Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([N:7]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])C.[OH-].[Na+].C(OCC)C>C1COCC1>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[O:6])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(N(C(=O)C(=O)O)c2ccccc2)c(C)c1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
N-(Mesityl)-oxanilic acid ethyl ester (1.99 g, 8.5 mmol) was dissolved in THF (50 ml), forming a solution. To this solution was added 1M NaOH solution (40 ml), and the mixture was then stirred for 2 hours. Diethyl ether (25 ml) was then added, and the layers were separated. The organic layer was washed with 1M NaOH solution (40 ml). The aqueous layer was then acidified with 2M HCl until precipitation occurred. The precipitate was then extracted with ethyl acetate (2×50 ml). The ethyl acetate was washed with brine (50 ml), and then dried over MgSO4. Removal of the solvent under reduced pressure provided the product as a white solid (1.74 g, 8.4 mmol, 99% yield). 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 6.93 (s, 2H), 2.29 (s,3H), 2.19 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 160.0, 156.1, 138.6, 134.7, 129.5, 128.9, 21.2, 18.5. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.59; H, 6.32; N, 6.79.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([O:12][CH2:14][C:15]#[N:16])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)=NN1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5(4H)-one (1.00 g, 6.24 mmol) in DMF (5.0 mL) was added 2-bromoacetonitrile (0.520 mL, 7.80 mmol) and K2CO3 (0.863 g, 6.24 mmol). The reaction was stirred at 25° C. for 12 h, quenched with water (40.0 mL), extracted with EtOAc (3×50.0 mL) and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give the title compound as a yellow oil. This yellow oil was purified by silica gel flash chromatography to give the title compound as a clear oil (0.990 g). LCMS m/z=200.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]2)=[CH:3][CH:4]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(F)cc2)CCN1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a mixture of 1-bromo-4-fluorobenzene (5.0 g, 0.0285 mol), (R)-2-methylpiperazine (3.15 g, 0.0313 mol) and sodium-tert-butoxide (4 g, 0.042 mol) in dry toluene (100 mL) under nitrogen was added Pd(OAc)2 (0.25 g, 0.0011 mol) followed by BINAP (0.75 g, 0.0012 mol). The reaction mixture was then refluxed for 18 h and cooled down to rt. The reaction mixture was washed with water, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude by chromatography on silica (chloroform:MeOH, 8:2) gave the title compound as a liquid (2.5 g, 46% yield). TLC: Rf=0.25 (Chloroform/MeOH: 9/1).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][N:25]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:26][CH2:27][C:21]=4[CH:20]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 18) (200 mg, 0.534 mmol), DIPEA (0.327 ml, 1.869 mmol) and ethyl 4-bromobutanoate (0.153 ml, 1.068 mmol) were stirred at room temperature in DMF (10 ml) for 5 hours, the reaction mixture then heated to 60° C. for 5 h, the reaction mixture was allowed to stand overnight at room temperature, further ethyl 4-bromobutanoate (0.076 ml, 0.534 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between ethylacetate (˜30 ml) and water (˜30 ml) and the aq. layer extracted once more with ethylacetate (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (218 mg, 0.402 mmol) as an orange oil. MS (ES): C28H32N4O4 requires 488; found 489 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13](Br)[CH:14]=3)[N:9]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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(O)C>[C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)[CH:14]=3)[N:9]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2cc(Br)cnc21
Reactant: COc1ccccc1B(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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc3c(c2)c(-c2ccccc2)cn3S(=O)(=O)c2ccccc2)cc1
Temperature: 85 °C
Yield: 98 %

