Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[F:31][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: ClCCl
Product: C[C@@H]1C[C@H](F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
tert-Butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.190 g, 3.558 mmol) was dissolved in methylene chloride (55 mL) and cooled to −20° C. The solution was treated with DAST (1.410 mL, 10.68 mmol) and stirred at −20° C. for 1 hour. The reaction was quenched with ice and then warmed to ambient temperature. The mixture was diluted with saturated NH4Cl and separated. The aqueous phase was extracted with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated to an oil. This oil was subjected to chromatography on SiO2 (Biotage 40S, load with methylene chloride) then eluted with 2.5% MeOH/DCM then 3.5% MeOH/DCM. The mixed fractions were concentrated, and the material was re-chromatographed on SiO2 (Biotage 40S, load with DCM) and eluted with 2 hexane/EtOAc. The product was collected as an oil to give tert-butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.725 g, 61%). LCMS (APCI+) m/z 337.0 [M+H]+; Rf 3.13 min.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)[CH3:24].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.C(O)C.CCCCCC>[Cl:16][C:17]1[C:22]([CH:29]([C:28]2[CH:31]=[CH:32][C:25]([CH2:23][CH3:24])=[CH:26][CH:27]=2)[OH:30])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: CCc1ccc(C=O)cc1
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2nccnc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
A 1.58 M n-hexane solution of n-butyllithium (19.0 mL, 0.0300 mol) and THF (50 mL) were mixed, followed by addition of 2,2,6,6-tetramethylpiperidine (4.2 g, 0.0300 mol) at −78° C. The reaction mixture was warmed to 0° C. and stirred for 20 minutes. After the reaction mixture was cooled again to −78° C., a solution of 2-chloropyrazine (2.5 g, 0.0218 mol) in THF (5 mL) was added dropwise thereto and stirred at −78° C. for 1 hour. A solution of 4-ethylbenzaldehyde (3.3 g, 0.0240 mol) in THF (5 mL) was added dropwise to the reaction mixture, followed by stirring for 30 minutes. Concentrated hydrochloric acid (10 mL) and ethanol (5 mL) were added to the reaction mixture. After warming to room temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give (2-chloropyrazin-3-yl)-(4-ethylphenyl)methanol (3.1 g, 57%) as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])=[O:5])[CH2:23][CH2:22]1
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2Cl)CC1

Procedure:
A mixture of 0.012 mole (3.6 g) of 2,2'-dichloro-5-nitrobenzophenone, of 0.018 mole (1.8 g ) of 4-methylpiperidine and of 0.012 mole (1.7 g) of potassium carbonate in 100 cm3 of anhydrous ethanol is heated for 1 hour to reflux.
Reaction SMILES: [N+](=[C:3]([C:17](=O)[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(C(C)C)CC)(C)C.[F:55][CH2:56][CH2:57][O:58][CH2:59][C@@H:60]1[CH2:64][C@H:63]([SH:65])[CH2:62][N:61]1[C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=1)=[O:67]>ClC(Cl)C.C(#N)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C(OCC)(=O)C.O>[F:55][CH2:56][CH2:57][O:58][CH2:59][C@@H:60]1[CH2:64][C@H:63]([S:65][C:17]2[C@H:18]([CH3:19])[C@H:20]3[N:21]([C:22](=[O:27])[C@@H:23]3[C@H:24]([OH:26])[CH3:25])[C:3]=2[C:4]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[O:5])[CH2:62][N:61]1[C:66]([O:68][CH2:69][C:70]1[CH:71]=[CH:72][C:73]([N+:76]([O-:78])=[O:77])=[CH:74][CH:75]=1)=[O:67]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1COCCF
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](COCCF)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.95 g) in dichloroethane (20 ml) was added rhodium(II) acetate (10 mg) under refluxing in a nitrogen stream. After refluxing for 1 hour, the mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in anhydrous acetonitrile (20 ml). To the mixture were added diphenyl chlorophosphate (0.52 ml) and N,N-diisopropyl-N-ethylamine (0.51 ml) at -10°~-5° C. in a nitrogen stream. The mixture was stirred at the same condition for 1 hour. To the mixture were added N,N-diisopropyl-N-ethylamine (0.51 ml) and a solution of (2S,4S)-2-(2-fluoroethyloxymethyl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.87 g) in acetonitrile (2 ml) successively at -20° C. The mixture was stirred at the same condition for 30 minutes and then at 0°-10° C. for 3 hours. The mixture was poured into a mixture of water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and dichloromethane (5:95 and then, 10:90 V/V) to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.83 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[CH:11][N+:12]([O-:14])=[O:13])(=[O:4])=[O:3].[Cl:15]N1C(=O)CCC1=O>ClC(Cl)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[C:11]([Cl:15])[N+:12]([O-:14])=[O:13])(=[O:3])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)N1CCCSC1=C(Cl)[N+](=O)[O-]

