Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([NH:29][CH2:16][C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)[CH2:27][CH2:28]1
Reactant: CCc1cc(-c2ccc(C=O)s2)c(C)[nH]c1=O
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Product: CCc1cc(-c2ccc(CNC3CCN(Cc4cc(F)cc(F)c4)CC3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]thiophen-2-carbaldehyde is reacted with 1-(3,5-difluoro-benzyl)-piperidin-4-ylamine as described in Method A of Example 123 to give the title compound. MS: m/e 458 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In a manner similar to Example 12, Step (b), (3,4-dichloro-phenyl)boronic acid (1.0569 g, 0.005539 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3636 g, 0.005019 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.1054 g, 0.0000912 mol) and 2.0 M aqueous sodium carbonate (5.5 mL, 0.011 mol) in toluene (11 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with hexanes-acetone (7:1) 1.432 g of 4-(3′,4′-dichloro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]1[CH:51]=[CH:52][C:53]([NH2:56])=[N:54][CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:49][C:50]1[CH:51]=[CH:52][C:53]([NH:56][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:24])=[N:54][CH:55]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cn1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To a DMF (0.25 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 25 mg, 0.076 mmol) and HATU (35 mg, 0.092 mmol) was added 5-fluoropyridin-2-amine (10 mg, 0.092 mmol), followed by drop-wise addition of DIEA (0.040 mL, 0.23 mmol) at ambient temperature. The reaction was heated at 70° C. overnight, cooled, and directly purified by reverse-phase chromatography (5 to 66% acetonitrile/water) to yield the final product as white solid (25 mg, 78%). LCMS (apci) m/z=422.0 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][N:13]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:14][CH2:15][CH2:16][N:17]([CH2:22][CH2:23][C:24]#[N:25])[CH2:18][CH2:19][C:20]#[N:21])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][N:13]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:11][CH2:10][N:5]([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:4][CH2:3][CH2:1][NH2:2])[CH2:22][CH2:23][CH2:24][NH2:25]
Reactant: N#CCCN(CCC#N)CCCN(CCCN(CCC#N)CCC#N)Cc1ccccc1
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCN(CCCN(CCCN)CCCN)Cc1ccccc1
Yield: 91.4 %

Procedure:
6.50 g of N,N-bis(3-(N,N-bis(2-cyanoethyl)amino)propyl)benzylamine, 0.65 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 6.16 g of the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:13]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(O)C.[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1CCCOc2ccc(Br)cc21
Agent: O=[Pt]
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Brc1ccc2c(c1)CCCCO2
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 7-bromo-3,4-dihydro-1-benzoxepin-5(2H)-one (20.0 g) in trifluoroacetic acid (32 ml) was added at room temperature triethylsilane (29.2 ml), and the mixture was stirred for 2 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure (0.8 mmHg/123° C.) to give colorless oil. The obtained oil (13.12 g) was dissolved in ethanol (200 ml), and to the solution was added platinum oxide (0.4 g). The mixture was stirred under hydrogen atmosphere for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane→ethyl acetate/hexane=1:19) to give colorless oil of 7-bromo-2,3,4,5-tetrahydro-1-benzoxepine (9.61 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].C=O.[BH3-][C:17]#N.[Na+]>>[CH3:17][N:8]1[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: C=O
Agent: [Na+]
Product: CN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 97.7 %

Procedure:
This compound was prepared by General Method 3 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (1.15 g, 6.38 mmol), paraformaldehyde (1.92 g, 64.1 mmol) and NaBH3CN (1.95 g, 30.9 mmol) to afford 1.21 g (98%) of 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine: Rf 0.83 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, 1H, J=9.0, 2.6), 7.65 (d, 1H, J=3.4), 6.56 (d, 1H, J=8.9), 4.27 (t, 2H, J=4.6), 3.46 (t, 2H, J=4.5), 3.05 (s, 3H).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[C:4]2=[CH:3][CH:2]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][CH2:13][CH:12]([OH:14])[CH2:11][O:10][C:9]1[C:4]2[N:5]([N:1]=[CH:2][CH:3]=2)[CH:6]=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: c1cc(OCC2CO2)c2ccnn2c1
Product: CC(C)NCC(O)COc1cccn2nccc12

