Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C1COCC1>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:14]2[C:13](=[O:15])[CH2:12][O:11][CH2:10][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C1COCC(c2ccc(F)c(F)c2)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (0.34 g, 1.57 mmol) in 10 mL of THF was added NaH (0.05 g, 1.9 mmol) and the resulting solution was stirred for 30 min. It was then transferred via a syringe into a solution of 4-nitrophenyl chloroformate in 20 mL of anhydrous THF at −78° C. under argon. The resulting solution was stirred for 2 hours after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2Cl2 to obtain 3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenyl ester as a colorless thick oil (0.31 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:4]2[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc2nc(Cl)cc(Cl)n2n1
Solvent: C1COCCO1
Product: Cc1cc2nc(Cl)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
There was dissolved, in 1,4-dioxane (20 mL), 5,7-dichloro-2-methyl-pyrazolo-[1,5-a]pyrimidine (1.00 g, 4.95 mM), then morpholine (863 μL, 9.90 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was then distilled off from this reaction mixture, the resulting residue was diluted with water and the mixture was extracted with methylene chloride. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (927 mg, yield: 74%).
Reaction SMILES: [Cl-:1].[CH2:2]([N+:9]12[CH2:16][C:13]([OH:17])([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:21][CH3:22]>CN(C=O)C>[Cl-:1].[CH2:2]([N+:9]12[CH2:16][C:13]([O:17][CH2:21][CH3:22])([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCBr
Reactant: OC12CCC[N+](Cc3ccccc3)(CC1)C2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC12CCC[N+](Cc3ccccc3)(CC1)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 1-benzyl-5-hydroxy-1-azoniabicyclo-[3.2.1]octane chloride (D7a, 3.05 g, 0.012 mole) in dry DMF (100 ml) under nitrogen was treated with sodium hydride (600 mg of 80% oil dispersion, 0.020 mole) and stirred at room temperature for 40 min. The mixture was then treated with bromoethane (4.7 ml, 0.063 mole) and stirred at room temperature for 16 h. The excess sodium hydride was destroyed by addition of ethanol (5 ml) and the mixture acidified with glacial acetic acid (5 ml) and then concentrated in vacuo to give an orange semi-solid containing the title compound (D8). This was used in the next step without any purification.
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[C:16]1[C:22]([OH:24])=[O:23]>CC(C)=O>[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[C:16]1[C:22]([O:24][CH3:4])=[O:23]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC1(c2ccccc2)CCC(=O)C=C1C(=O)O
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1=CC(=O)CCC1(C)c1ccccc1
Yield: 94.2 %

Procedure:
0.88 cm3 (14 mmol) of methyl iodide and 1.8 cm3 (12 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, dropwise, were successively added to a solution of 2.3 g (10 mmol) of (RS)-2-methyl-5-oxo-2-phenylcyclohexene-1-carboxylic acid in 20 cm3 of acetone. The reaction mixture was subsequently heated at reflux for two hours. The acetone was subsequently concentrated, the residue was then stirred with 100 cm3 of water and then extracted with three times 30 cm3 of ethyl acetate. After drying over magnesium sulphate and concentrating under reduced pressure, 2.3 g (94%) of methyl (RS)-2-methyl-5-oxo-2-phenylcyclohexene-1-carboxylate were obtained in the form of an orange oil, the characteristic of which was as follows:
Reaction SMILES: C(OC([CH:8]([NH2:33])[CH2:9][C:10]([N:12]1[C:16](=[O:17])[CH2:15][N:14]([N:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:21]=2)[C:13]1=[O:32])=[O:11])=O)(C)(C)C.[ClH:34].C(O)(=O)C>>[ClH:34].[NH2:33][CH2:8][CH2:9][C:10]([N:12]1[C:16](=[O:17])[CH2:15][N:14]([N:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[CH:22][CH:21]=2)[C:13]1=[O:32])=[O:11]
Reactant: CC(C)(C)OC(=O)C(N)CC(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(F)cc3)o2)C1=O
Agent: Cl
Solvent: CC(=O)O
Product: NCCC(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(F)cc3)o2)C1=O
Reaction time: 4 h

