Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])=[O:6])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(I)n2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a mixture of ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (3.7 g, 6.41 mmol) in CH2Cl2 (80 mL) was added Dess-Martin Periodinane (2.72 g, 6.41 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with sat. aq. NaHCO3 solution (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford the desired ethyl 6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (2.5 g, 5.8 mmol, 91% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 4.50 (dq, J=14.5, 7.1 Hz, 4H), 2.56 (s, 3H), 1.46 (t, J=7.2 Hz, 3H), 1.48 (t, J=7.2 Hz, 3H). LCMS (M+H)=431.87.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6]CN)[CH3:2].[CH:16]([N:19](C(C)C)CC)(C)C.Cl.[O:26]=[C:27]1[NH:36][C:35]2[N:34]=[CH:33][C:32](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:31][C:30]=2[CH2:29][CH2:28]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[C:12]([CH:13]([CH3:14])[CH3:15])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:19]([CH3:16])[C:39](=[O:41])/[CH:38]=[CH:37]/[C:32]1[CH:33]=[N:34][C:35]2[NH:36][C:27](=[O:26])[CH2:28][CH2:29][C:30]=2[CH:31]=1)[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCOc1c(CCN)cccc1C(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)cccc1C(C)C
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of (2-ethoxy-3-isopropylbenzyl)methylamine (0.223 g, 1.07 mmol) and diisopropyl-ethylamine (0.51 mL, 2.94 mmol) in DMF (20 mL) was treated sequentially with (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (0.250 g, 0.981 mmol), 1-hydroxybenzotriazole hydrate (0.144 g, 1.07 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.205 g, 1.07 mmol). After stirring for 18 h, the reaction mixture was diluted with H2O (30 mL). The resulting solids were collected by filtration, and when washed with Et2O (50 mL), unexpectedly dissolved. The filtrate was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to a light orange solid. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 99.5:0.5) gave the title compound (0.20 g, 52%) as a white solid and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 10.64-10.61 (m, 1H), 8.37-8.31 (m, 1H), 8.09-7.99 (m, 1H), 7.52-7.49 (m, 1H), 7.28-7.20 (m, 2H), 7.11-7.05 (m, 1H), 6.89-6.86 (m, 1H), 4.81-4.66 (m, 2H), 3.86-3.79 (m, 2H), 3.28-3.25 (m, 1H), 3.11-2.85 (m, 5H), 2.55-2.49 (m, 2H), 1.39-1.35 (m, 3H), 1.19-1.17 (m, 6H); MS (ESI) m/e 408 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][O:7][CH2:8][C:9]([NH2:28])([CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:2].[C:30]([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10][C:9]([NH:28][C:43](=[O:44])[CH2:42][CH2:41][NH:40][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])([CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8][O:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])[CH3:18]
Reactant: CCOC(=O)CCOCC(N)(COCCC(=O)OCC)COCCC(=O)OCC
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)CCOCC(COCCC(=O)OCC)(COCCC(=O)OCC)NC(=O)CCNC(=O)OCc1ccccc1
Yield: 90.1 %

