Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11]N(C)C)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15].[C-:16]#[N:17].[Na+]>C(OCC)(=O)C.CS(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:16]#[N:17])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15]
Reactant: CN(C)Cc1c[nH]c2cc(Br)c(F)cc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1c[nH]c2cc(Br)c(F)cc12
Temperature: 80 °C
Yield: 43.9 %

Procedure:
A mixture of (6-Bromo-5-fluoro-1H-indol-3-ylmethyl)-dimethyl-amine (1.0 g) and sodium cyanide (0.54 g, 11.02 mmol) in ethyl acetate (1.8 ml) and methylsulfoxide (16 ml) was heated at 80° C. for 24 hrs then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (anhydrous sodium sulfate), concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give (6-Bromo-5-fluoro-1H-indol-3-yl)-acetonitrile as a yellow solid (0.41 g, 44%). 1H NMR (CDCl3) d: 3.78 (d, 2H, J=1.0 Hz), 7.27 (dd, 1H, J=1.2 Hz), 7.31 (d, 1H, J=8.8 Hz, 7.58 (d, 1H, J=5.5 Hz), 8.23 (bs, 1H).
Reaction SMILES: C1(S[C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[N:12][CH:13]=2)C=CC=CC=1.Cl[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](C(OO)=O)[CH:22]=1.[S:31]([O:34]S([O-])=O)([O-])=[O:32].[Na+].[Na+]>ClCCl>[C:21]1([S:31]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[N:12][CH:13]=2)(=[O:34])=[O:32])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S([O-])OS(=O)[O-]
Reactant: c1ccc(Sc2ccc(Nc3nccs3)nc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2nccs2)nc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 41 %

Procedure:
(5-Phenylsulfanyl-pyridine-2-yl)-thiazole-2-yl-amine (0.07 mmol) is dissolved in dichloromethane, cooled to 0° C. and m-chloro-perbenzoic acid (3 eq.) is added. The reaction is stirred 30 min at 0° C. and 22 hours at RT. Sodium disulfite (40 ml) is added and extracted with dichloromethane. The combined organic layers are washed with saturated NaHCO3, dried over MgSO4 and the solvent is removed in vacuo. “A14” is obtained after reversed phase column chromatography (water/acetonitrile) as a colourless powder in a yield of 41%; HPLC (method C): 1.63 min; LC-MS (method A): 1.537 min, 317.95 (M+H+); 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 11.907 (s, 1H), 8.837-8.829 (m, 1H), 8.146 (dd, 1H, J=2.6 Hz, J=8.9 Hz), 8.006-7.976 (m, 2H), 7.714-7.671 (m, 1H), 7.645-7.605 (m, 2H), 7.456 (d, 1H, J=3.6 Hz), 7.185-7.154 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.C(O)(=O)C.CO>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3)c2)CC1
Yield: 101.4 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and benzoyl chloride (39 μL, 0.336 mmol) in methylene chloride (1 mL) was mixed for 18 h at ambient temperature. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column (Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360). The column was rinsed extensively with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 37.6 mg (>100%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][C:3]1=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][O:35][NH:36][CH3:37].CCN(CC)CC>C(Cl)Cl.O>[CH3:34][O:35][N:36]([CH3:37])[C:8]([C:5]1[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:11])[CH:4]=1)=[O:10]
Reactant: Cn1ccc(C(=O)O)cc1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
A suspension of 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (540 mg, 1.0 eq), EDCI (811 mg, 1.2 eq) and HOBt (572 mg, 1.2 eq) in 20 mL CH2Cl2 was stirred at r.t. for 5 min Then N-methoxymethanamine hydrochloride (413 mg, 1.2 eq) and Et3N (1.1 g, 3.0 eq) were added, and the reaction was stirred at rt overnight. Water was added, and the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (555 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J=6.8 Hz, 1H), 6.78 (s, 1H), 6.32 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3[nH]cnc23)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1cnc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 107.3 %

Procedure:
4-(2-Chloro-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (6.62 g) was dissolved in N,N-dimethylformamide (66 mL), methyl iodide (1.34 mL) and anhydrous potassium carbonate (3.51 g) were added to this solution cooled in an ice bath. After stirring the reaction solution at room temperature for five hours, 1 N hydrochloric acid (5 mL) and water (200 mL) were added to this reaction solution, which was then extracted using ethyl acetate. The obtained organic layer was washed sequentially with water and then saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound as a solid (7.40 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(OCC)(=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: NC1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cc(I)cc(NC2CCCCC2)n1
Temperature: 150 °C

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (5 g, 18.3 mmol) and cyclohexylamine (18.1 g, 183 mmol) was heated in a Biotage Initiator microwave at 150° C. for 30 min. Ethyl acetate (150 mL) was added and the mixture washed with water (100 mL) and brine (50 mL). The organics were concentrated and the residual oil purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to provide the title compound. Yield: 4.7 g (76%). MS (DCI/NH3) m/z 337 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([O:16]CC)=O)#[N:2].[CH3:19][NH2:20]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([NH:20][CH3:19])=[O:16])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1C#N
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccn2)c1C#N