Procedure:
The 3-(t-butoxycarbonyl-aminopropionyl)-1-{[5-(4-fluorophenyl) furfurylidene]amino}hydantoin (10.4 g, 0.023 mole) was added to 3% HCl/acetic acid (125 ml) and stirred for 4 hours. The yellow solid was filtered, washed with nitromethane and ether to yield 7 g, 28%, m.p. 195°-197° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH:14]C(OC(C)(C)C)=O)[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH:53]C(OC(C)(C)C)=O)[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH2:14])[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH2:53])[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(CC)NC(=O)OC(C)(C)C)[nH]c2cc(F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(N)CC)[nH]c2cc(F)ccc12
Temperature: 0 °C

Procedure:
A solution containing 11 (27.5 g, 30 mmol) in DCM (200 mL) was cooled to 0° C. TFA (50 mL) was added and the reaction was monitored by LC/MS analysis until complete conversion of 11 to 12 (ca. 3 h). The solvent was removed in vacuo and the dark, green-colored residue was dissolved in EtOAc (ca. 1 L). The EtOAc solution was carefully poured into a saturated aqueous NaHCO3/ice/water mixture to neutralize the residual TFA. The organic phase was separated and washed twice with saturated aqueous NaHCO3 then once with brine. The combined aqueous washes were back-extracted with EtOAc (2×100 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 22 g of crude 12 as an off-white solid. 1H NMR (300 MHz, CDCl3+d4-MeOH), mixture of rotomers: δ11.62 (br s, 2H), 7.48-7.62 (m, 4H), 6.89 (ddd, J=2.4, 9.3, 9.3 Hz, 2H), 5.48 (dd, J=4.5, 4.8 Hz, 2H), 4.52 (dd, J=9.3, 9.3 Hz, 2H), 4.06 (dd, J=4.8, 12.3 Hz, 2H), 3.78 (d, J=12.3 Hz, 2H), 3.54-3.70 (m, 4H), 3.30-3.40 (m, 2H), 2.33 (s, 6H), 2.02-2.16 (m, 2H), 1.70-1.96 (m, 4H), 1.09 (t, J=7.2 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3+d4-MeOH): δ173.5, 170.9, 161.8, 158.6, 137.2, 137.1, 128.2, 128.1, 125.6, 118.7, 118.6, 108.6, 108.3, 108.0, 98.6, 98.1, 74.6, 60.1, 53.5, 33.5, 28.0, 21.4, 9.7 ppm. Mass spectrum (ESI), m/z 721.4 [(M)+; calcd for C38H46F2N6O6: 720.8].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C:13]2[C:20]([CH3:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[CH3:22])[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>O>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([NH:23][C:2]2[N:3]=[C:4]([O:12][C:13]3[C:20]([CH3:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[CH3:22])[C:5]3[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:25][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccn(C)c12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 90 °C
Reaction time: 48 h
Yield: 35.9 %

Procedure:
In a sealed tube was added 4-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (294 mg, 0.94 mmol), 4-aminobenzonitrile (455 mg, 3.77 mmol), TFE (3.1 mL) and TFA (0.58 mL, 7.52 mmol). The reaction mixture was stirred at 90° C. for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (4:1-1:2), to give the product as an off-white solid (133 mg, 40%).
Reaction SMILES: [Na].[NH2:2][C:3]1[S:4][C:5]2[C:10]([NH:11][C@H:12]([CH3:15])[CH2:13][OH:14])=[N:9][C:8]([S:16]CC3C=CC=CC=3)=[N:7][C:6]=2[N:24]=1.[Cl-].[NH4+]>N>[NH2:2][C:3]1[S:4][C:5]2[C:10]([NH:11][C@H:12]([CH3:15])[CH2:13][OH:14])=[N:9][C:8]([SH:16])=[N:7][C:6]=2[N:24]=1
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12