Procedure:
To a solution of 3-phenyl-5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (309 mg, 0.75 mmol) in a 3:1 toluene/ethanol mixture (24 ml) are added 2-methoxy-benzene boronic acid (125 mg, 0.83 mmol), K2CO3 (2.4 ml of 2 M solution in water, 4.5 mmol), Pd(PPh3)4 (1.5 mol %), and the mixture is heated at 85° C. for 2 hours under argon. The mixture is cooled to room temperature, concentrated under a vacuum and redissolved in a water/CH2Cl2 mixture. The aqueous phase is extracted several times with CH2Cl2 and the combined organic phases are dried on MgSO4. The solvent is evaporated under reduced pressure and the residue purified by flash chromatography on silica gel (100% CH2Cl2) to yield the purified product in the form of a colorless oil with a yield of 98%.
Reaction SMILES: [CH3:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][C:53]1[CH:54]=[C:55]([CH:62]=[CH:63][CH:64]=1)[C:56]([NH:58][CH:59]([CH3:61])[CH3:60])=[O:57]>CN(C=O)C>[CH:59]([NH:58][C:56]([C:55]1[CH:54]=[C:53]([NH:52][C:18]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]3[C:9]4[C:16]([CH3:17])=[CH:15][NH:14][C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:6][CH2:7]2)=[O:19])[CH:64]=[CH:63][CH:62]=1)=[O:57])([CH3:61])[CH3:60]
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Reactant: CC(C)NC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(C(=O)NC(C)C)c4)CC3)c12
Temperature: 50 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from example 6, step B, (0.030 g, 0.11 mmol) in DMF (1 mL) were added HATU (0.042 g, 0.11 mmol), triethylamine (0.028 mL, 0.22 mmol) and 3-amino-N-isopropyl-benzamide (0.029 mg, 0.17 mmol). The reaction was stirred at 50° C. for 48 hours and concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.023 g, 48%).
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:5]=1[O-:13])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)C#CCC.O>CN(C)C=O>[CH2:8]([C:9]1[C:4]([C:5](=[O:13])[CH3:6])=[C:16]2[C:17]3[CH2:23][CH2:22][O:21][C:18]=3[CH:19]=[CH:20][N:15]2[N:14]=1)[CH3:7]
Reactant: N[n+]1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: CCC#CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn2ccc3c(c2c1C(C)=O)CCO3
Temperature: 40 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
A mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (2.00 g, 6.24 mmol), potassium carbonate (1.21 g, 8.75 mmol) and 3-hexyn-2-one (0.750 mL, 6.87 mmol) in dimethylformamide (30 mL) was stirred at 40° C. for 16 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→40/60) to give the title compound (314 mg, yield 22%).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[CH2:5]([NH2:9])[CH2:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:1]([N:9]1[CH2:8][CH:7]=[CH:6][CH2:5]1)[CH2:2][CH2:3][CH3:4]
Reactant: C/C=C\C
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCN1CC=CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of 60.0 g of the cis-2-butene derivative solution prepared in Example 1 and 250 g of toluene in a round flask reactor, 117.0 g (1.6 mol) of butylamine was added dropwise with stirring for 30 min. at about 5° C. using an ice-bath. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 46.1 g of 1-butyl-3-pyrroline (yield 92.0%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=1)=[O:32]
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2)c1
Yield: 30.9 %

Procedure:
The procedure is analogous to that described in Example 1 but 0.9 g of 2-(2-amino-N-phenyl-acetamido)-N-methyl-N-phenylacetamide and 0.4 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from a mixture of diethyl ether and ethyl acetate (60-40 by volume), 0.4 g of N-methyl-N-phenyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenyl-acetamido}acetamide melting at 168° C. is obtained.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH:5]([OH:9])[CH2:6][O:7][CH3:8])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.C([O-])(O)=O.[Na+].CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([N:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][C:5](=[O:9])[CH2:6][O:7][CH3:8])[CH3:2]
Reactant: CCN(CC(O)COC)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCN(CC(=O)COC)c1ccccc1
Yield: 0.1 %

