Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([PH:11](=[O:15])[O:12][CH2:13][CH3:14])([O:8][CH2:9][CH3:10])[CH3:7])[CH3:4].Cl[CH:17]([F:19])[F:18]>O1CCCC1>[CH2:9]([O:8][C:6]([P:11]([CH:17]([F:19])[F:18])(=[O:15])[O:12][CH2:13][CH3:14])([O:5][CH2:3][CH3:4])[CH3:7])[CH3:10]
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Reactant: FC(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(OCC)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 15.8 g of sodium hydride (dispersion in oil) in 500 ml of tetrahydrofuran are added dropwise 67 g (300 mMol) of ethyl 1,1-diethoxyethylphosphinate at such a rate so that the temperature does not exceed 25° C. This mixture is stirred for one hour at room temperature, then cooled to -10° C. and 77.8 g (900 mMol) of chlorodifluoromethane are introduced. Stirring is continued for another 2 hours at room temperature, then 100 ml of ice-cold water are added. The mixture is extracted three times with dichloromethane and the combined extracts dried over magnesium sulphate. Removal of the solvent in vacuo gives ethyl 1,1-diethoxyethyl(difluoromethyl)phosphinate as a viscous oil, Rf=0.44 (CH2Cl2 /CH3COOH, 9+1).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O.O>O1CCCC1>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1/[CH:20]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OC)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To an ice-cooled solution of ethyl diethylphosphonoacetate (9.45 g, 42.1 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% oil suspension, 1.54 g, 38.5 mmol) and the mixture was stirred for 15 min. A solution of 2-fluoro-4-methoxybenzaldehyde (5.00 g, 32.4 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 hrs. and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (7.07 g, yield 97%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1
Reactant: C[O-]
Reactant: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Agent: [Na+]
Solvent: CO
Product: COc1nc(/C=C/c2ccccc2)nc2c1CCC(=O)N2
Yield: 90.9 %

Procedure:
To a suspension of 4-chloro-2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.45 g, 1.58 mmol) in MeOH (10 mL) was added NaOMe (0.094 g, 1.74 mmol). The reaction mixture was heated at reflux for 3 h, at which time an additional 0.10 g NaOMe was added and refluxing was continued. This was repeated two more times over 9 h. After the disappearance of all starting material (LCMS), the reaction was concentrated onto silica gel and purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as an off-white solid (0.404 g, 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1>>[OH:35][C@@H:30]1[CH2:31][N:32]([CH2:6][CH2:5][C@H:4]([N:8]2[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[CH2:10][CH2:9]2)[CH2:3][O:2][CH3:1])[CH2:33][CH2:34][C:29]21[CH2:28][CH2:27]2
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 58 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-methoxy-3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyraldehyde and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 58% yield as light yellow foam. MS: 470.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH:25]4[CH2:27][CH2:26]4)[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.CCO.O>[CH:25]1([C:21]2[CH:20]=[C:19]([C:8]3([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:32]5[CH:33]=[N:28][CH:29]=[N:30][CH:31]=5)[CH:7]=4)[C:16]4[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:18])=[N:9]3)[CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:26]1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: NC1=NC(c2ccnc(-c3cncnc3)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: 150 °C
Yield: 50.5 %

