Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]#[C:3][CH3:4].[N+](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9])=[N-]>FC1C(F)=C(F)C(F)=C(F)C=1F.[Hg]>[CH3:1][C:2]1[C:7]([C:12]([O:14][CH3:15])=[O:13])([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[CH3:4]
Reactant: CC#CC
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Hg]
Solvent: Fc1c(F)c(F)c(F)c(F)c1F
Product: COC(=O)C1(C(=O)OC)C(C)=C1C
Reaction time: 100 h
Yield: 46.2 %

Procedure:
A nitrogen-degassed solution of 37.5 grams (0.69 mole) of 2-butyne and 20.0 grams (0.13 mole) of dimethyl diazomalonate in approximately 325 grams of hexafluorobenzene was photolyzed for approximately 100 hours, at 0° C.-5° C., employing a 100-watt Hanovia mercury lamp in a manner similar to that described in Example XCVI Part A. Similar workup of the reaction mixture afforded 10.8 grams (0.06 mole) of dimethyl 2,3-dimethyl-2-cyclopropene-1,1-dicarboxylate. NMR analysis of the product indicated the following:
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]1[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]1[C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:48][CH2:49][C:50](=[O:51])[N:52]2[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:65]([F:66])([F:68])[F:67])[CH2:56][CH2:57]2)=[O:23])=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 14.9 %

Procedure:
DIPEA (213 mg, 0.27 mL, 1.65 mmol) was added to a stirred solution of 4-(2-oxo-2H-pyridin-1-yl)-benzoic acid (120 mg, 0.55 mmol) in DMF (2 mL). HOBT (74.5 mg, 0.55 mmol) and EDCI (126.5 mg, 0.66 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (196 mg, 0.55 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 42 mg (14.7% yield) of 4-(2-Oxo-2H-pyridin-1-yl)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 94.83%. 1H NMR (DMSO-d6): δ 8.0 (m, 2H), 7.9 (m, 2H), 7.7 (m, 2H), 7.5 (m, 4H), 6.5 (m, 1H), 6.4 (t, 1H), 4.2 (m, 2H), δ 3.9-3.6 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:9](=[O:22])[C@@:8]12[CH2:24][C@@H:23]1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:4].[OH-].[Li+]>CO.C1COCC1.O>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2)[C@@:8]2([CH2:24][C@@H:23]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:9]1=[O:22]
Reactant: COC(=O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2Cc1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 20.7 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-methyl-1′-(3-fluorobenzyl)-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylate (50 mg) in methanol (5 mL), THF (5 mL) and water (1 mL) was added lithium hydroxide (50 mg) at room temperature. The mixture was heated to 60° C. and stirred at 60° C. for 3 hours. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. Purification by preparative HPLC gave the title compound as white powder (10 mg). LC/MS m/e calcd. for C24H17F2lNO3: 405, observed (M+H)+: 406.2 1H NMR (400 MHz, MeOD) δppm 7.83 (dd, J=8.34, 1.52 Hz, 1 H) 7.24-7.38 (m, 5 H) 7.15 (d, J=2.02 Hz, 1 H) 7.18 (d, J=7.83 Hz, 2 H) 7.06 (t, J=8.72 Hz, 2 H) 6.99 (d, J=8.08 Hz, 1 H) 6.75 (d, J=1.52 Hz, 1 H) 5.17 (s, 2 H) 2.24-2.35 (m, 2 H); MS calcd. C24H17F2NO3 406, obsd. (ESI+) [(M+H)+] 406.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([Cl:7])[Cl:6].[Cl:11]C(Cl)(Cl)C(Cl)(Cl)Cl.[OH-].[Na+]>ClC(Cl)=C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([Cl:11])([Cl:7])[Cl:6])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(Cl)Cl)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)=C(Cl)Cl
Product: Cc1cccc(C(Cl)(Cl)Cl)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 84.7 %

Procedure:
36.2 gms of 3-methyl benzal chloride in 207 gms of solvent, tetrachloroethylene, was added into a reaction vessel with 53.9 gms of hexachloroethane, 66.3 gms of 50% sodium hydroxide, and 1.4 gms of Aliquot 4. The mixture was stirred and refluxed under partial vacuum at about 90° C. for about 1 hour. 20.3 ml of water was removed from the mixture via a Dean Stark trap during this period. The mixture was refluxed for another hour an additional 10.5 ml of water was removed. 200 ml of water was added to the cooled mixture and 15 gms of HCl gas was added until the mixture turned acidic. After standing for 2 days, the organic layer was removed and the tetrachloroethylene was distilled off under reduced pressure. The remaining residue was then distilled to give 36.7 gms of a clear oil. b.p. 80° -90° C. (0.6-1.0 mm/Hg-0.8-1.33×105 pascals). (Yield 85% - 97.2 assay).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].CCN(C(C)C)C(C)C.C(#N)C>C1COCC1.O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6) (0.05 g) in THF (1 mL) was added acetic anhydride (12.8 μL) and DIPEA (23.1 μL). The reaction was stirred at room temperature for 2 hours. A sample of the reaction mixture was prepared for LC/MS analysis. 10 μL of the reaction mixture was diluted with H2O:ACN=6:4 to result in a 0.1 mg/mL preparation. LC/MS confirmed that the resulting product (having a m/z of 429) is the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 64.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (268 mg, 0.447 mmol) prepared in Example 25a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (130 mg, 65%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1.[N:13]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl.Cl[Sn]Cl.[OH-].[Na+]>O.Cl>[F:12][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH2:13])[C:4]=2[O:3]1
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: NNc1cccc2c1OC(F)(F)O2

