Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][NH2:30])[CH3:26]>C1C=CC=CC=1>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][N:30]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:26]
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CCOC(CN)OCC
Solvent: c1ccccc1
Product: CCOC(CN=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)OCC

Procedure:
73 g (0.23 mol) of 3,4-bis(benzyloxy)benzaldehyde was dissolved in 500 ml of benzene, and 25 ml (0.23 mol) of aminoacetaldehyde diethylacetal was added thereto. The mixture was stirred under reflux for 5 hours to remove the resulting water. The reaction solution was concentrated under reduced pressure to obtain a residue of 2-{N-[3,4-bis(benzyloxy)benzyliden]amino}acetaldehyde diethylacetal. This residue was dissolved in 700 ml of methanol, and 6.0 g (0.16 mol) of sodium borohydride was added thereto at room temperature. The mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, then washed with a saturated a sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue of 2-{N-[3,4-bis(benzyloxy)benzyl]-amino}acetaldehyde diethylacetal. This residue was dissolved in 600 ml of dry tetrahydrofuran, and 39.8 g (0.21 mol) of p-toluenesulfonyl chloride and 59 ml (0.42 mol) of triethylamine were added. The mixture was stirred at room temperature for 17.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane), whereby 70 g (yield: 54.3%) of 2-{N-(P)-trisulfonyl-N[3,4-bis(benzyloxy)benzyl]amino}-acetaldehyde diethyl acetal was obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)=[O:8])[C@@H:4]([CH3:6])[OH:5].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.Cl>>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:2][C@@H:3]([C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH2:11][CH2:10]1)=[O:8])[C@@H:4]([CH3:6])[OH:5])=[O:33])=[CH:26]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C[C@@H](O)[C@@H](N)C(=O)N1CCN(C2CCN(C)CC2)CC1
Agent: Cl
Product: C[C@@H](O)[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(=O)N1CCN(C2CCN(C)CC2)CC1

Procedure:
Prepared from 1-(D-allo-threoninyl)-4-(1-methylpiperidin-4-yl)piperazine hydrochloride and 5-chloroindole-2-carboxylic acid using methods substantially equivalent to General Coupling Method 1. The HCl salt is prepared following Salt Formation Method 1. The final crude product is treated with aqueous 0.2 N HCl and purified via prep-HPLC (80:20 to 40:60 0.01% HCl in water:acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[C:5]([CH3:12])=[N:4][CH:3]=1
Reactant: COC(=O)c1cc(Cl)cnc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(Cl)cc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a stirring solution of 950 mg (5.12 mmol) of methyl 5-chloro-2-methylnicotinate in 20 mL of THF at 0° C. was added 500 mg (13.2 mmol) of LiAlH4 in 2 portions. After stirring at 0° C. for about 1 h., the following were added in succession: 0.5 mL of H2O, 0.5 mL of 15% NaOH (aqueous), and 1.5 mL of brine. The ice bath was removed and stirring was continued for 2 h. The mixture was filtered through Celite and concentrated. Purification by flash silica gel chromatography (2% MeOH/CHCl3) provided 399 mg of (5-chloro-2-methylpyridin-3-yl)methanol as an orange-yellow oil in 50% yield.