Procedure:
1-(2-Bromopyridin-4-yl)-1-(2-cyclopropylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (92 mg, 0.22 mmol), 5-pyrimidinylboronic acid (35.0 mg, 0.28 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (8.87 mg, 10.87 μmol), cesium carbonate (0.052 mL, 0.65 mmol) and DME:EtOH:water (6:3:1) (3.00 mL) were put in a microwave vial and heated at 150° C. in a microwave reactor for 20 min. The mixture was filtered through a syringe filter and purified by prep-HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was redissolved in acetonitrile and water was added. The mixture was freeze dried to give the title compound (46.9 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 2 H) 9.24 (s, 1 H) 8.67 (d, 1 H) 8.29 (d, 1 H) 7.96 (d, 1 H) 7.87 (d, 1 H) 7.58 (td, 1 H) 7.46 (dd, 1 H) 7.31 (dd, 1 H) 7.21 (d, 1 H) 7.03 (dd, 1 H) 6.79 (br. s., 2 H) 1.96-2.07 (m, 1 H) 0.80-0.96 (m, 4 H); MS (ES+) m/z 423 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:12][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])([CH3:12])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(C#N)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cc(C#N)ccn1
Temperature: -40 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 2-acetylisonicotinonitrile (67.1 g, 0.457 mol) in tetrahydrofuran (2400 mL) was added dropwise a solution of methylmagnesium bromide (3.0 M, 167.6 mL, 0.503 mol) in toluene/tetrahydrofuran mixture (3:1) at −40° C. over a period of 2.5 h. The reaction mixture was stirred at −40° C. for another 2 h. A saturated aqueous solution of ammonium chloride (50 mL) was added. The resulting mixture was warmed to room temperature and another 400 mL of a saturated aqueous solution of ammonium chloride was added. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL×2). The combined organics were dried over sodium carbonate and sodium sulfate and concentrated. The residue was purified via flash chromatography (ethyl acetate/petroleum ether 1:20, 0.3% triethylamine) to afford 2-(2-hydroxypropan-2-yl)isonicotinonitrile (33.0 g, 44.3%).
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[C:20]1(=[O:25])[NH:19][C:23](=[O:24])[CH2:22][CH2:21]1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: C1COCCO1
Product: O=C1CCC(=O)N1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To Naproxen (2.303 g, 10 mmol) in 5 mL of dioxane was added N-hydroxysuccinimide (1.16 g, 10 mmol) dissolved in 15 mL of dioxane and dicyclohexylcarbodiimide (2.27 g, 11 mmol) in 25 mL of dioxane. The reaction was stirred overnight and the insoluble dicyclohexylurea removed by filtration. The solvent was removed by rotary evaporation and the residue dissolved in 30-40 mL CH2Cl2. Approximately 10 mL hexane was added and the mixture was chilled to 4° C. for 2 hr. Additional hexane was added dropwise until small planar white crystals began to form and the solution was refrigerated overnight. The activated ester was harvested, washed with hexane and dried in vacuum (2.30 g, 70.0%)
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]1(C)C=CC=C[CH:17]=1>N1C=CC=CC=1>[CH2:8]([CH:9]1[CH2:10][CH2:5][CH:3]=[CH:2][O:1]1)[CH2:7][CH:6]=[CH:16][CH3:17]
Reactant: Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC=CCCC1CCC=CO1

Procedure:
The acetyl derivative derived from the fragrant lactone (5 mmol) and pyridine (3-4 drops, 0.1 eq.) was added to a suspension of the hydroxy-acetophenone (10 mmol) in toluene (10 ml) The mixture was heated under reflux overnight. It was then poured into aq. NaHCO3 (sat.) and the separated aqueous phase was extracted with MTBE. The combined organic layers were washed with brine and dried over MgSO4. The crude, obtained after evaporation of the solvents, was purified by chromatography (SiO2, EtOAc/Hexane) to afford the desired product as a colorless to pale yellow oil.
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].Cl.C1COCC1.CN1CCOCC1.[NH:42]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:43](C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:44][CH2:45][CH2:46][CH2:47][NH:48]C(OCC1C=CC=CC=1)=O>CN(C=O)C>[NH:42]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:43]([C:22]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:24])[CH2:44][CH2:45][CH2:46][CH2:47][NH2:48]
Reactant: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Boc-Asn-Ala-OBzl (XXIII) (27.54 g, 70 mmol) was treated with 4 N HCl/THF (875 ml) for 30 minutes at room temperature. Evaporation and treatment with dry ether provided 23.08 g (100%). The hydrochloride salt was dissolved in DMF (250 ml), cooled to 0° C and NMM (4.9 ml, 70 mmol) was added under stirring followed by Boc-Lys(Z)-OPfp (39.5 g, 72.3 mmol). The mixture was stirred for 1 hr at 0° C and 3 hr at room temperature. After evaporation of the solvent to a smaller volume, 0.5 N HCl was added and the precipitated product was collected by filtration and washed on the funnel with H2O, (5%) NaHCO3 and H2O. After drying, it was triturated with EtOAc and then with petroleum ether, yield 41.5 g (90.4%); mp 148°-150° C; [α]D25 -15.3° (c 2, DMF). Anal. Calcd for C33H45N5O9 (655.76): C, 60.44; H, 6.92; N, 10.68. Found: C, 60.50; H, 6.97; N, 10.70.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26](S(C5C=CC=CC=5)(=O)=O)[CH:27]=[CH:28][C:21]=34)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[NH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.[OH-].[Na+].Cl>CC(O)C>[N:47]1([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]5[NH:26][CH:27]=[CH:28][C:21]=45)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Reactant: C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2ccnc3[nH]ccc23)cc2[nH]ncc12)c1csc(CN2CCCCC2)n1
Temperature: 90 °C
Reaction time: 29 h