Procedure:
A stirred solution of 0.238 g of (1A), 0.15 g of N-chlorosuccinimide and about 1 mg of azoisobutyronitrile in 10 ml of dichloroethane was refluxed overnight. The resulting mixture was cooled, washed with water, dried (MgSO4) and stripped of solvent, giving a yellow oil. The oil was flash-chromatographed over silica gel, using methylene chloride as eluent, to give (2).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([C:50]([F:53])([F:52])[F:51])=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:40][CH2:39]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]=2[CH:49]=1.[BH3-][C:55]#N.[Na+]>CO.C1COCC1>[Cl:3][C:4]1[C:5]([C:50]([F:53])([F:51])[F:52])=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:39][CH2:40]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)[CH3:55])[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]=2[CH:49]=1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(C(F)(F)F)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 1 h
Yield: 62 %

Procedure:
37% aq. Formaldehyde (54.07 uL, 0.722 mmol, 2 eq) was added to a solution of 7-[(3aS,4R,6R,6aR)-6-[({4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl}amino)methyl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (270 mg, 0.361 mmol, 1 eq) in MeOH:THF (1:1, 10 ml) at RT and stirred. NaCNBH3 was then added portionwise and continued stirring for 1 h. LCMS at 1 hr showed the reaction to be complete. The solvent was then removed in vacuo. The residue was dissolved in DCM (30 ml) and washed with water (30 ml) before drying over Na2SO4, filtering and evaporated. Purification by preparative TLC, eluting three times with MeOH:DCM (6:94) gave the desired product as a colorless oil (200 mg, 62%): MS (ESI+) for C37H51ClF3N7O3Si m/z 762.30 [M+H]+; HPLC purity 86% (ret. time, 1.75 min).
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[C:4]([C:18]([OH:25])=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[Cl:17])=[O:6].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:5]([C:4]1[C:3]([CH3:26])=[C:2]([C:2]2[CH:3]=[CH:4][CH:18]=[CH:19][CH:20]=2)[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]=1[OH:25])=[O:6]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3-Bromo-5-tert-butyl-N-(2-chloro-4-nitro-phenyl)-6-hydroxy-2-methyl-benzamide (0.18 g, 0.4 mmole) in dioxane (5 ml) under nitrogen phenylboronic acid (50.0 mg, 0.4 mmole), tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmole) and sodium carbonate (1.41 ml, 2 M solution in water) were added. The reaction mixture was heated at 100° C. for 6 hours. The reaction mixture was evaporated, diluted with ethyl acetate and the organic phase was washed with citric acid solution (10%). The organic phase was dried over sodium sulphate and evaporated. The crude compound was purified by column chromatography.
Reaction SMILES: C(OC(=O)[NH:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][C@H:23]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]1)[CH:16]=[CH:15]2)(=[O:10])=[O:9])(C)(C)C.[ClH:33].CO>>[ClH:33].[C@H:23]1([NH:22][C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([NH:11][S:8]([NH2:7])(=[O:10])=[O:9])[CH:13]=3)[N:18]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: Cl
Solvent: CO
Product: NS(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
tert-butyl[({2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}amino)sulfonyl]carbamate (0.012 mg, 0.026 mmol) was dissolved in HCl/methanol (2.5 M, 1.0 mL) and stirred for 2 h at 60° C. Upon evaporation of the solvent and drying on high vacuum the title compound was obtained as a yellow solid (8 mg; 80%); MS: m/e=392.0 (M+H+).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:13][N:14]([C:16]1[CH:32]=[CH:31][C:19]([CH:20](O)[C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)[CH3:15].COC.CN(C)C(=N)N(C)C>CS(O)(=O)=O.C(O)(=O)C.C1(C)C=CC=CC=1.CCCCCC.O1CCCC1>[CH3:29][N:27]([CH3:28])[C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:19]2[CH:31]=[CH:32][C:16]([N:14]([CH3:15])[CH3:13])=[CH:17][CH:18]=2)[O:3][CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([O:11][CH3:12])=[O:10])=[CH:26][CH:25]=1
Reactant: COC(=O)C(O)c1ccccc1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: COC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C(OC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)c1ccccc1