Reaction SMILES: [Li].[CH3:2]I.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]23[CH2:21][CH:16]([N:17]([CH3:20])[C:18]2=O)[CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=1.O>CCOCC.C1C=CC=CC=1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]23[CH2:21][CH:16]([N:17]([CH3:20])[C:18]2=[CH2:2])[CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C23CCCC(C2)N(C)C3=O)c1
Reactant: CI
Agent: [Li]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: C=C1N(C)C2CCCC1(c1cccc(OC)c1)C2
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
0.17 g of lithium is added to 8 ml of absolute ether in a nitrogen atmosphere, and a solution of 1.6 g of methyl iodide in 3 ml of absolute ether is added dropwise thereto at 0° to -5°C. The mixture is stirred at the same temperature for 30 minutes. Then, a solution of 1.0 g of 1-(3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane-7-one in 30 ml of benzene is added dropwise to the mixture at room temperature for 5 minutes. The mixture is refluxed for 3 hours. Water is added to the mixture under ice-cooling, and the aqueous mixture is extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent, whereby 1.0 g of 1-(3-methoxyphenyl)-6-methyl-7-methylidene-6-azabicyclo[3,2,1]octane is obtained. The product thus obtained is dissolved in 60 ml of ethanol. 300 mg of sodium borohydride are added to the ethanol solution at 10° to 15°C. Then, the mixture is stirred at room temperature for 20 hours. After the reaction, the mixture is concentrated under reduced pressure. Water is added to the residue, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. Methanolic hydrogen bromide is added to the residue in ether, and the crystalline precipitate is collected by filtration. The precipitate is recrystallized from a mixture of ethanol, acetone and ether. 1.1 g of 1-(3-methoxyphenyl)-6,7-dimethyl-6-azabicyclo[3,2,1]octane hydrobromide are obtained. M.p. 175° - 177°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:25]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)[CH2:30]CCC[CH2:26]1.C(/B(O)O)=C/C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH:26](/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:25]/[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: C/C=C\B(O)O
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C/C=C\c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 648.7 %

Procedure:
A mixed liquid of 1.50 g of tert-butyl(2-bromobenzyl)carbamate, 3.90 g of tripotassium phosphate, 348 mg of dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, 195 mg of tris(dibenzylideneacetone)dipalladium(0), 905 mg of (1Z)-prop-1-en-1-yl boronic acid, 30 ml of 1,4-dioxane, and 7.5 ml of water was stirred at 90° C. for 15 hours. The reaction mixture was left to be cooled to room temperature and then filtrated over Celite. The filtrate was concentrated under reduced pressure, and then to the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain 1.36 g of tert-butyl {2-[(1Z)-prop-1-en-1-yl]benzyl}carbamate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:24]([O:31][C:32]1[C:47](Cl)=[CH:46][CH:45]=[CH:44][C:33]=1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:24]([O:31][C:32]1[C:47]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:46][CH:45]=[CH:44][C:33]=1[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: O=C(OCc1ccccc1)c1cccc(Cl)c1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1cccc(-c2cccnc2)c1OCc1ccccc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (0.25 g), tripotassium phosphate (0.47 g), palladium(II) acetate (4.5 mg), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.1 mg) were added to a toluene (5.3 mL) solution of the obtained benzyl 2-(benzyloxy)-3-chlorobenzoate (0.35 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, and then 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g), tripotassium phosphate (0.23 g), palladium(II) acetate (4.5 mg), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.1 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 3 hours. After cooling the reaction mixture to room temperature, a 10% aqueous solution of citric acid and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-65% hexane/ethyl acetate] to obtain 0.35 g of benzyl 2-(benzyloxy)-3-(pyridin-3-yl)benzoate.
Reaction SMILES: C([O:3][P:4]([C:9]([C:36]#[N:37])([CH3:35])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>CN(C=O)C.C(Cl)Cl>[C:36]([C:9]([P:4](=[O:3])([OH:5])[OH:8])([CH3:35])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])#[N:37]