Procedure:
2-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (40 mg) and piperidine (0.5 ml) were added to a microwave vial then heated in the microwave for 15 min at 90° C. The solvent was blown off under nitrogen. IPA (3 ml) and 2M NaOH (aq) (2 ml) were added and the reaction mixture was stirred for 29 h. The reaction was heated to 50° C. for 5 min then cooled to RT for stirring overnight. The mixture was neutralised to pH 7 with 2M HCl (aq.) and the solvent was removed under a stream of nitrogen. The resultant solid was dissolved in DMSO (2 ml), filtered and purified by MDAP (method K). The fractions were combined and solvent was removed under nitrogen. The residue was dissolved in water:1,4-dioxane (1:1) then freeze-dried to give title compound, as an orange solid, 15 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][CH2:15][CH2:16][CH2:17]Cl.O.C(=O)([O-])[O-].[Na+].[Na+].[Br-:26].[K+]>C(O)(C)C>[Br-:26].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N+:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1
Reactant: ClCCCCCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1

Procedure:
A mixture of 1-(2-pyrimidinyl)piperazine (16.4 g., 0.1 mole), 1,4-dichlorobutane (23.8 g., 0.19 mole), sodium carbonate monohydrate (30.8 g., 0.25 mole) and potassium bromide (44.6 g., 0.375 mole) in 150 ml. of isopropanol is stirred and refluxed for an 8-hr. period. The hot reaction mixture is filtered and insolubles washed with hot isopropanol. Concentration of the combined filtrates under reduced pressure and trituration of residual material with acetone provides 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide in yields of 50-90%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]([F:69])([F:68])[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH2:67])[CH:61]=[CH:60]2>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH:67][C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:56]([F:68])([F:55])[F:69])[CH:58]=4)[N:63]=3)=[O:21])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:24])([F:23])[F:25])([O-:3])=[O:2]
Reactant: Nc1ccc2cc(C(F)(F)F)ccc2n1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)Nc1ccc2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and triethylamine (85 mg, 0.84 mmol). After 15 minutes 6-(trifluoromethyl)quinolin-2-amine (68 mg, 0.32 mmol) was added and the resulting solution was stirred overnight at room temperature. The contents were then quenched with water (100 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 3% methanol in dichloromethane to afford 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]-oxy]-N-[6-(trifluoromethyl)quinolin-2-yl]acetamide as a yellow solid (80.6 mg, 52%). (ES, m/z): [M+H]+ 557.20; 1H NMR (300 MHz, CD3OD): δ 8.51-8.47 (m, 2H), 8.29 (s, 1H), 8.05-7.99 (m, 2H), 7.93 (dd, J=1.8, 9.0 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.83 (dd, J=2.4, 9.0 Hz, 1H), 4.27 (s, 2H), 3.63-3.45 (m, 2H), 2.27-2.14 (m, 4H), 1.70-1.56 (m, 2H), 1.46-1.34 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:35]=[CH:34][C:13]([C:14]([NH:16][C@H:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][NH:19][C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[O:15])=[CH:12][CH:11]=1.[CH3:36][C:37]([CH3:39])=O.C(O)(=O)C.C([BH3-])#N.[Na+].[NH4+].[OH-]>CO.C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][C@H:17]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:18][NH:19][C:20]([CH:22]2[CH2:27][CH2:26][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:24][CH2:23]2)=[O:21])=[O:15])=[CH:34][CH:35]=1
Reactant: COc1ccc(C(=O)N[C@@H](CNC(=O)C2CCNCC2)c2ccccc2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(=O)N[C@@H](CNC(=O)C2CCN(C(C)C)CC2)c2ccccc2)cc1
Reaction time: 4 h
Yield: 70.8 %