Procedure:
Sodium metal was added portionwise to a solution of the product of example 32 step a) (5.0 g) in ammonia (150 ml) until a blue colouration persisted. Ammonium chloride was then added and the solvent allowed to evaporate. The residue was dissolved in H2O (200 ml) and filtered before neutralising with 2M HCl solution. The grey precipitate was filtered, washed with H2O (200 ml) and dried in vacuo for 48 h to yield the subtitle compound as a brown solid (3.0 g).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([CH:24]1[CH2:26][CH2:25]1)[CH2:8][O:9][C:10]1[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[Cl:16])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:24]1([CH:7]([OH:6])[CH2:8][O:9][C:10]2[C:15]([Cl:16])=[N:14][C:13]([Cl:17])=[N:12][C:11]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)OC(COc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(COc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a solution of 4-{5-[2-(tert-butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethoxy]-2,6-dichloro-pyrimidin-4-yl}-morpholine (386 mg, 0.86 mmol) in THF (10 mL) was added TBAF (947 μL, 0.95 mmol, 1.0 M solution in THF) dropwise. The reaction mixture was stirred at RT for 3 hours before the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3×20 mL) and then combined organic phases were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-50% ethyl acetate) giving 1-Cyclopropyl-2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethanol as a colourless gum (196 mg, 68%). LCMS: RT=3.04 min, [M+H]+=334/336.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[O:21])=[CH:16][CH:15]=1.[C:37](C1C=CC(C(N(OC)C)=O)=CC=1)([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[O:23][Si:24]([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CON(C)C(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)c1ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c2ccncc2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a cooled solution of diisopropylamine (183 mg, 1.81 mmol) in dry THF (0.35 mL) at -20° C. was added a solution of n-butyllithium in hexanes (0.83 mL of a 2.5M solution, 2.08 mmol). Stirred at -20° C. for 1 hr and then added a solution of 4-pyridyl-t-butydimethylsilyloxymethyl 4-fluorophenyl ketone from Step B (383 mg, 1.72 mmol) in THF (0.45 mL). Stirred at -20° C. for 45 min, resulting in a thick yellow-brown solution. A solution of 4-t-butyl-N-methoxy-N-methyl-benzamide (400 mg, 1.81 mmol) in THF (0.5 mL) was added and the solution stirred at -20° to 0° C. for 5 h. The reaction was cooled to -20° C. and quenched by the addition of a saturated ammonium chloride solution. The reaction mixture was then extracted with ethyl acetate (3 times) and the combined extracts washed successively with water (2 times) and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 5-10% ethyl acetate in hexanes to yield the title compound as a yellow oil (341 mg, 49% yield).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]>CN(C)C=O.CO.[Cu]>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Cc1ccc(O)cn1
Reactant: Clc1ccccc1Br
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2Cl)cn1

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine, 5.2 g of o-bromochlorobenzene and 250 mg of a copper powder were suspended in 10 ml of dimethylformamide, and the mixture was allowed to react in a nitrogen gas stream at 115° C. for 23 hours under stirring. The reaction mixture was diluted with 70 ml of methanol and filtered. The filtrate was dried to a solid, and 120 ml of chloroform was added to the residue. The mixture was washed with 70 ml of an aqueous sodium hydroxide solution at pH of 9. The solvent layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 2.8 g of oily 5-(o-chlorophenoxy)-2-methylpyridine.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[C:20]([F:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:7]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.CCOC(C)=O>[N:33]([CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[C:20]([F:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:7]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(OS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(N=[N+]=[N-])C4)cc3)ncc2F)n1C(C)C
Temperature: 80 °C
Yield: 50.2 %