Procedure:
The 2,2-Difluoro-benzo[1,3]dioxol-4-ylamine (1.99 g, 11.5 mmol) was cooled and cone hydrochloric acid (10 mL) added. After recooling to 0° C. or less a solution of the sodium nitrite (873 mg, 12.7 mmol) in water (10 mL) was added dropwise. The reaction was stirred at the same temp for 30 min when tin chloride (6.55 g, 34.5 mmol) in hydrochloric acid (10 mL) was added dropwise again keeping temp ea 0° C. (nb initial additions of SnCl2 were very exothermic and the initial thick ppt required a large stirrer to keep things moving). The reaction was stored in the fridge overnight at 0° C. The resulting solid was filtered off, washed with sat NaCl (50 mL) and then ether:hexane 1:2 (50 mL) before drying to give a white solid. The solid was treated with 50% aqueous sodium hydroxide (100 mL) and extracted with ether (3×50 mL). The combined extracts were dried and filtered to give a yellow oil which crystallised to long needles on standing (1.28 g, 60%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([CH2:29][CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CCC1(CCNCC1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CCc5ccccc5O4)CC3)nn2)n1

Procedure:
The object product (74 mg, 44%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (95 mg), 3,4-dihydrospiro[chromene-2,4′-piperidine] hydrochloride (105 mg) and potassium carbonate (138 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.Cl[Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Brc1ccccc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1Br
Reaction time: 0 h
Yield: 81 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with chlorotributylstannane (Bu3SnCl) (0.32 M) in THF (flow rate: 6 mL/min, 1.92 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The resulting solution was passed through the tube reactor R2 and was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=50 cm) was 1.78 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was concentrated, then the residue was subjected to silica gel column chromatography (hexane) to refine, 2-bromophenyltributylstannane was obtained as colorless oil in 81% yield, 146.6 mg. 1H NMR (400 MHz, CDCl3) δ: 0.88 (t, J=7.2 Hz, 9H), 1.12-1.17 (m, 6H), 1.27-1.38 (m, 6H), 1.51-1.60 (m, 6H), 7.10-7.15 (dt, J=7.6, 1.6 Hz, 1H), 7.18-7.23 (dt, J=7.6, 1.2 Hz, 1H), 7.27-7.31 (dd, J=7.6, 1.6 Hz, 1H), 7.44-7.50 (dd, J=7.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 11.0, 13.8, 27.4, 29.1, 126.1, 129.8, 131.5, 133.2, 137.8, 146.5. HRMS (EI) m/z: calcd. for C14H22BrSn (M+-C4H9) 388.9927, found 388.9925.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27]C)=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([OH:27])=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCOC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@H]1COCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-3-(3-methylmorpholino)quinoxaline-6-carboxylate (140.0 mg, 0.37 mmol,) in methanol (15 mL) and CHCl3 (5 mL) was added a solution of NaOH (45 mg, 1.12 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(4-fluorophenyl)-3-(3-methylmorpholino)quinoxaline-6-carboxylic acid as a yellow solid (91.2 mg, 68%).
Reaction SMILES: [NH:1]=[C:2](OC)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH:5]=1.[CH3:28][NH:29][NH:30][C:31]([C:33]1[O:37][N:36]=[C:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=2)[N:34]=1)=O>CO>[CH3:28][N:29]1[C:2]([CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:14][CH2:15]3)[CH:5]=2)=[N:1][C:31]([C:33]2[O:37][N:36]=[C:35]([C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:46])[F:47])=[CH:42][CH:43]=3)[N:34]=2)=[N:30]1
Reactant: CNNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: COC(=N)Cc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Solvent: CO
Product: Cn1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
To a solution of benzyl 4-(4-(2-imino-2-methoxyethyl)pyridin-2-yl)piperazine-1-carboxylate (500 mg, 1.5 mmol) and TEA (1 mL, 7.5 mmol) in dry MeOH (5 mL), N′-methyl-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (450 mg, 1.5 mmol) was added slowly at 0° C. The mixture was stirred at 80° C. for 3 h, and then concentrated to give the crude product, which was purified by reverse phase chromatography (Mobile phase: MeCN/H2O containing 0.01% TFA, 50%˜60%) to afford benzyl 4-(4-((2-methyl-5-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-2H-1,2,4-triazol-3-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate as a white solid (280 mg, 27%). MS (ES+) C30H27F3N8O4 requires: 620, found: 621 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15](=O)[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.CCOC(C)=O>O1CCOCC1.C(O[Hg]OC(=O)C)(=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH2:4][CH:3]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:28])=[O:29])[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CN(C(=O)OC(C)(C)C)CCC4C)cnc32)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CN(C(=O)OC(C)(C)C)CCC4C)n23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 