Procedure:
The compound 23 was prepared using General Procedure B with amine 1 (4.0 g, 9.49 mmol), N-Cbz-β-alanine (2.54 g, 11.39 mmol), 1-hydrobenzotriazole (HOBt) (1.53 g, 11.39 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (2.18 g, 11.39 mmol) in CH2Cl2 (50 mL). Purification by flash column chromatography (on silica gel, EtOAc:n-hexane=1:3) afforded 5.36 g (90%) of the desired product 23 as a colorless syrup. 1H NMR (CDCl3): δ 7.31 (m, 5H, ArH), 6.16 (s, 1H, NH), 5.66 (s, 1H, NH), 5.08 (s, 2H, OCH2Ar), 4.12 (q, J=6.4 Hz, 6H, OCH2), 3.67 (m, 12H, CH2O), 3.45 (dt, J=7.4, 15.0 Hz, 2H, CH2NHCO), 2.51 (t, J=8.4 Hz, 6H, CH2CO), 2.37 (dt, J=7.4, 8.6 Hz, 2H CH2CO), 1.24 (t, J=6.4 Hz, 9H, CH3).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:61])=[C:20]([CH2:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53]C(=O)OC(C)(C)C)=[CH:28][CH:27]=3)(=[O:25])=[O:24])[N:21]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>FC(F)(F)C(O)=O>[NH2:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([CH2:22][C:20]2[N:21]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[CH:16][CH:15]=3)[O:18][C:19]=2[CH3:61])(=[O:24])=[O:25])=[CH:27][CH:28]=1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3ccccc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccc(C(=O)NCc3ccccc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCN)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of carbamate 62 (55 mg, 0.064 mmol) in a mixture of trifluoroacetic acid (2 mL) and anhydrous DCM (8 mL) was stirred at 20° C. for 1 h. The solvent was evaporated and the residue was purified by column chromatography, eluting with 10% MeOH/DCM containing 1% aqueous NH3, to give the amine 63 (38 mg, 78%) as a white gum: 1H NMR δ 9.18 (t, J=5.9 Hz, 1H, CONH), 8.01 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d, J=8.6 Hz, 2H, H-3, H-5), 7.79 (br d, J=8.5 Hz, 2H, H-2″, H-6″), 7.68 (br d, J=8.5 Hz, 2H, H-3″, H-5″), 7.33-7.34 (m, 4H, H-2′, H-3′, H-5′, H-6′), 7.22-7.28 (m, 1H, H-4′), 4.74 (s, 2H, CH2SO2), 4.49 (d, J=5.9 Hz, 2H, CH2NH), 4.45 (s, 2H, CH2C≡C), 3.62-3.65 (m, 2H, CH2O), 3.56-3.59 (m, 2H, CH2O), 3.50-3.52 (m, 16H, CH2O), 3.38 (t, J=5.7H, 2H, CH2O), 2.69 (t, J=5.5 Hz, 2H, H-21′″), 2.17 (s, 3H, CH3), NH2 not observed; 13C NMR δ 165.4, 158.1, 150.1, 139.5, 138.2, 135.7, 132.0 (2), 128.7, 128.6, 128.3 (2), 128.1 (2), 127.4, 127.2 (2), 126.8 (2), 125.7, 125.4 (2), 90.1, 84.1, 71.7, 69.8 (6), 69.7, 69.6, 69.5, 68.8, 58.0, 52.7, 42.7, 40.8, 9.7; HRMS calcd for C40H50N3O10S (MH+): m/z 764.3211. found m/z 769.3227.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](OCC)=O.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:24]([CH2:23][C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1cccs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccs3)nc(=O)c1-2
Temperature: 25 °C
Yield: 40.3 %

Procedure:
Sodium (414 mg) was dissolved in ethanol (45 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2 g, 9 mmol), followed by ethyl 2-thienylacetate (3.1 g, 18 mmol) were added. The reaction mixture was refluxed overnight, cooled to room temperature and the ethanol was stripped. Water, followed by 2N HCl were added to the residue and the product was collected by filtration, and washed with water. The product was recrystallized from ethyl acetate and dried at 90° C. and 0.2 mm Hg to afford 1.19 g of 1-cyclopentyl-3-ethyl-6-(2-thienylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 173-174° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]S(C(F)(F)F)(=O)=O.F[N+:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=5)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:31])[F:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: F[n+]1ccccc1
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CC1CCn2c1c(-c1ccccn1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 0 °C
Yield: 9.4 %

Procedure:
The 1st enantiomer (described as the enantiomer isolated and having the retention time of 15 min per the conditions reported in Example 1.7) of 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (0.100 g, 0.219 mmol) was dissolved in anhydrous DCM (2.2 mL) using a plastic vial. The reaction was cooled to 0° C., and N-fluoropyridinium triflate (0.073 g, 0.295 mmol) was added. The reaction was allowed to warm to 25° C. and after 4 h there was a dark solution. The reaction was diluted with EtOAc (40 mL), washed with water/brine (2×10 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo. The residue was purified by HPLC to give the titled compound (0.011 g) as a yellow solid. LCMS m/z=535.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.54-1.78 (m, 4H), 1.79-1.92 (m, 2H), 2.05 (dd, J=9.92, 4.48 Hz, 2H), 2.43-2.53 (m, 2H), 2.57-2.73 (m, 2H), 3.29-3.41 (m, 1H), 4.09-4.28 (m, 3H), 5.17 (d, J=3.54 Hz, 2H), 6.99 (dd, J=8.84, 2.27 Hz, 1H), 7.34 (d, J=8.84 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.53 (t, J=6.25 Hz, 1H), 7.56-7.61 (m, 1H), 7.64-7.69 (m, 1H), 7.73 (s, 1H), 7.90 (d, J=8.34 Hz, 1H), 8.23 (td, J=7.86, 1.58 Hz, 1H), 8.66 (d, J=4.42 Hz, 1H).
Reaction SMILES: Br[C:2]1N=C(SC)C(=O)N(C(CC)CC)[CH:7]=1.Br[C:17]1[N:18]=[C:19]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([Cl:39])=[CH:35][C:36]=3[Cl:38])[CH2:31][CH2:30]2)[C:20](=[O:28])[N:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:22]=1.C([Al](CC)CC)C>>[Cl:39][C:34]1[CH:33]=[C:32]2[C:37](=[C:36]([Cl:38])[CH:35]=1)[N:29]([C:19]1[C:20](=[O:28])[N:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:22]=[C:17]([CH2:2][CH3:7])[N:18]=1)[CH2:30][CH2:31]2
Reactant: CCC(CC)n1cc(Br)nc(SC)c1=O
Reactant: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O
Agent: CC[Al](CC)CC
Product: CCc1cn(C(CC)CC)c(=O)c(N2CCc3cc(Cl)cc(Cl)c32)n1