Procedure:
Then, the Compound (6) is reacted with isopropylamine to produce 1-(isopropylamino)-3-(pyrazolo[1,5-a]pyrid-4-yloxy)-2-propanol (A), with approximately quantitative yields being achieved.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-:20][C:21]#[N:22].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:21]([NH2:22])=[O:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#C[O-]
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 15.2 %

Procedure:
To a solution of 3-amino-2-benzoyl-6-chloroindole (step 1, 60 mg, 0.21 mmol) in acetic acid (10 ml) was added sodium cyanate (14 mg, 0.21 mmol) and the mixture was stirred for 1.5 h at 90° C. After cooling, the mixture was poured into a saturated sodium bicarbonate (50 ml) and extracted with ethyl acetate (40 ml×2), dried (MgSO4) and concentrated. The residual solids were purified by flash column chromatography eluting with hexane/ethyl acetate (1/1) to give 10 mg (15%) of the title compound as yellow solids.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[CH:7][CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][C:5]1[C:4]2[NH:3][C:2](=[O:1])[N:11]3[C:23](=[O:24])[NH:18][N:12]=[C:10]3[C:9]=2[CH:8]=[CH:7][C:6]=1[CH3:19]
Reactant: CCOC(=O)N(N)c1nc(O)nc2c(C)c(C)ccc12
Reactant: CN(C)C=O
Product: Cc1ccc2c([nH]c(=O)n3c(=O)[nH]nc23)c1C
Temperature: 25 °C

Procedure:
3.88 g (0.012 mol) of ethyl 2-hydroxy-7,8-dimethylquinazoline-4-yl-carbazate in 220 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off and dried in a vacuum. There were obtained white crystals which were recrystallized from dimethylformamide. Yield: 1.62 g (50%) of 7,8-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. 380°-382° C.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](OS(C(F)(F)F)(=O)=O)=[N:7][C:6]3[C:23]([CH3:27])=[CH:24][CH:25]=[N:26][C:5]2=3)[CH2:3][CH2:2]1.[OH-].[NH4+:29]>O1CCOCC1.C(OCC)(=O)C>[NH2:29][C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[N:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:6]=2[N:7]=1
Reactant: [NH4+]
Reactant: Cc1ccnc2c1N=C(OS(=O)(=O)C(F)(F)F)c1cccnc1N2C1CC1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccnc2c1N=C(N)c1cccnc1N2C1CC1
Temperature: 100 °C
Yield: 30 %

Procedure:
To a solution of 11-cyclopropyl-4-methyl-6-trifluoromethanesulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.22 g, 0.55 mmol) in 1,4-dioxane (3 mL) was added 30% ammonium hydroxide (3 mL). The mixture was heated at 100° C. for 15 min. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with water, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 1:1:1 ethyl acetate/hexane/methylene chloride→50% ethyl acetate/hexane) to give the title compound (0.045 g, 0.17 mmol, 30%) which crystallized from ethyl acetate/hexane, m.p. 242°-244° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.O>CN1CCCC1=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Oc1ccc2nc(Cl)n(Cc3ccccc3)c2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2nc3ccc(O)cc3n2Cc2ccccc2)cc1OC
Temperature: 150 °C
Yield: 38.9 %

Procedure:
A mixture of 3-benzyl-2-chloro-3H-benzoimidazol-5-ol (250 mg) and 4-amino veratrole (296 mg) in N-methylpyrrolidinone (3 ml) was heated at 150° C. in a sealed tube for 4 hours then allowed to cool. The reaction mixture was then poured into water (30 ml) and extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5, v/v) to give 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) as a yellow solid. Mass spectrum: 376 [M+H]+ retention time: 3.44 minutes.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2.[Br:21]N1C(=O)CCC1=O>ClCCl.O1CCCC1>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:20])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc2c(-c3ccccc3C)cccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2cccc(-c3ccccc3C)c2c1Br
Temperature: 0 °C

