Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:32])[C:10]1[CH:15]=[C:14]([Br:16])[C:13]([Cl:17])=[CH:12][C:11]=1[N:18]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][O:24][C:22]([CH:21]1[CH2:20][CH2:19][N:18]([C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:11]2[CH:12]=[C:13]([Cl:17])[C:14]([Br:16])=[CH:15][C:10]=2[C:9]1=[O:32])=[O:23]
Reactant: COC(=O)CCCN(C(=O)OC(C)C)c1cc(Cl)c(Br)cc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc2C1=O
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a heated mixture of potassium t-butoxide (1.27 g, 11.3 mmol) in toluene (50 ml) at 70° C. was added a solution of 5-Bromo-4-chloro-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-benzoic acid methyl ester (2.55 g, 5.66 mmol) in toluene (50.0 ml) over 30 minutes. After the addition was completed, the mixture was cooled to room temperature and diluted with ethyl acetate (100 ml), and then washed with 1.00N HCl(aq) (120 ml) and brine (3×120 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (gradient eluent, 0-15% ethyl acetate in hexane) provided 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1,4-dicarboxylic acid 1-isopropyl ester 4-methyl ester (1.46 g, 62%) as oil. MS (ES+): 418, 420 (M+H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27]
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-trien-17-one is dissolved in 15 ml of methanol, mixed in portions with 252 mg of sodium borohydride and stirred for 15 minutes at room temperature. For working-up, the reaction solution is added to saturated common salt solution, extracted several times with methylene chloride, the organic phases are washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 540 mg of 11β-fluoro-7α-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+63° (c=0.5 in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20](Cl)=[O:21]>O1CCCC1>[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:21]
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Reactant: O=C(Cl)C1CC1(Cl)Cl
Solvent: C1CCOC1
Product: O=C1NN=C(c2ccc(NC(=O)C3CC3(Cl)Cl)cc2)C2CC12
Yield: 48.9 %

Procedure:
5.0 g (24.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, 5.2 g (30.0 millimoles) of 2,2-dichlorocyclopropanecarboxylic acid chloride and 100 ml of absolute tetrahydrofuran are refluxed for 6 hours. The product is filtered off at 10° C., washed with water and recrystallized from a dimethylformamide/water mixture. 4.1 g (49% of theory) of 2-[p-(2,2-dichlorocyclopropylcarbonylamino)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as colorless crystals, of melting point 264°-265° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16](=[O:32])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([F:31])[CH:20]=1)[CH3:18]>CN(C)C=O>[F:31][C:21]1[CH:20]=[C:19]([CH:17]([CH3:18])[C:16](=[O:32])[CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:23][C:22]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a suspension of sodium hydride (1.88 g as 60% in oil, 47.0 mmoles) which was washed with hexane to remove mineral oil and dried, in dimethylformamide (DMF, 23 ml) was added dropwise a solution of diethyl malonate (7.52 g, 47.0 mmoles) in DMF (5 ml) at 0° C. under the stream of nitrogen gas. After elevating the temperature to 50° C., a solution of 1-chloro-3-(2-fluoro-4-biphenylyl)butan-2-one (10.0 g, 36.1 mmoles) in DMF (40 ml) was added dropwise, and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice water and extracted with diethyl ether. The organic layer was washed with 1M hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by medium pressure silica gel column chromatography gave the desired diethyl 2-(3-(2-fluoro-4-biphenylyl)-2-oxobutyl)malonate (8.98 g, 22.4 mmoles, yield 62%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29](I)[CH:30]=4)[C:25]([CH3:34])([CH3:33])[CH2:24]3)=[C:7]([CH3:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:34][C:25]1([CH3:33])[C:26]2[C:31](=[CH:30][C:29]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[N:23]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])[C:7]=2[CH3:22])[CH2:24]1
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 95 °C