Procedure:
To a solution of 2.5 g of 5cyano-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 20 ml of DMF was added an excess of 40% aqueous monomethylamine so as not to precipitate out the pyrazole starting material. Approximately 24 hours later additional monomethylamine was added to the reaction mixture as well as additional DMF so as to keep these reactants in solution. The reaction mixture was heated and subsequently added to 150 ml of ice water. The precipitated solid was collected by filtration and recrystallized from methanol to afford 1.2 g of 5-cyano-1-(2-pyridinyl)-N-methyl-1H-pyrazole-4-carboxamide. mp=200°-202° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(O)C2C(C=1O)=CC=C(OC1C=CC3N=C(N4CCOCC4)SC=3C=1)C=2)=O)CCC.P(Cl)(Cl)([Cl:73])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:73])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Agent: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc4nc(N5CCOCC5)sc4c3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Temperature: 120 °C

Procedure:
A solution of the regioisomeric mixture of 1,4-dihydroxy-6-(2-morpholin-4-yl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxy-7-(2-morpholin-4-yl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester synthesized as described above (1.51 g, 3.04 mmol), and phosphorus oxychloride (417 μL, 4.56 mmol) in dichloroethane (23 mL) was stirred at 120° C. in a CEM microwave apparatus for thirty minutes. The mixture was then stirred at ambient temperature with saturated sodium bicarbonate solution for one hour. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give a solid (1.05 g). It was recrystallized from ethyl acetate to give the title compound as a white solid (484 mg): MS: (+) m/z 514.17 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:40][CH2:41][N:42]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:29])[F:31])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:23])[CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=640.96 (M+H+); retention time=0.95 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C>[C:13]([O:12][C:11]([NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:3][CH:4]=1)[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][CH:25]=[CH:24]2)=[O:19])=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenoxy)acetate (E250) was prepared from E249 according to the scheme in FIG. 14. To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E249) in DMF cooled to −35° C. was added NaH, and the solution was stirred at −35° C. for 30 min. Then, methyl bromoacetate was added and the solution was warmed and stirred at 0° C. for 1 h. The solution was poured into NaHCO3(sat)/EtOAc and further extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3-4% MeOH/CH2Cl2) gave pure methyl 2-(4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenoxy)acetate (E250).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CN3CCOCC3)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), morpholine (17.4 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 3 hours at that temperature. After cooling to room temperature, the solution was diluted with water (5 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL) gave the title compound (48 mg) as a flocculent white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]=[CH:21][C:16]=2[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)C>ClCCl>[NH2:29][C@@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9](=[O:37])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17]=2[CH:18]=1
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(Cc3ccccc3)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C[C@H](N)COc1ccc2c3ccncc3c(=O)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-benzyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (35 mg, 0.070 mmol) in anhydrous dichloromethane (1 mL) was added a 2 M solution of HCl in diethyl ether (0.17 mL, 0.349 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford crude product which was purified by preparative TLC (ethyl acetate in petroleum ether) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-benzylbenzo[c][2,7]naphthyridin-5(6H)-one (10 mg, 0.024 mmol, 35% yield) as a light yellow solid. LC/MS (ESI) m/e 402.2 [(M+H)+, calcd for C25H28N3O2 402.2]; LC/MS retention time (method C): tR=1.77 min; HPLC retention time (method A): tR=5.54 min; HPLC retention time (method B): tR=6.17 min. 1H NMR (400 MHz CD3OD) δ ppm 9.61 (br. s., 1H), 8.87 (d, J=4.52 Hz, 1H), 8.53 (d, J=9.04 Hz, 1H), 8.47 (d, J=6.02 Hz, 1H), 7.28-7.38 (m, 5H), 7.15 (dd, J=8.91, 2.38 Hz, 1H), 7.04 (d, J=2.26 Hz, 1H), 5.72 (d, J=5.77 Hz, 2H), 4.27 (dd, J=10.54, 3.26 Hz, 1H), 4.10 (dd, J=10.42, 6.40 Hz, 1H), 3.69 (dd, J=6.65, 3.14 Hz, 1H), 1.68-1.81 (m, 1H), 1.57-1.67 (m, 2H), 1.00-1.05 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.Cl[C:17](Cl)([O:19][C:20](=[O:26])OC(Cl)(Cl)Cl)Cl.[F:28][C:29]1[CH:34]=[C:33]([F:35])C=[CH:31][C:30]=1O.CO>C(OCC)(=O)C>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[N:5]([C:20]([O:19][C:17]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][C:33]=2[F:35])=[O:26])[CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)Oc2ccc(F)cc2F)C[C@@H]1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A 1.5 mL reaction vial was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (0.2 M in 4:1:1,2-dichloroethane/N,N-disopropylethylamine, 100 μL, 0.02 mmol). Triphosgene (0.4 M solution in 1,2-dichloroethane, 20 μL, 0.008 mmol) was then added, and the reaction mixture was placed on a heater shaker at room temperature for 4 h. 2,4-Difluorophenol (0.2 M solution in 1,4-dioxane, 110 μl, 0.022 mmol) was then added, and the reaction was heated to 50° C. on a heater shaker overnight. Methanol (100 μl) was added and the reaction was placed on a heater shaker at 50° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution. The aqueous layer was separated and washed with ethyl acetate and the combined organic layers were concentrated under a stream of nitrogen and vacuum. The crude product was purified by mass triggered preparatory HPLC. The product, 2,4-difluorophenyl (5)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate, was used without further purification.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10](=O)[CH2:11][CH2:12][CH3:13].C[Si](C)(C)[O:17][C:18]1[CH2:21][CH2:20][C:19]=1[O:22][Si](C)(C)C.C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([CH:10]1[C:19](=[O:22])[CH2:20][CH2:21][C:18]1=[O:17])[CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC1C(=O)CCC1=O