Procedure:
To a solution of 1-(4-{[5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}phenyl)azetidin-3-yl methanesulfonate (Example 138; 876 mg, 1.90 mM) in dry DMF (7.3 ml), sodium azide (619 mg, 9.5 mM) was added. The reaction was stirred and heated at 80° C. under nitrogen for 18 hours. The reaction mixture was diluted with EtOAc and the solution extracted with water (twice), saturated sodium chloride and then dried with anhydrous sodium sulphate filtered and evaporated. The crude product was purified by silica chromatography eluting with MeOH:DCM (2:98) to give the title compound as a brown foam (389 mg, 50%). NMR 1.4 (d, 6H), 2.53 (s, 3H+DMSO), 3.65 (m, 2H), 4.1 (m, 2H), 4.44 (m, 1H), 5.4 (m, 1H), 6.44 (d, 2H), 7.33 (m, 3H), 8.35 (d, 1H); m/z 408.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:17])[CH3:16].[OH-].[Na+]>CN(C)C=O.O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:16]/[C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(F)c(-c2cccs2)c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccc(F)c(-c3cccs3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
4-Fluoro-3-thiophen-2-yl-benzaldehyde (1.0 g, 4.85 mmol, from Ex-20A) and 4-acetylbenzoic acid (0.80 g, 4.87 mmol) were dissolved in dimethylformamide (55 mL). Sodium hydroxide solution (5 N, 3.88 mL) was added in one portion, and the mixture was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and washed with ethyl acetate (100 mL). The aqueous phase was acidified with conc. HCl and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from ethanol provided 0.90 g (53%) of the title compound as a solid, m.p. 242–244° C. 1H-NMR (300 MHz, d6-DMSO) δ 13.31 (bs, 1H), 8.32 (dd, 1H, J=8.2 and 2.0 Hz), 8.24 (d, 2H, J=8.2 Hz), 8.07 (d, 2H, J=7.9 Hz), 7.98 (d, 1H, J=16.1 Hz), 7.92 (m, 1H), 7.80 (d, 1H, J=16.1 Hz), 7.69–7.73 (m, 2H), 7.41 (dd, 1H, 10.8 and 9.2 Hz), 7.20 (m, 1H). MS m/z=352 ([M]+, 50%), 343 (100%). HRMS (EI) Calcd. for C20H13FO3S: 352.0569. Found: 352.0571.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[C:15]3[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=2)=[N:5][N:6]=1>CO.[Pd]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[C:15]3[C:14]([C:16]4[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=4)[NH2:22])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:8]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc([N+](=O)[O-])c4)c23)o1
Agent: [Pd]
Solvent: CO
Product: Cc1nnc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc(N)c4)c23)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-methyl-5-[4-(3-nitrophenyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3,4-oxadiazole (0.40 g, 0.88 mmol) in methanol (10 mL), was added Pd on carbon (200 mg, 10 wt. %). The atmosphere was purged with hydrogen and the reaction was stirred for 12 hours at room temperature under a hydrogen atmosphere (1 atm). The solution was filtered and the filtrate was concentrated in vacuo to afford crude 3-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline as a black solid. LRMS (ESI) calc'd for C21H27N6O2Si [M+H]+: 423, found 423.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1>C(N)C.CS(C)=O.CO>[CH3:6][N:7]([CH3:2])[C:5]1[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:7][C:2]([NH:10][CH2:11][CH3:12])=[CH:3][CH:4]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Agent: CCN
Solvent: CS(C)=O
Solvent: CO
Product: CCNc1ccc(N(C)C)c(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 19 %

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) was placed in a microwave vial and dissolved in ethylamine (70% weight in water, 1 ml). The mixture was heated at 160° C. for 3 h under microwave irradiation. The solvent was removed under a stream of nitrogen to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (5 mg) as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]OS(C)(=O)=O)[C@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])[C@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](COS(C)(=O)=O)[C@H](O)C1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](CN2C(=O)c3ccccc3C2=O)[C@H](O)C1
Temperature: 60 °C
Reaction time: 7 h
Yield: 103 %

Procedure:
To a solution of cis-1-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpiperidine (2.0 g) in dimethylformamide (40 ml) was added potassium phthalimide (1.44 g), and the resulting mixture was stirred at 60° C. for 7 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2.4 g of cis-1-tert-butoxycarbonyl-4-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)methyl-3-hydroxypiperidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[Cl-].C(C[P+](C)(C)C)#N.[CH:23]1(O)[CH2:26][CH2:25][CH2:24]1.[H-].[Na+]>C1COCC1.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:10]=1
Reactant: OC1CCC1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Agent: C[P+](C)(C)CC#N
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc(Br)cc2c1ccn2C1CCC1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
In an oven dried 100 ml RBF, equipped with a stir bar, septum, nitrogen inlet was added methyl 6-bromo-1H-indole-4-carboxylate (1.0 g, 3.94 mmol) and (cyanomethyl)(trimethyl)phosphonium chloride (1.491 g, 9.84 mmol). Added in THF (40 mL) and stirred suspension for 5 min. The reaction was cooled with an ice bath for 10 min, then was added cyclobutanol (0.616 mL, 7.87 mmol), followed by sodium hydride (0.346 g, 8.66 mmol) portionwise. The ice bath was removed and the reaction stirred at ambient temperature for 45 min, then heated at 50° C. for 18 h. LCMS showed mostly SM. Heated at 75° C. for 24 h. The reaction was allowed to cool to RT, then poured into water (200 ml) and extracted with EtOAc (2×). The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (40 g Isco silica column; gradient B: 2-25%; A:hexane, B: EtOAc) gave methyl 6-bromo-1-cyclobutyl-1H-indole-4-carboxylate (0.3 g, 25% yield, ˜45% pure by HPLC). MS(ES) [M+H]+ 308.2.