Reactant: CCOP(=O)(OCC)C(C)(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(C)(C#N)P(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of {1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonic acid diethyl ester (18 mg, 0.04 mmol) in DMF (0.5 mL) and DCM (0.5 mL) was added TMSBr (51 μL, 0.4 mmol) and 2,6-lutidine (46 μL, 0.4 mmol). The reaction solution was allowed stir at room temperature overnight before quenching with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 4.5 mg (33%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 1.37 (d, 3H), 1.87 (s, 3H), 2.13 (s, 3H), 2.26 (m, 1H), 2.64 (m, 1H), 3.39 (m, 2H), 3.75 (s, 3H), 5.18 (s, 2H), 5.34 (m, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 21.47 ppm; MS (m/z) 422 [M−H]−, 424 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:50][O:51][CH2:52]CCO>>[CH2:26]([C:16]1[N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:18]=[C:13]2[C:12](=[O:28])[NH:11][C:10]([C:9]3[C:4]([O:3][CH2:1][CH2:2][CH2:50][O:51][CH3:52])=[N:5][CH:6]=[C:7]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]4)(=[O:30])=[O:31])[CH:8]=3)=[N:15][C:14]=12)[CH3:27]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Reactant: COCCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCCOC)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
A mixture of the title compound of Example 1 (200 mg, 0.36 mmol), potassium bis(trimethylsilyl)amide (361 mg, 1.81 mmol) and 3-methoxypropan-1-ol (1.5 ml) was stirred at 90° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (97:3 to 95:5), to give the title compound (81 mg, 38%) as a foam. Found: C, 55.36; H, 6.11; N, 18.18. C28H36N8O5S; 0.50 H2O requires C, 55.52; H, 6.16; N, 18.50%. δ (CDCl3): 1.01 (3H, t), 1.29 (3H, t), 2.19 (2H, m), 2.40 (2H, q), 2.54 (4H, m), 3.02 (2H, q), 3.12 (4H, m), 3.39 (3H, s), 3.65 (2H, t), 4.76 (2H, t), 5.68 (2H, s), 7.09 (1H, d), 7.21 (1H, m), 7.62 (1H, m), 8.56 (1H, d), 8.62 (1H, s), 8.93 (1H, s), 10.84 (1H, s). LRMS: m/z 597 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][C@@H:13]([CH3:14])[CH2:16][CH3:17])=[O:6]
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC[C@H](C)COC(=O)c1ccc(O)c(F)c1
Reaction time: 8 h
Yield: 66 %

Procedure:
In a 250-ml, round-bottomed flask equipped with a heating mantle, magnetic stirrer, condenser and Dean Stark trap, were placed 2.5 g (16.0 mmol) of 3-fluoro-4-hydroxybenzoic acid, ten g (113.4 mmol) of (S)-2-methyl-1-butanol, 0.347 g of p-toluenesulfonic acid monohydrate and 100 ml of benzene. The reaction mixture was stirred overnight under reflux. The reaction mixture was extracted using saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered through cotton and evaporated to an oil. The product was purified by flash chromatography on silica gel with 3% diethyl ether in dichloromethane. Fractions containing the desired product were combined and evaporated to a pale-yellow oil. Analysis by NMR showed that considerable starting alcohol remained. The oil was placed under vacuum (at 70° C.) for two days. No alcohol was shown by gas chromatography to be present. The desired product was obtained in the amount of 2.39 g (66% yield) and had the following structure. ##STR30##
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]#N)=[CH:19][CH:20]=[C:3]12.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:36].[Na+].[K+]>C(Cl)Cl>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([CH:21]=[O:36])=[CH:19][CH:20]=[C:3]12
Reactant: N#Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile (Example 2) (55 mg, 0.18 mmol) in methylene chloride (1 mL) cooled −75° C. was treated dropwise with 1M diisobutylaluminum hydride in methylene chloride (275 μL, 0.27 mmol). The reaction was stirred at −75° C. for 1.5 h. At this time, the reaction was treated with additional 1M diisobutylaluminum hydride in methylene chloride (0.1 mL, 0.1 mmol) and allowed to stir at −75° C. for an additional 1 h. At this time, the reaction was treated with a solution of Rochelle's salt, and the mixture was allowed to warm up to room temperature where it stirred overnight. At this time, the resulting suspension was absorbed onto silica gel. Flash chromatography (4 g silica column, 0-50% ethyl acetate/hexanes) afforded 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbaldehyde (22 mg, 40%) as light yellow solid. 1H NMR (acetone-d6) δ ppm 10.02 (s, 1H), 8.11 (d, J=1.5 Hz, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.89 (d, J=8.5 Hz, 2H), 7.85 (s, 1H), 7.42 (s, 1H). LC-MS calcd. for C15H10F3N2O2 [(M+H)+] 307, obsd. 306.8.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>CO.[Pd](Cl)Cl.[Li]>[CH3:23][O:22][C:18](/[CH:19]=[CH:20]/[C:16]1[C:14]([NH2:15])=[N:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])=[O:21]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: C=CC(=O)OC