Procedure:
To a solution of BF3.OEt2 (1.30 g, 9.2 mmol) and butyraldehyde (0.40 g, 5.5 mmol) in DCM (5 ml) under N2 at −78° was added a solution of 1,2-bis trimethylsilyloxycyclobutene (1.4 g, 6.1 mmol) in DCM (3 ml) maintaining a temperature of less than −70°. After 2 h at −78° the solution was poured into saturated NaHCO3, extracted into EtOAc, washed (brine), dried (MgSO4) and the solution concentrated in vacuo to yield a clear liquid. To this liquid was added TFA (20 ml) and the solution heated at reflux for 24 h.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].[OH:32][C@H:33]([CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:34][NH2:35]>C(#N)C>[ClH:1].[OH:32][C@H:33]([CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:34][NH:35][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OC/C=C/CCl
Reactant: NC[C@H](O)COc1ccccc1
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OC/C=C/CNC[C@H](O)COc1ccccc1
Product: Cl
Yield: 42.4 %

Procedure:
3.1 g of dimethyl 4-[2-[(E)-4-chloro-2-butenyloxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 5.8 g (S)-2-hydroxy-3-phenoxypropylamine were dissolved in 35 ml of acetonitrile, and the resultant solution was refluxed under heating for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 30 ml of chloroform. After washing the solution with water three times, the organic layer was concentrated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel. The product was eluted with chloroform-methanol (95:5 V/V), was converted to HCl salt, and then was treated with ether-ethyl acetate to give 1.8 g of dimethyl 4-[2-[(E)-4-[[(S)-2-hydroxy-3-phenoxypropyl]amino]-2-butenyloxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate HCl salt.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:19][CH3:20])[CH2:16][C:17]#[N:18])[CH3:14].[C:21](OCC)(=[O:24])[CH2:22][CH3:23]>C1COCC1.CCCCCC>[C:17]([CH:16]([CH:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[C:21](=[O:24])[CH2:22][CH3:23])#[N:18]
Reactant: CCOC(=O)CC
Reactant: CCC(CC)CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCC(=O)C(C#N)C(CC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part B. A solution of diisopropylamine (7.50 mL, 57.2 mmol) in THF (100 mL) was cooled to −78° C., and treated with n-butyllithium (34.0 mL of a 1.6 M solution in hexane). The solution was warmed briefly to 0° C., and then recooled to −78° C. The nitrile compound from Part A was then added by syringe, and the solution was allowed to stir for 1 hour. Then, ethyl propionate (6.50 mL, 56.7 mmol) was added by syringe, and the resulting mixture was allowed to stir and warm to ambient temperature for 12 hours. It was poured into 200 mL of satd. aq. NH4Cl solution, and this was extracted with ethyl acetate (2×200 mL). The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The residual oil was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the product, 4-cyano-5-ethyl-3-heptanone, as an oil 4.06 g, 24.3 mmol, 49%). TLC RF 0.47 (20:80 ethyl acetate-hexane). Spectral data: 1H NMR (300 MHz, CDCl3): δ 3.49 (1H, d, J=4.4 Hz), 2.74 (2H, q, J=7.3 Hz), 2.08-1.98 (1H, m), 1.70-1.58 (1H, m), 1.50-1.20 (3H, m), 1.12 (3H, t, J=7.3 Hz), 0.95 (3H, t, J=7.3 Hz), 0.91 (3H, t, J=7.3 Hz). MS (H2O-GC/MS): m/e 167 (100).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:14])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 42.9 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-[cyclohexyl(5-cyclohexyl-2-ethylthiophen-3-yl)methoxy]benzoic acid (200 mg) synthesized in Example 77 (4) and ethyl 3-(methylamino)propanoate (73.8 mg) to give the title compound (103 mg, 43%).