Procedure:
Prepared according to procedure N using 7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (68 mg, 0.12 mmol) (described herein), morpholine (20 μL, 0.23 mmol), Pd2dba3 (7.4 mg, 8.1 μmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (8.2 mg, 0.017 mmol), and sodium tert-butoxide (22.1 mg, 0.23 mmol) in toluene (2.2 mL), and heated at 95° C. for 15 h. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline was obtained as a yellow glass. 1H NMR (400 MHz, chloroform-d) δ ppm 8.17-8.28 (1H, m), 7.94 and 8.08 (1H, m), 7.74-7.84 (1H, m), 7.63-7.74 (2H, m), 7.42-7.53 (1H, m), 7.29-7.40 (1H, m), 6.98-7.13 (1H, m), 6.21-6.39 (1H, m), 5.65 and 5.82 (1H, m), 3.94 and 3.66 (1H, m), 3.69-3.82 (5H, m), 3.15 (1H, m), 3.05-3.12 (3H, m), 2.84-3.05 (4H, m), 1.94 (2H, s), 1.47-1.55 (3H, m), 1.40-1.47 (3H, m). Mass Spectrum (ESI) m/e=546 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:32]>CO.O1CCOCC1.[Pd]>[ClH:32].[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH2:22][CH2:23][NH:11][CH2:12][C:13]2=3)=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(F)cc3)c3ccccc23)C1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 2-benzyloxycarbonyl-9-{[4-(fluoro)phenyl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.28 g, 12.7 mmole) in methanol (50 mL), dioxane (50 mL) and HCl (19 mL, 1M in dioxane) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 6 hr. The suspension was filtered through celite®, and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (3.61 g, 90%) as a white solid: MS (ES) m/e 281 (M+H−HCl)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:31](OCC(F)(F)F)=[O:32]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[CH2:18]2)[CH2:13][CH2:14][N:15]([CH:31]=[O:32])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=COCC(F)(F)F
Reactant: CCOc1cc(C(CCNO)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC

Procedure:
(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of Example 7 from N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (0.7 g, 1.7 mmol) and 2,2,2-trifluoroethyl formate (2.2 g, 17 mmol) in THF (10 mL) to give a white solid (480 mg, 64% yield): mp: 79-81° C. 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 2.32-2.42 (m, 2H, CH2), 3.40-3.52 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.98-4.02 (m, 2H, CH2), 4.14 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH), 5.23-5.28 (m, 1H, NCH), 6.92-6.96 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.24-8.27 (m, 1.5H, Ar, CH), 9.64 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.30 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 24.50, 28.34, 28.52, 43.39, 45.81, 46.19, 46.74, 51.14, 51.92, 55.45, 63.81, 111.97, 112.39, 116.63, 117.39, 119.66, 131.60, 132.70, 137.02, 142.21, 142.30, 147.96, 148.54, 157.35, 168.21, 168.38, 168.51; Anal Calcd for C23H27N3O6+0.4 H2O: C, 61.57; H, 6.25; N, 9.36; H2O, 1.61. Found: C, 61.77; H, 6.18; N, 8.97; H2O, 0.55.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([C:25]4[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=4)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CNCC2C1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CN(c3ccc(C#N)cn3)CC2C1
Temperature: 45 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (112.0 mg, 0.36 mmol) and 6-chloropyridine-3-carbonitrile (102.5 mg, 0.74 mmol) in a mixture of DCM (5 mL) and MeOH (5 mL) was added Et3N (200.7 mg, 1.98 mmol). The reaction mixture was stirred at 45° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) to give the title compound as a beige solid (0.12 g, 81%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].C1(=O)CCCCC1.OOC(O)=O.OCC(CO)(C)C([O-])=O.C([NH+](CC)CC)C.[I-].[K+].Cl[CH2:41][C:42]([O:44][CH3:45])=[O:43]>C(N(CC)CC)C>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[O:5]
Reactant: CC(CO)(CO)C(=O)O
Reactant: COC(=O)CCl
Agent: CC(CO)(CO)C(=O)[O-]
Agent: CC[NH+](CC)CC
Agent: O=C(O)OO
Solvent: CCN(CC)CC
Solvent: O=C1CCCCC1
Product: COC(=O)COC(=O)C(C)(CO)CO
