Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C@H:6]([C:7]([O-])=O)[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:10]([O-])=O.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:7]1[C@H:6]1[NH:1][C@@H:2]([C:10]2[NH:20][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[C@@H]1CCC[C@H](C(=O)[O-])N1
Reactant: Nc1ccccc1N
Product: c1ccc2[nH]c([C@@H]3CCC[C@H](c4nc5ccccc5[nH]4)N3)nc2c1

Procedure:
2k was synthesised by an analogous procedure to that described for 2a using cis-2,6-piperidinedicarboxilate (1.4 g, 6.97 mmol) and o-phenylenediamine (1.51 g, 13.94). Yield 1.92 g (87%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([CH3:17])[N:5]=1)[CH3:2].[I:18]N1C(=O)CCC1=O>CC#N>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]([I:18])=[C:6]([CH3:17])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(C)cc(NC2CCCCC2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCNc1nc(C)c(I)c(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of 2-ethylamino-4-cyclohexylamino-6-methylpyrimidine (600 mg, 2.56 mmol) in CH3CN (10 mL) was added N-iodosuccinimide (NIS, 658 mg, 2.92 mmol). The reaction was stirred for 2 h at room temperature. After removal of the solvent, the residue was dissolved in EtOAc. The organic phase was then washed with sodium bisulfite, brine, and dried over Na2SO4. Purification by flash column chromatography gave 660 mg (73% yield) of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[S:39])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=S)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 3-(3,5-dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide from Example 118 (3.61 g, 8.0 mmol) and Lawesson's reagent (3.57 g, 8.8 mmol) was stirred at room temperature overnight in tetrahydro-furan (250 mL). The reaction mixture was warmed to 50° C. for about one hour, then to 65° C. for about 4 hours then stirred at room temperature overnight. The mixture was concentrated to dryness and the residue dissolved in ethyl acetate and filtered through silica gel. Concentration of the eluant followed by trituration in hexanes/ethyl acetate (1:1) afforded the crude product (3.06 g). A portion (0.8 g) of this was chromatographed on silica gel in hexanes/ethyl acetate (1:1) to afford a pure sample (0.324 g); m.p. 206-208° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]2.[CH3:24][O:25][C:26](=[O:43])[CH:27](OS(C(F)(F)F)(=O)=O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([O:25][CH3:24])=[O:43])[CH:17]=[CH:16]2
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3C)ccc2c1
Reaction time: 4 h
Yield: 94.7 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 1.00 mmol), prepared in step 2 of Example 5, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.469 g, 1.50 mmol) and cesium carbonate (0.653 g, 2.00 mmol) with the exception that this reaction was complete after 4 hours at ambient temperature. Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 25% to 55% methylene chloride in hexane as the eluent gave methyl 2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.437 g, 94%), mp 117–118° C. Elemental Analysis for C31H27NO3 Calc'd: C, 80.67; H, 5.90; N, 3.03. Found: C, 80.35; H, 6.16; N, 2.91.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Cl[CH2:17][C:18]1[C:19]([CH3:24])=[N:20][O:21][C:22]=1[CH3:23]>CN(C)C=O>[CH3:24][C:19]1[C:18]([CH2:17][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)c2c(n1C)[C@]1(C)CC[C@H]2C1(C)C
Temperature: 100 °C