Procedure:
A solution of methyl mandelate (97%, 6.44 g, 0.039 mole), 4,4'-bis(N,N'-dimethylamino)benzhydrol, methyl ether (11.0 g, 0.039 mole), 70 ml of tetrahydrofuran, 240 ml of n-hexane, 3 drops of methanesulfonic acid and 10 drops of acetic acid was refluxed for 6 hours, during which time an additional 200 ml of solvent was added. The volume was reduced to 200 ml, and decolorized with tetramethylguanidine and filtered hot. The filtrate was stripped, leaving a light blue clear oil. The oil was dissolved in toluene and chilled, yielding a white solid (2.8 g, mp 102°-105° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C=O.C[C:16](C)([O-:18])C.[K+].C1COCC1>CS(C)=O.O.C(OCC)(=O)C>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH2:1][CH2:16][OH:18]
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: CC(C)(C)[O-]
Agent: C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1CCO
Reaction time: 8 h
Yield: 71 %

Procedure:
In a dry 25 mL flask 0.17 mg (1.0 mmol) of 2-methyl-3-nitroanisole is combined with 30 mg (0.97 mmol) paraformaldehyde in 7 mL of dimethylsulfoxide (sure-seal). This solution is treated with 1M Potassium t-butoxide/THF (0.20 mL) with the reaction mixture becoming bright red in color. After 2 hours the reaction mixture is diluted with water and ethyl acetate is added. The layers are separated followed by two ethyl acetate extractions. The organics are combined, washed with brine, dried over MgSO4, filtered, and concentrated to give a crude yellow oil that solidifies overnight. This material is purified by LC (45% ethyl acetate/heptane) to yield 140 mg (71%) of 2-(2-methoxy-6-nitrophenyl)-1-ethanol as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ2.90 (t, J=7 Hz, 2H), 3.50 (q, J=7 Hz, 2H), 3.88 (s, 3H), 4.74 (t, J=5 Hz, 1H), 7.32 (dd, J=2, 8 Hz, 1H), 7.46-7.36 (m, 2H); 13C NMR (75 MHz, CDCl3) δ158.5, 127.8, 116.2, 114.2, 62.0, 56.3, 29.2; IR (drift) 1536, 1469, 1458, 1352, 1279, 1266, 1217, 1065, 1040, 1031, 1014, 895, 806, 796, 740 cm−1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl.[OH-].[Na+].CCOC(C)=O>CCO>[F:17][C:15]([F:16])([F:18])[C:8]1[C:9]([C:13]#[N:14])=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][NH:4]2
Reactant: CC(=O)n1ncc2c(C(F)(F)F)c(C#N)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccc2[nH]ncc2c1C(F)(F)F
Temperature: 70 °C
Yield: 28.1 %

Procedure:
The crude 1-acetyl-4-(trifluoromethyl)-1H-indazole-5-carbonitrile from Example 210A (ca. 1.28 mmol) was dissolved in EtOH (5 mL) and conc. HCl (5 mL). The resulting mixture was heated to 70° C. for 20 min. The cooled reaction's pH was adjusted to ca. 8 with 6 N NaOH. EtOAc (20 mL) was added and the isolated organic portion was dried (Na2SO4), filtered and concentrated. Purification by semipreparative HPLC afforded the title compound as a pale yellow solid (0.076 g, 28% overall): 1H NMR (DMSO-d6) δ 14.13 (s, 1H), 8.41 (s, 1H), 8.06 (d, J=6.0 Hz, 1H), 7.93 (d, J=6.0 Hz, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27](Cl)[C:28](OCC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[NH2:35][C:36]([NH2:38])=[S:37].S1(CCCC1)(=O)=O.Cl.C(=O)(O)[O-].[Na+].C(=O)=O>O.C(O)(=O)C>[OH:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]3[S:37][C:36](=[NH:35])[NH:38][C:28]3=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2
Yield: 25.4 %

Procedure:
A mixture of 9.6 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate, 1.8 g of thiourea and 11 ml of sulfolane was reacted for 80 minutes under a nitrogen stream at 115°-120° C. Subsequently, a mixture of 90 ml of acetic acid, 30 ml of concentrated hydrochloric acid and 15 ml of water was added to this, and the resulting mixture was further heated for 12 hours at 85°-90° C. 27 g of sodium bicarbonate were added to this reaction mixture, and, once evolution of carbon dioxide had ceased, the solvent was distilled off. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue, and the crude product was washed with a mixture of equal volumes of a saturated aqueous solution of sodium bicarbonate and water. The white powder produced was removed by filtration and washed again with water. It was then recrystallized from acetone to give 2.2 g of 5 -[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one, melting at 205°-207° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=4)[CH:15]=3)[N:10]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][C@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:31]1.CS(C)=O>>[F:23][C:21]1[CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:30]5[CH2:35][CH2:34][CH2:33][C@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19][CH:20]=1
Reactant: Fc1cncc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cncc(F)c5)cc34)n2)C1
Temperature: 95 °C

