NC(Cc3cc(F)cc(F)c3)c3cnc(-c4ccc(Cl)cc4)o3)c2n1
Solvent: CC(=O)O
Product: O=C(Cc1c[nH]c2ccc(O)nc12)NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C

Procedure:
A solution of 21 (20 mg, 0.038 mmol) and KI (33 mg, 0.2 mmol) in acetic acid (5 mL) was heated in a microwave reactor at 160° C. for 10 min. After cooling to room temperature and removing the volatiles in vacuo, the resulting residue was purified by reverse phase HPLC to yield the title compound. 1H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.80 (s, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.02 (s, 1H), 6.86 (m, 3H), 5.10 (m, 1H), 3.20-3.16 (m, 1H), 3.01-2.95 (m, 1H). MS (m/z) 508.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:33]=[C:15]3[N:16]=[C:17]([N:27]4[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]4)[CH:18]=[C:19]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:14]3[N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C.O>ClCCl>[CH3:34][S:35]([O:32][C@H:29]1[CH2:30][CH2:31][N:27]([C:17]2[CH:18]=[C:19]([NH:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:14]3[N:13]=[C:12]([C:3]4[C:2]([CH3:1])=[N:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH:33]=[C:15]3[N:16]=2)[CH2:28]1)(=[O:37])=[O:36]
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(N3CCC(O)C3)cc(NC3CCOCC3)n2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc2ccccc2nc1-c1cc2nc(N3CC[C@H](OS(C)(=O)=O)C3)cc(NC3CCOCC3)n2n1
Reaction time: 2 h

Procedure:
To a solution of 1-[2-(3-methylquinoxalin-2-yl)-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-3-ol (200 mg, 0.449 mmol) and methanesulfonyl chloride (77 mg, 0.673 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.125 mL, 0.898 mmol) at 0° C. After being stirred for 2 h, the reaction mixture was poured into water. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=97:3) to give (3S)-1-[2-(3-methylquinoxalin-2-yl)-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-3-yl methanesulfonate (the compound of Example 1.008 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.73-1.83 (2H, m), 2.12-2.15 (2H, m), 2.30-2.39 (1H, m), 2.47-2.52 (1H, m), 3.04 (3H, s), 3.08 (3H, s), 3.56-3.63 (2H, m), 3.68-3.89 (4H, m), 3.99-4.02 (1H, m), 4.07-4.10 (2H, m), 5.19 (1H, s), 5.44-5.46 (1H, m), 6.20 (1H, d, J=8.2 Hz), 6.67 (1H, s), 7.70-7.77 (2H, m), 8.03-8.06 (1H, m), 8.16-8.19 (1H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH2:22][C@H:23]([N:28]([C:30](=[O:54])[C@H:31]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[CH:16]=2)=[CH:11][C:10]=1[CH2:55][C@H:56]([NH:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C:57]([OH:59])=[O:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:71][C:72]1[C:77](O)=[C:76]([F:79])[C:75]([F:80])=[C:74]([F:81])[C:73]=1[F:82].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH2:22][C@H:23]([N:28]([C:30](=[O:54])[C@H:31]([NH:46][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[CH:16]=2)=[CH:11][C:10]=1[CH2:55][C@H:56]([NH:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])[C:57]([O:59][C:77]1[C:76]([F:79])=[C:75]([F:80])[C:74]([F:81])=[C:73]([F:82])[C:72]=1[F:71])=[O:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
0.89 g (crude product, about 0.922 mmol) of (2S)-3-(4-(benzyloxy)-3′-{(2S)-2-[{(2R)-5-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]pentanoyl}(methyl)amino]-3-methoxy-3-oxopropyl}-4′-fluorobiphenyl-3-yl)-2-{[(benzyloxy)carbonyl]amino}-propionic acid (Example 20O) are introduced into 50 ml of dichloromethane. At −25° C., 0.85 g (4.61 mmol) of pentafluorophenol, 0.21 g (1.11 mmol) of EDC and 45 mg (0.37 mmol) of DMAP are added under argon. The mixture slowly warms to RT overnight. The reaction mixture is concentrated in vacuo and briefly dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:13][CH2:14][C:15]([O:17][C@H:18]1[C:35]([CH3:37])([CH3:36])[O:34][C:33]2[C:20](=[C:21]3[C:30](=[C:31]([O:38][CH3:39])[CH:32]=2)[C:29](=[O:40])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]4[CH:44]=[CH:43][CH:42]=[CH:41][C:27]4=2)[N:22]3[CH3:45])[C@H:19]1[O:46][C:47](=[O:49])[CH3:48])=[O:16])=O)(C)(C)C>C(Cl)(Cl)Cl>[NH2:13][CH2:14][C:15]([O:17][C@H:18]1[C:35]([CH3:36])([CH3:37])[O:34][C:33]2[C:20](=[C:21]3[C:30](=[C:31]([O:38][CH3:39])[CH:32]=2)[C:29](=[O:40])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]4[CH:44]=[CH:43][CH:42]=[CH:41][C:27]4=2)[N:22]3[CH3:45])[C@H:19]1[O:46][C:47](=[O:49])[CH3:48])=[O:16]
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](OC(C)=O)[C@@H](OC(=O)CNC(=O)OC(C)(C)C)C(C)(C)O2
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](OC(C)=O)[C@@H](OC(=O)CN)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Add 0.14 μl of iodotrimethylsilane to a solution, at ambient temperature, of 0.1 mmol of the compound of Example 11 in 1 ml of chloroform. The reaction mixture is stirred at ambient temperature for 5 minutes and then evaporated to dryness under reduced pressure. Chromatography over silica gel (dichloromethane/methanol:85/15) allows the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:19]=1[C:20]([NH:22][CH3:23])=[O:21].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:17][C:18]2[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: CNC(=O)c1cc(Cl)cc(C)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (93.6% purity, 16.16 g, 50.0 mmol) and 2-amino-5-chloro-N,3-dimethylbenzamide (i.e. the product of Examples 1, 2 or 3) (10.43 g, 52.5 mmol) in acetonitrile (35 mL) was added 3-picoline (12.65 mL, 12.11 g, 130 mmol). The mixture was cooled to −5° C., and then a solution of methanesulfonyl chloride (4.64 mL, 6.89 g, 60 mmol) in acetonitrile (10 mL) was added dropwise at −5 to 0° C. The mixture was stirred for 15 minutes at this temperature, and then for 3 h at room temperature. Then water (15 mL) was added dropwise and the mixture was cooled to 0° C. for 1 h. The mixture was filtered, and the solids were washed with 3:1 acetonitrile-water (2×10 mL), and then with acetonitrile (2×10 mL), and dried under nitrogen to afford the title compound as a light tan powder, 23.98 g (92.9% uncorrected yield), m.p. 239-240° C. 1H NMR (CDCl3) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H).