Yield: 41 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-chloromethyl-3,5-dimethyl-isoxazole (60 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. A further portion of and 4-chloromethyl-3,5-dimethyl-isoxazole (30 μL, 0.24 mmol) was added and the solution was heated at 100° C. for 2 h. The reaction mixture was evaporated and the residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 3% methanol/dichloromethane to give (4S,7R)-2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (62 mg, 41%) as an off-white solid. ES(+)-MS (M+H) 316.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44].O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:26]=1[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1C(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6′-hydroxyacetophenone (0.6 g) in N,N-dimethylformamide (5 mL) were added potassium carbonate (0.26 g) and methyl bromoacetate (0.13 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.62 g).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:18]([C:19]#[N:20])=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[NH:16][N:15]=1.C(O)(=O)C>ClCCl>[CH3:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]2[N:16]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:18]([C:19]#[N:20])=[C:14]2[N:13]=1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)n2nc(N3CCN(Cc4ccccc4)CC3)c(C#N)c2n1
Yield: 74.8 %

Procedure:
A mixture of 2.9 g (0.018 moles) of 1-phenyl-1,3-butanedione, 5.0 g (0.018 moles) of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 1) and 25 ml of glacial acetic acid was refluxed for 4 hours. The reaction mixture was evaporated in vacuo and gave a thick oil. The oil was dissolved in dichloromethane and partitioned with saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and passed through magnesium silicate. The solution was evaporated in vacuo and gave a yellow solid which was recrystallized from isopropanol and cyclohexane and gave 5.5 g of the desired product as a light yellow solid, mp 160°-164° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:48][CH2:49][C:50]([NH:52]O)=[NH:51]>CN(C=O)C.CCOC(C)=O>[Cl:48][CH2:49][C:50]1[N:52]=[C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=2)[CH2:7]3)[O:25][N:51]=1
Reactant: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: N=C(CCl)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(CCl)no2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 135 °C
Yield: 29.4 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (80.0 mg, 0.49 mmol), EDCI (104.0 mg, 0.54 mmol), HOBT (73.0 mg, 0.54 mmol) and 2-chloro-N-hydroxyacetamidine (59.0 mg, 0.54 mmol) were mixed in DMF (4.0 mL) over the weekend. The reaction mixture was diluted with EtOAc and washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was subjected to column chromatography (100% EtOAc). The product was heated to 135° C. in DMF for 1.5 hours. The reaction mixture was cooled and diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was purified by column chromatography to yield the title compound as a brown oil (63.0 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 8.01 (d, 2H), 7.37 (d, 2H), 7.21 (d, 2H), 4.81 (s, 2H), 4.69 (s, 2H), 4.34 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: [F-].[K+].[C:3]([C:7]1[C:8](=[O:18])[C:9](=[O:17])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C.C([Si](CC)(CC)[C:26]([F:29])([F:28])[F:27])C>C(#N)C>[C:13]([C:11]1[CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[C:8](=[O:18])[C:9]([OH:17])([C:26]([F:29])([F:28])[F:27])[CH:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(O)(C(F)(F)F)C(=O)C(C(C)(C)C)=C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A mixture of 100 mg (1.7 mmol) of potassium fluoride, 132 mg (0.60 mmol) of 3,5-di-tert-butyl-1,2-benzoquinone, and 2 mL of acetonitrile was treated successively with 40 μL (0.70 mmol) of glacal acetic acid and 129 mg (0.70 mmol) of triethyltrifloromethylsilane, and stirred vigorously at room temperature for 15 minutes. The mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates afforded a residue which was purified by PTLC (one 2 mm silica gel plate eluted with 20% dichloromethane--80% petroleum ether) to give 27 mg (16% yield) of 4,6-di-tert-butyl-2-hydroxy-2-trifluoromethyl-3,5-cyclohexadiene-one.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]C)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11](C2N=C(C3C=CC=CC=3)NC=2)=[CH:10][C:9]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][C:3]([C:11]1[CH:12]=[CH:13][C:8]([F:7])=[C:9]([CH3:25])[CH:10]=1)=[O:5]