Procedure:
A solution containing 3-(6-fluoropyridin-2-yl)-5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (0.055 g, 0.14 mmol) and (S)-tert-butyl piperidin-3-ylcarbamate (0.196 g, 0.979 mmol) in Dimethyl sulfoxide (0.840 mL, 11.8 mmol) was heated at 95° C. for 18 h. The reaction was quenched with water and then extracted with EtOAc 2×. The combined organic layer was dried with Na2SO4, filtered and concentrated. The crude product was dried under high vacuum overnight to give tert-butyl (3S)-1-(6-(5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate which was dissolved in 1,4-Dioxane (1.50 mL, 19.2 mmol) and treated with 4.0 M of Hydrogen chloride in 1,4-Dioxane (2.50 mL). The reaction was stirred at RT for 18 h. The reaction was concentrated then submitted for rHPLC to give 206 (37.8 mg, 69% yield). ESI MS m/z=390.1 (M+1). 1H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 9.18 (s, 1H), 9.03 (s, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.32 (d, J=10.3 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.37-4.25 (m, 2H), 3.08-2.96 (m, 1H), 2.85-2.75 (m, 2H), 2.00-1.88 (m, 1H), 1.85-1.75 (m, 1H), 1.68-1.56 (m, 1H), 1.42-1.25 (m, 1H)
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].O=C1[CH:12]2[CH:10]3[CH:11]2CC1[CH:9]3[C:14]1[NH:22][C:21]2[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=2[N:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:5]=[C:4]1[CH:11]2[CH:10]3[CH:12]2[CH2:2][CH:3]1[CH:9]3[C:14]1[NH:22][C:21]2[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=2[N:15]=1
Reactant: [Li]CCCC
Reactant: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=O)C53)nc2n(CCC)c1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1C2CC3C1C3C2c1nc2c([nH]1)c(=O)n(CCC)c(=O)n2CCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-triphenyl-phosphonium bromide (2.08 g) was taken in THF (50 ml) at −78° C. nBuLi (3.66 ml, 1.6 M) was added slowly at −78° C. and stirred for 1 hr. 8-(5-Oxo-tricyclo[2.2.1.02,6]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 1) (1 g) was dissolved in THF and added to the reaction mixture at −78° C. slowly. After the addition was over, the reaction mixture was allowed to warmed to room temperature slowly and stirred at room temperature overnight. The next day, the reaction mixture was quenched with 1N HCl and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water, brine and dried over Na2SO4. After concentration the product was purified by silica gel column. Mass (ES+ 341).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[C:11]([Cl:23])[C:10]=1[O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:32]N1C(=O)CCC1=O.CN(C=O)C>O>[Br:32][C:12]1[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[C:10]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[C:11]=1[Cl:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 120 h
Yield: 66.9 %

Procedure:
A mixture of 0.650 g (1.30 mmol) of 14 and 0.276 g (1.60 mmol) of N-bromosuccinimide (NBS) in 10 Ml of DMF under argon was stirred at 25° C. for 5 days. The reaction mixture was diluted with 30 Ml of water, extracted three times with diethyl ether (50 Ml each), and the combined extracts were washed with 30 Ml of water, and 30 Ml of brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and diethyl ether as eluent gave 0.506 g (67% yield) of bromide 4. 1H NMR (CDCl3) δ 6.41 (s, 1H, Ar, C3-H), 1.03 (s, 9H, t-Bu), 1.02 (s, 9H, t-Bu), 0.97 (s, 9H, t-Bu), 0.23 (s, 6H, Me), 0.22 (s, 6H, Me), 0.18 (s, 6H, Me); 13C NMR (CDCl3) δ 147.3 (s), 147.2 (s), 139.4 (s), 128.3 (s), 111.1 (d), 108.4 (s), 29.9 (q, t-Bu), 26.3 (q, t-Bu), 26.2 (q), 26, 18.9 (s), 18.6 (s), −3.3 (q, Me), −3.4 (q, Me), −3.5 (q, Me), −4.0 (q). Anal. Calcd for C24H46BrClO3Si3: C, 49.51; H, 7.96. Found: C, 49.78; H, 8.11.