83 mmol) in 1,4-dioxane (500 mL) was added Lawesson's reagent (20.2 g, 50.0 mmol). The reaction was heated at about 80° C. for about 1 h. The reaction was allowed to cool to ambient temperature followed by the addition of diacetoxymercury (26.6 g, 83.0 mmol). After about 1 h, additional diacetoxymercury (13.3 g, 42.0 mmol) was added. After about 15 min, the reaction was poured into stirred EtOAc (2 L). After about 15 min, the reaction was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resulting residue was triturated with EtOAc (500 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (330 g column) eluting with a gradient of 10-50% EtOAc in heptane to provide tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (19 g, 44%) as a white solid: LC/MS (Table 2, Method a) Rt=2.57 min; MS m/z: 510 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COCCOC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOCc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a mixture of ethyl 3-[({4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (216 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (69.6 mg, 34%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19]([C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)=[O:20].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(=O)(O)[O-].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[CH:3]=2)[NH:8][C@@H:7]([CH3:18])[CH2:6]1)=[O:20]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: C[C@H]1CN(C(=O)c2ccco2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(C(=O)c2ccco2)c2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2N1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.626 g, 1.5 mmol), 1,4-dioxane (15 mL), 4-(methylsulfonyl)phenylboronic acid (0.360 g, 1.8 mmol), and sodium bicarbonate as a 1M solution in water (4.5 mL, 4.5 mmol). The reaction mixture was purged with nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (0.01 M solution in DMF, 7.5 mL, 0.075 mmol) was added, and the reaction mixture was purged with nitrogen and heated to 80° C. overnight. The reaction was diluted with ethyl acetate (30 mL) and washed with brine (15 mL). The aqueous layer was separated and washed with ethyl acetate (30 mL) and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 1:1 hexanes-ethyl acetate) to afford (S)-furan-2-yl(3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (0.33 g, 55% yield) as a viscous yellow oil. MS (ESI, pos. ion) m/z 397 [M+1]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][C:20](OCC)=[O:21])[S:5]([N:8]([CH2:16][CH:17]=[CH2:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:7])=[O:6])[CH:2]=[CH2:3].[H-]>ClCCl>[CH2:16]([N:8]([S:5]([N:4]([CH2:1][CH:2]=[CH2:3])[CH2:19][CH:20]=[O:21])(=[O:6])=[O:7])[C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:17]=[CH2:18]
Reactant: C=CCN(CC(=O)OCC)S(=O)(=O)N(CC=C)C(=O)OC(C)(C)C
Agent: [H-]
Solvent: ClCCl
Product: C=CCN(CC=O)S(=O)(=O)N(CC=C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of ethyl (allyl{[allyl(tert-butoxycarbonyl)amino]sulfonyl}amino)acetate (1.11 g, 3.05 mmol) in dichloromethane (15 mL) at −78° C. under N2 was treated with 1.0 M diisobutylaluminun hydride in dichloromethane (3.66 mL, 3.66 mmol, 1.2 equiv.). The reaction mixture was stirred at −78° C. for 1 h and then quenched with methanol (1.5 mL) and treated with a saturated solution of sodium potassium tartrate (65 mL). This solution was stirred at room temperature overnight. The aqueous layer was then extracted with dichloromethane (3×20 mL). The combined dichloromethane solution was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (0.62 g, 64%) as a crude thick colorless oil, which was used in subsequent reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 5.76 (m, 2H), 5.18 (m, 4H), 4.15 (m, 4H), 3.72 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O.O.[NH2:26][NH2:27].C(O)C>C1COCC1>[C:19]1([C:2]2[CH:3]=[C:4]([CH:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[NH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)c2ccccc2)CC1
Reactant: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccc3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl 4-(3-oxo-3-phenylpropanoyl)piperidine-1-carboxylate (3.1 g), hydrazine monohydrate (0.5 mL), ethanol (30 mL), and THF (30 mL) was stirred at room temperature for about 15 hours, and at 60° C. for 1 hour. Hydrazine monohydrate (0.5 mL) was further added thereto, followed by stirring again at 60° C. for 3 hours. Hydrazine monohydrate (4.0 mL) was added thereto again, followed by stirring at 60° C. for 8 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and to the residue were added diisopropyl ether and methanol, followed by stirring. The resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(3-phenyl-1H-pyrazol-5-yl)piperidine-1-carboxylate (2.46 g).