Reactant: Cc1cc(-c2c[nH]c(-c3ccccc3)n2)ccc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.41 mL methyl bromoacetate was added to 1 g 4-(4-fluoro-3-methyl-phenyl)-2-phenyl-1H-imidazole and 1.66 g potassium carbonate in 10 mL DMF. The reaction was stirred 3 h at RT. Then 0.41 mL methyl bromoacetate was added and the reaction was stirred overnight at RT. The reaction mixture was added to ice water and extracted with DCM. The organic layer was dried and evaporated to give 1 g desired product. Rt: 0.94 min (method A), (M+H)+: 325
Reaction SMILES: [Br:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>>[C:7]([O:4][CH2:3][C:2]([Br:1])([F:6])[F:5])(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCC(F)(F)Br
Product: CC(C)(C)C(=O)OCC(F)(F)Br

Procedure:
One exemplary compound may be synthesized by reacting 2-bromo-2,2-difluoroethanol with pivalic chloride or anhydride to form 2-bromo-2,2-difluoroethyl pivalate, converting the bromo group into sodium sulfinate using a sulfur compound such as sodium dithionite, and converting sulfinic acid into sulfonic acid using an oxidizing agent such as hydrogen peroxide. This is followed by cation exchange with a triarylsulfonium halide or the like. The pivalic ester is then subjected to alkaline hydrolysis. Through reaction with (meth)acrylic anhydride, the alcohol resulting from hydrolysis is converted into a (meth)acrylic derivative, yielding the end compound.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=c1[nH]c2ccccc2cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2ccccc2nc1Cl
Temperature: 110 °C
Yield: 95.1 %

Procedure:
3-Nitroquinolin-2(1H)-one (1.40 g, 7.36 mmol) obtained in Step 1 was dissolved in phosphorus oxychloride (3.50 mL, 36.8 mmol) and the mixture was stirred with heat at 110° C. for 4 hours. The reaction mixture was poured into an ice bath and thereby the reaction was stopped. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 50/1) to give 2-chloro-3-nitroquinoline (1.46 g, yield: 95%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([N:1]=[O:3])[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: O=C(O)CNc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Product: O=NN(CC(=O)O)c1ccc(F)cc1
Reaction time: 6 h

Procedure:
Sodium nitrite (3.97 g), 57.5 mmol) in 10 mL water was added to a suspension of N-(4-fluorophenyl)glycine 9.25 g (54.7 mmol) in water (50 mL) under nitrogen. The reaction mixture was stirred until clear, ca. 6 hours. Acidification to pH 3 with HCl precipitated the product which was filtered and washed with water (50 mL) and dried to afford the title product.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+](C1C=CC([O:38][C:39]([O:41][CH2:42][C:43]2[S:47][CH:46]=[N:45][CH:44]=2)=O)=CC=1)([O-])=O>CN(C=O)C>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:11][C@H:10]([OH:28])[C@@H:2]([NH:1][C:39]([O:41][CH2:42][C:43]1[S:47][CH:46]=[N:45][CH:44]=1)=[O:38])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
The product of Example 68D (6.0 g, 15.6 mmoles) was dissolved in 60 mL of DMF under nitrogen atmosphere. To this stirred solution at room temperature was added 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole (4.67g, 15.6 mmole) and the resulting solution was stirred for 4 h. The solvent was removed under reduced pressure by rotary evaporation and the residue dissolved in 150 mL EtOAc. This solution was washed with 5×75 mL 1N NaoH solution, 100 mL brine, dried over Na2SO4. The solvent was removed to afford 8.02 g of a sligthly yellowish oil. This material was crystallized from 30 mL EtOAc and 40 mL hexane to afford 6.53 g (80%) of the desired product as a white solid. mp 118°-120° C. H 1NMR (CDCl3) δ8.79 (s, 1H), 7.83 (s, 1H), 7.30-7.15 (m, 8H), 7.08 (m, 2H), 5.23 (s, 2H), 5.14 (d, 1H, J=9 Hz), 4.52 (m, 1H), 3.92-3.72 (m, 3H), 3.65 (m, 1H), 2.85 (d-apparent, 2H, J=7.5 Hz), 2.72 (d-apparent, 2H, J=7 Hz), 1.61 (m, 2H), 1.38 (s, 9H). CIMS m/z (526) (M+H)+, 543 (M+18)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:26])[C:24]#[CH:25]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:26][CH2:23][C:24]#[CH:25])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A stirred mixture of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle syringe then stirred for an additional 18 hr. The reaction mixture was diluted with 200 ml of water and the resulting solid collected by filtration to yield 7.1 g of crude product. Recrystallization from isopropyl ether yielded 4.98 g (83.2%) of pale beige crystals, m.p. 119°-121° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:12][CH2:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=O.