Agent: Cl[Pd]Cl
Agent: [Li]
Solvent: CO
Product: COC(=O)/C=C/c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of 19.1 g of 5-chloromercuriccytidine (b) in 150 ml of methanol was prepared and then 210 ml of a methanol solution of 0.1 M lithium palladium chloride (Li2PdCl4), 40 ml of methyl acrylate, and 4.12 g of cupric chloride were added to above suspension and the mixture was stirred at room temperature for 14 hours. The palladium precipitate was removed by filtration and hydrogen sulfide was bubbled into the filtrate and the formed precipitate was removed by Celite filtration. The filtrate was neutralized with a saturated sodium bicarbonate solution and evaporated to dryness under reduced pressure. The residue was recrystallized from aqueous solution to give 4.62 g of (E)-5-(2-methoxycarbonyl ethenyl) cytidine (c).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[C@@H:9]([C:17](O)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:23]1[C:27]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN>CN(C)C=O.CO.O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:20])[C@@H:9]([C:17](=[O:18])[NH:23][CH3:27])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
N-Tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.22 g, 4.4 mmol), 1-hydroxybenzotriazole hydrate (0.59 g, 4.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (0.88 g, 4.6 mmol) were dissolved in N,N-dimethylformamide (25 mL) and stirred for 30 min. Methylamine (0.51 g of a 40% solution in methanol, 6.6 mmol) was added and the mixture was stirred overnight. Methylene chloride (80 mL) and water (100 mL) were added and the phases were separated. The organic phase was washed with sodium hydroxide (20 mL, 1 N), sodium hydrogensulfate (50 mL, 10%) and water (50 mL). The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 1.39 g of N-methyl-N-((R)1-(methylcarbamoyl)-2-phenylethyl)carbamic acid tert-butyl ester.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1>CN(C=O)C>[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH:60][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn[nH]c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.9 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 11% yield: LCMS (ESI) m/z 348 (MH+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1([C:18]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)C=CC=CC=1.ClC(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.O>[NH:21]1[CH2:22][CH2:23][CH:18]([C:24]([OH:26])=[O:25])[CH2:19][CH2:20]1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CCNCC1
Reaction time: 3 h

Procedure:
To a suspension of 3.77 g (10 mmol) of 4-phenyl-4-piperidine-carboxylic acid p-toluenesulfonic acid salt (commercially available) in 31 ml of 10% Na2CO3 and 15 ml of dioxane was added at 0° C. a solution of 2.58 g (10 mmol) of fluorenylmethyl chloroformate in 20 ml of dioxane dropwise. The reacion mixture was stirred for 3 hours, diluted with 50 ml of water and extracted with EtOAc (3×20 ml). The aqueous phase was acidified with conc HCl while stirring vigorously in an ice bath. The resulting solid was collected by filtration, washed with water and dried in vacuo to provide the title compound. 1H-NMR (CDCl3, 300 MHz): 1.85 (bm, 2H); 2.50 (bm, 2H); 3.15 (bm, 2H); 3.80-4.10 (m, 2H); 4.25 (t, 1H); 4.5 (d, 2H); 7.25-7.50 (m, 9H); 7.59 (d, 2H); 7.80 (d, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:9]=[C:8]1[CH3:26].N1C=CC=CC=1>C(Cl)Cl>[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:9]=[C:8]1[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N)cc3)n2)n1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncc(-c2ccnc(Nc3ccc(NS(C)(=O)=O)cc3)n2)n1C
Temperature: 4 °C
Yield: 65.4 %

Procedure:
Methanesulphonyl chloride (0.055 ml, 0.711 mmole) was added to a solution of 4-(1,2-dimethylimidazol-5-yl)-2-(4-aminoanilino)pyrimidine (Example 165; 0.18 g, 0.64 mmole) and pyridine (0.052 ml, 0.64 mmole) in DCM (2.0 mL) cooled at 4° C. The mixture was allowed to warm to ambient temperature. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was separated, the volatiles evaporated and the residue purified by column chromatography on silica gel eluting with DCM/7M methanolic ammonia (96:4) to give the title compound (0.15 g, 65%) as a solid. NMR: 2.36 (s, 3H), 2.90 (s, 3H), 3.91 (s, 3H), 7.06 (d, 1H), 7.14 (d, 2H), 7.57 (s, 1H), 7.64 (d, 2H), 8.33 (d, 1H), 9.37 (br s, 1H), 9.42 (s, 1H); m/z 359.