Procedure:
To a solution of EXAMPLE 126A (205 mg) in dichloromethane (5 ml) and tetrahydrofuran (5 ml) at 0° C. was added dropwise N-bromosuccinimide (144 mg) in tetrahydrofuran (3 ml). The mixture was stirred while the ice bath slowly reached room temperature. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2Cl.[CH2:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:17][CH3:18])[CH2:20][CH2:21]1
Reactant: CCN1CCC(N)CC1
Reactant: Clc1ccc2c(Cl)c3ccccc3nc2c1
Product: CCN1CCC(Nc2c3ccccc3nc3cc(Cl)ccc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 3,9-dichloroacridine (J. Med. Chem. 1985, 28. 940-944) and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=340).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Reactant: BrCC1CCOCC1
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3CC2CCOCC2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 49 step D from methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 4-(bromomethyl)tetrahydro-2H-pyran, and was isolated as beige solid after reverse phase chromatography (45%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29 (d, J=8.6 Hz, 0.5H), 7.02-6.96 (m, 0.5H), 6.96-6.90 (m, 1H), 6.80-6.66 (m, 1H), 5.81-5.67 (m, 1H), 5.46-5.10 (m, 1H), 4.54-4.28 (m, 2H), 4.28-4.12 (m, 2H), 4.03-3.91 (m, 2H), 3.75-3.64 (m, 3H), 3.46-3.30 (m, 2H), 2.81-2.55 (m, 2H), 2.22 (d, J=3.7 Hz, 1H), 2.17-2.05 (m, 2H), 2.05-1.88 (m, 3H), 1.65-1.46 (m, 2H), 1.46-1.28 (m, 2H), 1.15 (s, 6H), 1.02 (s, 3H); LCMS (m/z) ES+=523 (M+1).
Reaction SMILES: [K].[CH3:2][CH:3]([CH:5]1[CH2:10][C:9](=[O:11])[CH:8]([C:12]2[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=2)[C:7](=[O:21])[CH2:6]1)[CH3:4].[C:22](Cl)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C.CCCCCC>[C:22]([O:21][C:7]1[CH2:6][CH:5]([CH:3]([CH3:2])[CH3:4])[CH2:10][C:9](=[O:11])[C:8]=1[C:12]1[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1nc(C)c(C2C(=O)CC(C(C)C)CC2=O)nc1C
Reactant: CCCCCC(=O)Cl
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCC(=O)OC1=C(c2nc(C)c(C)nc2C)C(=O)CC(C(C)C)C1
Temperature: 25 °C

Procedure:
The subject compound was prepared by reaction of 5-(1-methylethyl)-2-(3,5,6-trimethyl-2-pyrazinyl)-1,3-cyclohexanedione potassium salt (Example 8) with hexanoyl chloride employing the general procedure described in Example 3, but allowing the reaction mixture to stir at room temperature over the weekend. Following the reaction, the ether solution of crude product was extracted quickly with ice-cold 0.25N NaOH, dried (MgSO4), filtered and evaporated to give a residue product showing some acid chloride contamination by IR examination. Dry-column chromatography using 1:1 ethyl acetate/hexane gave analytically pure material as shown by the elemental analysis of Table II.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4]O.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[Cl:13][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: Cc1cccc(Cl)c1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(Cl)c1CCl