[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])([CH3:15])[CH3:14].C1(C)C(C)=CC=CC=1>O>[C:24]([C:21]1[CH:20]=[C:19]([CH2:28][CH2:29][C:30]([NH:32][N:33]2[C:9](=[O:10])[CH:4]3[CH2:3][CH:2]([CH3:1])[CH2:12][CH2:11][CH:5]3[C:6]2=[O:8])=[O:31])[CH:18]=[C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:22]=1[OH:23])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1CCC2C(=O)N(NC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(=O)C2C1
Yield: 100.5 %

Procedure:
A mixture of 4-methylhexahydrophthalic anhydride (32.8 g, 200 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (58.4 g, 200 mmol) and 650 ml of xylene was refluxed for 90 minutes under a nitrogen atmosphere with the azeotropic removal of water. The solvent was removed on a rotary evaporator to afford approximately 89 g of a white solid having a melting range of 87°-92° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (2.0 g, 0.0059 mol) in DCM (60 mL) with 3-[(methyloxy)carbonyl]benzoic acid (1.16 g, 0.00648 mol) and HATU (2.68 g, 0.00706 mol) and TEA (1.19 g, 1.64 mL, 0.0118 mol) gave a yellow solution upon stirring overnight at RT. The solution was washed in turn with sat. aq. NaHCO3, H2O, and sat. aq. NaCl, then dried (Na2SO4), and concentrated to a viscous syrup/foam (3.68 g). This was purified on a ‘CombiFlash’ 40 g silica gel column (hexane-EtOAc) [20-100% EtOAc] to afford the title compound (3.02 g). LC-MS m/z 466.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])(C)(C)C.[Br:30][CH2:31][Si:32]([CH3:35])([CH3:34])Cl.O>C(OCC)C>[C:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Si:32]([CH2:31][Br:30])([CH3:35])[CH3:34])[CH:3]=2)[CH2:17][CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: C[Si](C)(Cl)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Br)cc(C(F)(F)F)c2)CC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cc([Si](C)(C)CBr)c2)CC1
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-[3-bromo-5-(trifluoromethyl)-phenyl]-1-piperazine carboxylate (75 g, 183 mmoles) in diethyl ether, previously dried on molecular sieves, (1000 ml) was cooled to −65° C. and a 1.7M solution of tert-butyl lithium (215.6 ml, 366 mmoles) was added. After 30 minutes stirring bromomethyl-dimethyl-chlorosilane (49.9 ml, 366 mmoles) was added dropwise. After 2 hours stirring at −65° C., the reaction mixture was left at room temperature overnight. Water (600 ml) was added and the organic layer was washed with water, dried on MgSO4, filtered and evaporated.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[C:31]([OH:33])=[O:32])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[NH2:23][C@H:20]1[CH2:19][C@@H:18]([C:31]([OH:33])=[O:32])[C@@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]2=[O:34])[CH2:22][CH2:21]1.[C:37]([OH:39])([C:36]([F:41])([F:40])[F:35])=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirring solution of (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (38 g, 0.0799 mol; see Example 1, Step 4) in dichloromethane (400 mL) was charged with trifluoroacetic acid (100 mL) at 0° C. The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml) and the resultant solution was added dropwise to diethyl ether (1500 ml) with stirring. The solid formed was collected with filtration and washed with diethyl ether (3×50 ml). The white solid was dried in vacuo to give (1R,2S,5R)-5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid as its TFA salt (35.5 g, 86%). The compound was used to next step without further purification. LC/MS found [M+H]+=376.