Procedure:
Prepared in a similar fashion as described for XXXII (Example 481, part B) using 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) as the starting material and triethylaluminum in place of trimethylaluminum. mp 136-137° C.; 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=1.8 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.54 (s, 1 H), 4.90-4.79 (m, 1 H), 4.30 (t, J=8.1 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 2.44 (q, J=7.4 Hz, 2 H), 1.84-1.69 (m, 2 H), 1.67-1.61 (m, 2 H), 1.18 (t, J=7.5 Hz, 3 H), 0.86 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C19H24N3OCl2 (M+H)+: 380.1296; Found m/z 380.1280.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:37])=[CH:22][C:23]([CH3:36])([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[CH3:24])(=O)C>O1CCCC1>[F:37][C:21](=[CH:22][C:23]([CH3:36])([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=1)[CH3:24])[CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OCC(F)=CC(C)(C)c1ccc(OC(F)(F)F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C=C(F)Cc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Yield: 41.7 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.3 g), tetrahydrofuran (2 ml) and magnesium (22 mg), and 2-fluoro4-methyl-4-(4-trifluoromethoxyphenyl)pent-2-enyl acetate (Example 15) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to give the title compound (56 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]([OH:18])[CH:15]([Br:17])[CH3:16])=[CH:12][CH:11]=[C:10]([O:19][CH3:20])[C:8]=2[N:9]=1>O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=[O:18])[CH:15]([Br:17])[CH3:16])=[CH:12][CH:11]=[C:10]([O:19][CH3:20])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(O)C(C)Br)c2s1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc(C(=O)C(C)Br)c2s1
Temperature: 70 °C

Procedure:
5.0 g of [7-(2-bromo-1-hydroxy-propyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester 0.0133 Mol) were suspended in water (30 ml) and 2.0 g of CrO3 (0.02 Mol), dissolved in acetic acid (30 ml), were added. The reaction mixture was heated to 70° C. for 2 hrs. and then evaporated to dryness. The residue was taken up in sat. NaHCO3 (200 ml), extracted 4× with ethyl acetate (200 ml each) and the combined organic phases were dried over MgSO4. The title compound was obtained as orange crystals (74%); F.p.: 199-201° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:42])[NH:12][C@H:13]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:14](=[O:32])[N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:24])[CH2:22][CH2:23][C:17]2([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16]1)([CH3:10])[CH3:9])(C)(C)C.Cl>CCOCC>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:14](=[O:32])[N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:24])[CH2:22][CH2:23][C:17]2([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16]1)=[O:42]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)CCC2(Cc2ccccn2)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(N)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)CCC2(Cc2ccccn2)C1

Procedure:
Compound of Example 202, Step E (12 mg, 0.020 mmol) was deprotected as described in General Procedure C to provide, after trituration with ether, Example 202, Step F as its HCl salt (5 mg, 50%): +APcl MS (M+1)+ 494; 1H NMR (400 MHz, CD3OD) δ: 8.90-7.15 (arom, series of m, 9H), 5.31 (m, 0.5H), 5.15 (m, 0.5H), 2.86 (d, 0.5H), 2.77 (d, 0.5H), 1.60 (Me, m, 6H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>CCCCCC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1C2CC3CC(C2)CC1C3