Procedure:
(Alkylation Method A) (R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]piperidine-4-carboxamide trifluoroacetate (0.50 g, 1.0 mmol), acetone (4.5 mL, 61 mmol), acetic acid (0.28 mL, 4.9 mmol), and sodium cyanoborohydride (0.32 g, 5.1 mmol) were combined in methanol, and stirred. After 4 h, TLC (79% CH2Cl2, 19% methanol, 1% NH4OH) indicated reaction completion. The solution was diluted with methanol (100 mL), and passed through H+ form ion exchange resin (Varian SCX cartridge, Catalog #1225-6035) washed with methanol, and then with 2 M NH3 in methanol to collect the product. The product was recrystallized from methanol and ether to afford 0.30 g (70%) of a white crystalline solid
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[N:47][C:46]([CH3:49])=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[CH:48]=[N:47][C:46]([CH3:49])=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cnc(-c2cc(C)c(Br)c(C)c2)cn1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnc(C)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-pyrazine following a procedure analogous to that described in Step 5 of Intermediate 1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:24][O:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1cccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1OC

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dimethoxy-benzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[CH2:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[C:10]2=O)=O)[CH:2]=1.O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:9]3[CH2:16][C:12]4[S:13][CH:14]=[CH:15][C:11]=4[C:10]=3[NH:20][N:19]=2)[CH:2]=1
Reactant: O=C(c1cccnc1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: c1cncc(-c2n[nH]c3c2Cc2sccc2-3)c1
Temperature: 25 °C
Yield: 40 %

Procedure:
5-(Pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g, 5 mmol), hydrazine monohydrate (0.38 mL, 7.5 mmol), glacial acetic acid (0.9 mL) and ethanol (15 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-Pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.5 g, 2 mmol) as white solid in 40% yield.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: Clc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(Cl)cc5)ccc5ccc2c3c54)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A mixed solution of 3.5 g of 1-bromo-6-(4-chlorophenyl)pyrene, 1.6 g of 4-methylphenylboronic acid, 4.9 g of tripotassium phosphate, 0.75 g of tetrabutylammonium bromide, 52 mg of palladium acetate and 30 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 3 hours. The solution was cooled to room temperature and 100 ml of water was poured into the solution, followed by filtration. The resulting solid was dissolved in 100 ml of dichloromethane and then filtered through Celite. The filtrate was evaporated, and then the resulting solid was washed with 30 ml of ethyl acetate and vacuum-dried to obtain 2.6 g of 1-(4-methylphenyl)-6-(4-chlorophenyl)pyrene. Next, a mixed solution of 2.6 g of 1-(4-methylphenyl)-6-(4-chlorophenyl)pyrene, 1.4 g of carbazole, 820 mg of sodium t-butoxide, 145 mg of tri-t-butylphosphine tetrafluoroborate, 320 mg of bis(dibenzylideneacetone)palladium and 50 ml of m-xylene was heated and stirred under a nitrogen gas stream at 140° C. for 6 hours. The solution was cooled to room temperature, filtered through Celite and then concentrated by evaporation. The resulting solid was purified by silica gel chromatography and then vacuum-dried to obtain 2.3 g of a white solid. 1H-NMR analytical results of the resulting powder are as follows and reveal that the resulting white solid is compound [29].