Procedure:
The 2-chloro-6-methylbenzyl alcohol is dissolved in 100 ml of benzene, treated with 25 ml of thionyl chloride and the mixture is heated at reflux for 3 hours. Concentration of this mixture to dryness leaves a liquid which partly solidifies. The product containing liquid is decanted from the solid by-product and distilled to yield 7.8 g of alpha,2-dichloro-6-methyltoluene as a colorless liquid with bp. 118°-122° C./17-18 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(Cl)(Cl)Cl>[C:12]1([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
0.1 m. Quantities of 2-aminopyridine and α-bromoacetophenone are heated in 150 ml. of chloroform at reflux for 2 hours. The chloroform is evaporated and the oily residue taken up in 10% HCl, warmed, charcoal added and filtered. The filtrate is neutralized with NH4OH and the solid product isolated and recrystallized from ethanol. The yield of product is 12.7 g., melts at 135°-137° C. and has the structure: ##STR19##
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2].[I-].[Na+].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCN1CCCCC1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
1-(4-Acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one (0.72 g, 2.26 mmol), sodium iodide (0.15 g, 0.1 mmol), and piperidine (1.72 g, 20 mmol) were combined in DMF (8.0 mL) and the mixture was heated to 80° C. for 4.5 hours. Water was then added to form a precipitate. Filtration gave 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)pentan-1-one (0.8 g, 2.18 mmol), m.p. 74°-75° C.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH3:25])[C:7]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[C:8]([CH3:13])[CH:9]=2)[O:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[CH3:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:25])[C:7]=1[OH:14])[O:4][CH2:3][C@@H:2]([N:36]1[CH2:35][CH2:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)([OH:39])[CH2:38][CH2:37]1)[C@H:11]2[OH:12]
Reactant: Cc1cc2c(=O)c(Br)coc2c(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc2c(c(C)c1O)OC[C@@H](N1CCC(O)(c3ccc(F)cc3)CC1)[C@H]2O
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-6,8-dimethyl-7-triisopropylsilyloxychromen-4-one (the compound of Example 19, 0.23 g, 0.54 mmol), 4-(4-fluorophenyl)-4-hydroxypiperidine (0.22 g, 1.12 mmol) and triethylamine (0.3 mL, 2.15 mmol) in acetonitrile (15 mL) was stirred over the weekend at ambient temperature. The precipitate which formed was collected and rinsed with water and ether. This solid was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (100 mL), nil; 25% ethyl acetate/hexane (200 mL), 0.065 g (22%) 6,8-dimethyl-7-triisopropylsilyloxy-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one which had: mp 226.5-227° C. Analysis calculated for C31H42FNO4Si: C, 68.98; H, 7.84; N, 2.59. Found: C, 69.00; H, 7.94; N, 2.37. This product was identical to the product isolated in the first step of example 19 and was converted to the title product following the procedure of example 19.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)#[N:6].[CH2:19](O)[CH3:20]>>[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2)#[N:6]
Reactant: N#Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1

Procedure:
Thionyl chloride (1 mL) was added to a solution of 5-cyano-1H-indole-2-carboxylic acid (D20) (1.1 g) in ethanol (120 mL) at RT. The resulting solution was heated to reflux and stirred when refluxing for 20 hours. Another portion of thionyl chloride (0.5 mL) was added. The reaction mixture was refluxed for 2 hours. The solvent was evaporated to afford ethyl 5-cyano-1H-indole-2-carboxylate (D21) (0.9 g) as a light green solid. MS (ES): C12H10N2O2 requires 214; found 215.2 (M+H+)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1>C(O)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[C:4]1[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][CH:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:5]=1
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (1 eq) in acetic acid (0.1M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.10 eq) was added. The reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. The organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (89%). LC/MS (m/z): MH+=348.3, Rt=0.79.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)([O-:16])=[O:15].CN(C)C=O>O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:20]1[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CNCCN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 72 h

Procedure:
A mixture of N,N,N′-trimethylethane-1,2-diamine (2.17 g), potassium carbonate (3.0 g), 4-nitrofluorobenzene and dimethylformamide (30 ml) was stirred for 72 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried and concentrated. The product with the molecular weight of 223.28 (C11H17N3O2); MS (ESI): 224 ([M+H]+), was obtained in this way.