Procedure:
A hexane solution containing 2-adamantanone (2 g) and tert-butyl carbazate (1.76 g) was heated to reflux for 3 hours. When the solution cooled, the title compound crystallized and was filtered (3.28 g). M.p. 175-177°
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.Cl>CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:17]1([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(C(F)(F)F)CCOCC1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
Tetrahydrofuran (110 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (4.13 mL, 28.0 mmol) was then added and stirred under N2 and then cooled to 0° C. Dihydro-2H-pyran-4(3H)-one (1.845 mL, 19.98 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.200 mL, 0.200 mmol) was added dropwise slowly via syringe. The reaction was then allowed to warm up to RT for 30 min. The reaction was then cooled back down to 0° C. and added 1M HCl (50 mL) and then stirred at RT for overnight. The reaction was diluted with EtOAc and separated with brine. The organic layer was dried over MgSO4, filtered and evaporated to give the crude material which was crystallized from hexane to give the product 4-(trifluoromethyl)tetrahydro-2H-pyran-4-ol (1.45 g, 8.52 mmol, 42.7% yield) as white crystals. 1H NMR (400 MHz, CHLOROFORM-d) d 3.96-3.84 (m, 2H), 3.76 (td, J=12.1, 2.1 Hz, 2H), 2.08-1.90 (m, 3H), 1.65-1.48 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:20])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cncc2ccccc12
Solvent: ClCCl
Product: Cc1c[n+]([O-])cc2ccccc12
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a solution of 4-methylisoquinoline (0.6 g, 4.19 mmol) in DCM (20 ml) was added m-CPBA (2.169 g, 12.57 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The reaction mass was diluted with DCM and extracted with water. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get desired compound (0.65 g, 88%) as a semi solid. The crude compound was taken further without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4OC[CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)[O:33][CH2:32]2)C1=O.Cl[CH2:46][C:47]1[S:51][CH:50]=[N:49][CH:48]=1.BrCCCCC>>[S:51]1[C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[CH2:32][O:33][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:48][N:49]=[CH:50]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: ClCc1cncs1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1N(Cc2cncs2)c2ccccc2C12COc1cc3c(cc12)OCOC3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 5-(chloromethyl)thiazole to replace 1-bromopentane, 1′-(1,3-thiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (56%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 7.89 (s, 1H), 7.29-6.86 (m, 4H), 6.47 (d, J=2.0 Hz, 1H), 6.16 (d, J=2.0 Hz, 1H), 5.13 (ABq, 2H), 4.74 (ABq, 2H), 4.20-4.03 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.0, 155.2, 153.8, 144.7, 142.6, 141.0, 138.3, 133.0, 132.2, 128.9, 124.1, 123.8, 120.7, 111.5, 108.7, 99.4, 79.9, 64.5, 63.9, 57.9, 36.2; MS (ES+) m/z 392.4 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](O)([CH2:14][CH:15]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:16]([F:19])([F:18])[F:17])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:26][C:24]1[CH:25]=[C:20]([CH:15]([C:16]([F:17])([F:19])[F:18])/[CH:14]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:7][CH:8]=2)\[CH3:13])[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CC(O)(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C/C(=C\C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a solution of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of p-toluenesulfonic acid (PTSA) and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to room temperature and dissolved in ethyl acetate. The solution was washed with sat aq NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH:15]=[O:16])[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:17][O:18][C:19](=[O:24])[CH2:20][N+:21]([O-:23])=[O:22].C(OCC)(=O)C.Cl>CCO.N1CCCCC1>[CH3:17][O:18][C:19](=[O:24])[CH:20]([N+:21]([O-:23])=[O:22])[CH:15]1[C:13]2[C:14]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[C:3](=[O:4])[O:16]1)[CH:10]=[CH:11][CH:12]=2
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: COC(=O)c1cccc2cccc(C=O)c12
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(C1OC(=O)c2cccc3cccc1c23)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 8-formylnaphthalene-1-carboxylic acid methyl ester (2.5 g, 11.68 mmol) in EtOH (20 mL) is added 8 drops of piperidine followed by nitroacetic acid methyl ester (2.78 g, 23.4 mmol) and the mixture is stirred at RT for 20 h. Ethyl acetate is added followed by 1N HCl. The resulting precipitate is filtered to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:30]([C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH2:25][C:23]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:24])[CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1cccc(OCC(=O)N2CCOCC2)c1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCC(=O)N4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.87 g), 3-[4-morpholinylcarbonylmethoxy]benzaldehyde (2.1 g, 8.43 mmol) and xylenes (20 ml) was heated at 160° C. for about 2 days. The solvent was removed, then methanol was added to the residue and the product was collected by filtration. Additional product was obtained from the filtrates and the product fractions were pooled and recrystallized from CH3CN/CHCl3 to afford 1-cyclopentyl-3-ethyl-6-[3-(4-morpholinylcarbonylmethoxy)-phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 212°-213° C.