Procedure:
A solution of 1-(ethyl-phenyl-amino)-3-methoxy-propan-2-ol (1.95 g, 9.32 mmol) and NMO (2.18 g, 2.0 eq.) in dichloromethane (15 mL) was treated with TPAP (150 mg, 0.05 eq.) at room temperature until reaction was completed. The reaction mixture was diluted with sat. NaHCO3 (50 mL) and extracted with 3×30 mL EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated and the product was purified by chromatography (10 to 15% EtOAc-hexanes) to give 1-(ethyl-phenyl-amino)-3-methoxy-propan-2-one (0.98 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:14]#[N:15])[CH2:9][CH2:10]2)=[O:25])[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)O
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 75 mg of 4-(4-chloro-phenyl)-piperidine-4-carbonitrile (0.34 mmol, 1.0 equiv), 90 mg of (4-chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-acetic acid (0.37 mmol, 1.00 equiv), 194 mg HATU (0.51 mmol, 1.5 equiv), 189 μL TEA (1.36 mmol, 4.00 equiv) and 2 mL NMP. A stir bar was placed in the vial and the reaction mixture stirred overnight at room temperature. The crude reaction mixture was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 1-[2- (4-chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carbonitrile: MS (ES) M+H expected=444.3, found=444.1.
Reaction SMILES: CC(C)([S@@]([NH:6][C:7]([C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[N:20][CH:21]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:8])=O)C.Cl>O1CCOCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C@@:7]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)([NH2:6])[CH3:8])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(C)(N[S@@](=O)C(C)(C)C)c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@](N)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-(5-(1-((S)-1,1-dimethylethylsulfinamido)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (2.5 g, 5.0 mmol) in dioxane (5.0 mL) was dropwise added HCl (4M in dioxane, 10 mL). The reaction solution was stirred at room temperature overnight. Then the solution was concentrated under vacuo to give the title compound (1.5 g, crude yield 100%) as a yellow solid. MS (ES+) C16H20FN5 requires: 301, found 302 [M+H]+; purity: 100% (UV at 254 nm). The above racemate (1.5 g) was separated by Chiral-HPLC to afford the desired single enantiomer (600 mg, 40%) as a yellow solid. MS (ES+) C16H20FN5 requires: 301, found: 302 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCC1CC(c2ccc(Br)cc2)=NO1)c1ccc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: O=C(NCC1CC(c2ccc(-c3ccccn3)cc2)=NO1)c1ccc(Cl)s1

Procedure:
Combined the bromide from Example 1 (50 mg, 0.13 mmol) with 2-pyridyltributyl stannane (55 mg, 0.15 mmol) and 5 mL of toluene. The mixture was degassed for three minutes then treated with tetrakistriphenylphosphine palladium (14 mg, 0.013 mmol) and stirred at reflux overnight. The following day the reaction was checked by TLC which showed consumption of the starting bromide and a more polar spot. The reaction was partitioned with aqueous sodium fluoride and ethyl acetate, separated and dried over magnesium sulfate. After filtration and concentration the crude residue was purified by preparative HPLC affording the desired product as a white solid. MS found for C20H16ClN3O2S as (M+H)+ 398.1, 400.1
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccncc1)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccncc2)CC1
Yield: 48.1 %

Procedure:
Using alkylation method A, 3-chloro-N-[1-(4-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (67 mg, 0.16 mmol) and acetone (2 mL, 27 mmol) afforded 35 mg (47%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]=1[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:11][C:10]=1[C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CCO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CC=O)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-(2-benzyloxy-5-tert-butylphenyl)-3-methylbutan-1-ol (1.7 g, 5.2 mmol) in 20 mL of dichloromethane was added 3.27 g of Dess-Martin periodinane and reaction stirred until TLC indicated the reaction was complete. After 2 hours, the reaction mixture was passed through a pad of silica, eluting with 5% ethyl acetate-hexanes to afford 1.67 g of 3-(2-benzyloxy-5-tert-butylphenyl)-3-methylbutyraldehyde as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.ClC([C:13]([C:15]1[NH:16][C:17]([Br:21])=[C:18]([Br:20])[CH:19]=1)=[O:14])(Cl)Cl>C(#N)C>[Br:20][C:18]1[CH:19]=[C:15]([C:13]([NH:1][CH2:2][CH2:3][CH:4]2[O:8][CH2:7][CH2:6][O:5]2)=[O:14])[NH:16][C:17]=1[Br:21]
Reactant: NCCC1OCCO1
Reactant: O=C(c1cc(Br)c(Br)[nH]1)C(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(NCCC1OCCO1)c1cc(Br)c(Br)[nH]1