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 5-liter reaction vessel which has been equipped with a stirrer, an internal thermometer, a reflux condenser and a 1-liter dropping funnel is charged with 550 g of 2,2-bis-(hydroxymethyl)-propionic acid and 2,460 g of cyclohexanone, and the mixture is heated to 100° C. When the bulk of the dihydroxycarboxylic acid has gone into solution, the temperature is lowered to 60° C., and 414 g of triethylamine are added dropwise. The temperature is held at 60° C. by cooling. The resulting triethylammonium 2,2-bis-(hydroxymethyl)-propionate stays in solution. 7 g of potassium iodide are then added, followed, in dropwise fashion, by 565 g of methyl chloroacetate in the course of 30 minutes. The batch is held at this temperature for a further 4 hours, is then allowed to cool down to room temperature and is filtered to remove the triethylammonium chloride formed. The filtrate is concentrated in a rotary evaporator and is then adjusted with xylene to a solids content of 90%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[N:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[N:3]=1)(=[O:29])[CH3:28]
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)n2)C1
Reactant: CC(=O)c1ccccc1B(O)O
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1-c1cccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
5-(2-Bromo-pyridin-6-yl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 4 of Preparation 9, 2-acetylphenylboronic acid (11.0 mg, 0.07 mmol), Pd(PPh3)4 (2.0 mg, cat.) and a 2N sodium carbonate solution (210.0 uL) were added to a mixed solvent of ethanol (210.0 uL) and toluene (310.0 uL). The reaction mixture was stirred at 80° C. for 1 hour and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 8.0 mg of the titled compound as a white liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[C:15](Br)Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[CH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=C(Br)Br)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 3-(2,2-Dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.42 mmol) in THF (1 ml) wad added at −78° C., 0.5 ml of n-BuLi 2.5 M in hexane (1.23 mmol). After 1 h at −78° C., the reaction mixture was quenched with 1 ml of water and the aqueous phase was extracted with AcOEt. The combined organic phase was dried over K2CO3, filtered and evaporated to give 80 mg (93%) of 3-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][OH:15])=[CH:8]2)[C:2]([CH3:4])=[O:3]>C(O)C.O=[Mn]=O>[NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[O:15])=[CH:8]2)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2[nH]c(CO)cc2c1
Agent: O=[Mn]=O
Solvent: CCO
Product: CC(=O)Nc1ccc2[nH]c(C=O)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 15 (100 mg, 0.5 mmol) in ethanol (10 mL) was added MnO2 (250 mg) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was filtered and the solid was washed with ethanol. The solvent was removed in vacuo and a grey solid 16 was obtained (97 mg, 100% yield). An analytical sample was recrystallized in ethyl acetate. mp: 200° C. (dec). 1H NMR (DMSO-d6, ppm): 11.80 (s, 1 H, NH), 9.84 (s, 1 H, NH), 9.81 (s, 1 H, CHO), 8.09 (s, 1 H, Ar--H), 7.38-7.32 (m, 3 H, Ar--H), 2.04 (s, 3 H, CH3), Anal. (C11H10N2O2 0.4H2O), C, H, N.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[C@H:6]([CH2:21][CH3:22])[CH2:5]1)=[N+]=[N-].[F:23][C:24]([F:32])([F:31])[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>CCO.[OH-].[OH-].[Pd+2]>[CH2:21]([C@H:6]1[N:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[CH2:8][C@@H:4]([NH:1][S:27]([CH2:26][CH2:25][C:24]([F:32])([F:31])[F:23])(=[O:29])=[O:28])[CH2:5]1)[CH3:22]
Reactant: CC[C@@H]1C[C@H](N=[N+]=[N-])CN1c1ncc2cnc3[nH]ccc3n12
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)CCC(F)(F)F)CN1c1ncc2cnc3[nH]ccc3n12
Yield: 15.7 %

Procedure:
To slurry of palladium hydroxide on carbon (20 mol %, 0.013 g, 0.019 mmol) in EtOH (5 mL) was added a solution of 1-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.110 g, 0.371 mmol, prepared using E from (2R,4S)-tert-butyl-4-azido-2-ethylpyrrolidine-1-carboxylate (synthesized as described in. J. Med. Chem. 1988, 31, 1598-1611) with HCl, J with Example #5, Step C, OO, D with NaOH) in EtOH (2 mL). The reaction mixture was sparged with hydrogen and an atmosphere of hydrogen was maintained via balloon. After about 2 h the reaction mixture was filtered and concd under reduced pressure The residue was dissolved in DCM (5 mL) and 3,3,3-trifluoropropane-1-sulfonyl chloride (0.080 g, 0.41 mmol, Matrix) was added. After about 15 h additional 3,3,3-trifluoropropane-1-sulfonyl chloride (80 mg, 0.408 mmol, Matrix) was added. After about 2 days the reaction mixture was partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The crude product was purified by chromatography on silica gel eluting with EtOAc to provide N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide (0.025 g, 16%) as a brown solid: LC/MS (Table 1, Method a) Rt=1.81 min; MS m/z: 431 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.CS(O)(=O)=O.II.CC(C)=O>C(O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C.O.[Pd]>[CH3:22][S:19]([OH:21])(=[O:20])=[O:18].[CH:1]([N:14]1[CH2:15][CH:16]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17]1)([CH3:8])[CH3:2]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: CS(=O)(=O)O
Agent: II
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)N1CC(OS(C)(=O)=O)C1

Procedure:
Hydrogenate a mixture of 1.0 mole 1-benzhydryl-3-methanesulfonyloxyazetidine, 1.0 mole methanesulfonic acid and 20% palladium hydroxide-on-carbon in ethyl alcohol at ca. 60 psi until the reaction is complete as shown by absence of the Compound IV using thin layer chromatography. (Silica gel GF plates are developed in chloroform:ethyl acetate (9:1) and visualized using iodine). Add additional 20% palladium hydroxide-on-carbon and acetone and continue the hydrogenation at ca. 60 psi for 5 days. Remove the catalyst by filtration and wash with ethanol. Remove the ethanol from the combined filtrates and washes by distillation at about 40° C. under reduced pressure and wash the residue with diethyl ether and air-dry to afford 1-isopropyl-3-methanesulfonyloxyazetidine methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:10]1[C:5]2[C:4]([Cl:11])=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (105 mg, 0.560 mmol) in CH2Cl2 (7 mL) at room temperature, NBS (109 mg, 0.610 mmol) was added. The mixture was stirred at room temperature for 18 h. CH2Cl2 was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (142 mg).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.[Li]CCCC.N(C(C)C)C(C)C.Br[CH2:41][C:42]1[O:43][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:46]=1.[NH4+].[Cl-]>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:18])([CH3:19])[O:6][C:7]1[CH:8]=[C:9]([CH:13]([CH2:41][C:42]2[O:43][C:44]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:46]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:1])[CH3:3]
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COC(=O)Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
A solution of methyl 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzeneacetate (12.00 g, 43 mmol) in dry THF (40 mL) was added dropwise to a solution of LDA (prepared from nBuLi (20.70 mL of a 2.5 M solution, 3.32 g, 51 mmol) and iPr2NH (4.79 g, 6.60 mL, 47 mmol)) in THF (300 mL) maintained at about -78° C. under an atmosphere of N2. After about 15 minutes, 2-bromomethyl-4,5-diphenyloxazole (14.86 g, 47 mmol) in THF (20 mL) was added dropwise. The mixture was stirred for about 30 minutes at about -78° C., poured onto saturated NH4Cl solution and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, concentrated and the residual oil chromatographed on a column of silica gel. Elution with a mixture of hexanes and Et2O (9:1) gave methyl α -[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-4,5-diphenyl-2-oxazolepropanoate (12.40 g, 56%) 1H NMR (CDCl3) δ0.18 (6H, s, Si(CH3)2), 0.98 (9H, s, (CH3)3C), 3.23 and 3.65 (2H, d of ABq, J=16 Hz, J'=8 Hz, CH2 -oxazole), 3.72 (3H, s, CO2CHH3), 4.29 (1H, dd, J=8 Hz, CHCO2CH3), 6.77 (1H, d, J=9 Hz, aromatic H), 6.88 (1H, s, aromatic H), 6.98 (1H, d, J=9 Hz, aromatic H), 7.20 (1H, t, J=8Hz, aromatic H), 7.25 to 7.45 (6H, m, aromatic H), 7.45 to 7.70 (4H, m, aromatic H).