Procedure:
A solution of 2-(2-aminoethyl)-1,3-dioxolane (2.4 g, 20.6 mmol) and 4,5-dibromopyrrol-2-yl trichloromethyl ketone (7.6 g, 20.5 mmol) in 30 mL of acetonitrile was stirred at room temperature for 16 h. The reaction mixture was filtered and the precipitate 11 (6.8 g, 90%) was collected as a colorless solid: mp 155-157° C.; 1H NMR (CDCl3) d 1.99 (dt, 2H, J=6.0, 4.2), 3.61 (dt, 2H, J=6.0, 5.6), 3.92 (m, 2H), 4.05 (m, 2H), 5.00 (t, 1H, J=4.2), 6.51 (d, 1H, J=2.8), 6.66 (bs, 1H), 10.57 (bs, 1H); 13C NMR (CD3COCD3) d 34.3 (e), 35.5 (e), 65.4×2 (e), 99.4 (e), 103.4 (o), 105.4 (e), 113.0 (o), 129.1 (e), 160.0 (e); IR (nujol) 3358, 1646, 1569, 1412, 1372 cm−1; UV (CH3OH) 1max 275, 233, 214 (sh) nm; MS m/z (relative intensity) 371 (M++5, 50), 369 (M++3, 100), 367 (M++1, 50), 289 (13), 118 (25), 101 (50), 73 (30); Anal. Calcd for C8H10N2O2Br2: C, 32.63; H, 3.29; N, 7.61; Found: C, 32.77; H, 3.17; N, 7.51.
Reaction SMILES: [OH:1][C:2]1[C:23]2[C:22](=[O:24])[C:9]3[O:10][C:11](=[O:21])[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=4[C:8]=3[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][C:2]1[C:23]2[C:22](=[O:24])[C:9]3[O:10][C:11](=[O:21])[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=4[C:8]=3[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(OC(C)=O)c1C3=O
Reaction time: 8 h

Procedure:
In pyridine (10 ml) was dissolved 8-hydroxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione (150 mg) as obtained in Example 15, followed by addition of acetic anhydride (5 ml). The mixture was allowed to stand overnight. The solvent was then distilled off under reduced pressure and the residue was extracted with chloroform. The solvent layer was washed with dilute HCl and water, and dried over sodium sulfate. The solvent was distilled off and the residue was crystallized from diethyl ether to give crystals (45 mg) of 8-acetoxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])#[N:20]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=2)[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N)c(NC(=O)c2cccc(C#N)c2)c1
Reaction time: 12 h
Yield: 56.4 %

Procedure:
To a solution of 4-methoxycarbonyl-1,2-benzenediamine (8 g, 48 mmol) and pyridine (4 mL, 48 mmol) in acetonitrile (300 mL) at 0° C. was added 3-cyanobenzoyl chloride (8 g, 48 mmol). After 12 h, the reaction was concentrated and the residue was suspended with vigorous stirring in ethyl acetate (500 mL) and 1 M citric acid (200 mL). The solid was filtered, washed with diethyl ether and vacuum dried to give the title compound as an off-white solid (8 g, 56%); MS(FD): 295.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([N:7]1[CH:11]=[C:10]([NH2:12])[N:9]=[C:8]1[CH3:13])([CH3:6])[CH3:5].[F:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([NH:26][CH:27]([CH2:31][CH2:32][CH3:33])[C:28](O)=[O:29])=[O:25])[CH:19]=[C:20]([F:22])[CH:21]=1>>[CH3:1][O:2][C:3](=[O:14])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:28](=[O:29])[CH:27]([NH:26][C:24](=[O:25])[CH2:23][C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([F:15])[CH:17]=2)[CH2:31][CH2:32][CH3:33])[N:9]=[C:8]1[CH3:13])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)n1cc(N)nc1C
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C(=O)OC)c(C)n1

Procedure:
2-(4-Amino-2-methyl-imidazol-1-yl)-2-methyl-propionic acid methyl ester was coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.8, 14.7, 18.9, 26.1, 26.7, 35.5, 42.9, 53.3, 61.1, 102.7, 105.3, 112.3, 112.5, 134.9, 138.9, 140.9, 169.5, 169.7, 173.4; MS m/z 451.2 (M+1).
Reaction SMILES: [CH2:1]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:2]([C:4]([F:7])([F:6])[F:5])=O.Cl.[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:1]=[C:2]([C:4]([F:7])([F:6])[F:5])[N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[N:25]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: O=[N+]([O-])c1cccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)c1
Yield: 94 %

Procedure:
Using hexafluoroacetylacetone and 3-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.