Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+].C(O)C>[Cl-].[Na+].O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[N:20]/[OH:19])[CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: Cc1cc(C=O)cc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(/C=N/O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 3-(benzyloxy)-5-methylbenzaldehyde (948 mg), hydroxyl ammonium chloride (320 mg), sodium bicarbonate (837 mg), and ethanol (10 mL) was stirred overnight at room temperature. To the reaction mixture, water and brine were added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (804 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7]2.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:27]([C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5][CH2:4]2)#[N:28]
Reactant: CN(C)C=O
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.25 h

Procedure:
A solution of 1,1-dimethylethyl 5-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 15; 395 mg; 1.00 mmol) in DMF (4 ml) was de-gassed under high vacuum with stirring for 15 min, followed by addition of zinc cyanide (153 mg; 1.30 mmol) and tetrakis(triphenylphosphine)palladium (0) (116 mg; 0.10 mmol) under nitrogen. The resulting deep yellow mixture was stirred at 100° C. for 6 h. The solvent was removed, the residue dissolved in ethyl acetate, and the solution washed with saturated sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4), and evaporated to give the crude product. Purification by flash chromatography on silica gel, eluting with a gradient of 5-25% ethyl acetate in cyclohexane, gave the title compound (214 mg) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (70 mg, 88%), MS (ISP) m/z=320.5 [(M+H)+], mp 292° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]([F:8])(I)[C:3]([F:6])([F:5])[Cl:4].[CH2:9]([Si](C)(C)C)[CH:10]=[CH2:11]>>[Cl:1][C:2]([F:8])([C:3]([Cl:4])([F:6])[F:5])[CH2:11][CH:10]=[CH2:9]
Reactant: FC(F)(Cl)C(F)(Cl)I
Reactant: C=CC[Si](C)(C)C
Product: C=CCC(F)(Cl)C(F)(F)Cl

Procedure:
A mixture of 279 mg (1.0 mmol) of 1,2-dichloro-1-iodotrifluoroethane and 114 mg (1.0 mmol) of allyltrimethylsilane was sealed in a Pyrex glass tube and externally radiated with a high pressure mercury lamp (400 W) in an ice-bath for 3 hours to obtain 4,5-dichloro-4,5,5-trifluoro-1-pentene (Compound 39) in a yield of 60%.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([O:33][CH3:34])[CH:26]=1)[NH2:24].O1CCCC1>CO>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[O:33][CH3:34])#[N:30]
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Reactant: COc1cc(NN)ccc1C#N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Yield: 49 %

Procedure:
The title compound was prepared from Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (310 mg, 1.09 mmol) and 4-hydrazinyl-2-methoxybenzonitrile hydrochloride; Preparation 4 (282 mg, 1.42 mmol) according to Method B (methanol was used in place of ethanol as solvent) and Method C. The crude precipitate was purified by reverse phase chromatography with 40-95% acetonitrile/water to give the title compound (yellow solid, 220 mg, 0.53 mmol, 49% yield). The title compound was largely present as (±)-(3SR,3aRS)-2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (m, 7H), 1.65-1.90 (m, 2H), 1.99-2.12 (m, 1H), 2.18-2.27 (m, 1H), 2.82-2.95 (m, 1H), 3.04-3.13 (m, 1H), 3.52-3.63 (m, 1H), 3.90 (s, 3H), 4.94 (dd, J=9.67, 5.37 Hz, 1H), 6.80 (dd, J=8.59, 1.88 Hz, 1H), 6.90 (d, J=1.61 Hz, 1H), 7.45 (d, J=8.59 Hz, 1H), 7.81 (dd, J=8.19, 1.48 Hz, 1H), 7.85 (s, 1H), 8.08 (d, J=8.06 Hz, 1H), 13.02 (s, 1H). ES-MS m/z 416 (M+H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[F:1]
Reactant: Nc1cccc(F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ccc(Br)c(F)n1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A solution of 6-fluoropyridin-2-amine (Alfa Aesar, Ward Hill, Mass., 5.16 g, 46.0 mmol) in ACN (230 mL) was set stirring at 0° C. before adding NBS (8.19 g, 46.0 mmol) as a solution in ACN (100 mL) by addition funnel over 30 min. After complete addition, the resulting green solution was stirred for an additional 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in DCM (20 mL) and adsorbed onto silica. Chromatographic purification (silica gel, 0-75% EtOAc in hexanes) gave 5-bromo-6-fluoropyridin-2-amine (7.6 g, 39.8 mmol, 86% yield) as a white foam. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.59 (1H, t, J=8.9 Hz), 6.32 (1H, dd, J=8.5, 1.5 Hz). m/z (ESI, +ve ion) 191.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]2[C:54]=1[N:53]=[CH:52][CH:51]=[CH:50]2>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:44][C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:54]=2[N:53]=[CH:52][CH:51]=[CH:50]3)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(C(=O)Nc2cccc3cccnc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a flask charged with 4-oxocyclohexane carboxylic acid (commercially available from Alfa Aesar, Ward Hill, Mass.) (2.000 mL, 14.07 mmol) were added DCM (56.3 mL), DIEA (5.16 mL, 29.5 mmol), HATU (5.35 g, 14.07 mmol) and 8-aminoquinoline (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (2.130 g, 14.77 mmol) respectively. The resulting light brown suspension was stirred overnight at room temperature without much color change but complete dissolution of materials. LC-MS indicated product as the primary species. The solution was dried under reduced pressure and purified ramping with EtOAc in heptane from 0-50%, then isocratic at 50% which led to the system clogging up a bit due to precipitation of product. Product eluted following a less polar impurity and the system was flushed with DCM:MeOH:NH4OH (90:10:1) to elute the remainder of the product. Solid 4-oxo-N-(quinolin-8-yl)cyclohexanecarboxamide (1.900 g, 7.08 mmol, 50.3% yield) was obtained as a tan. 1H NMR (400 MHz, CDCl3) δ=10.02 (br. s., 1H), 8.83 (dd, J=1.7, 4.2 Hz, 1H), 8.78 (dd, J=2.2, 6.7 Hz, 1H), 8.20 (dd, J=1.7, 8.3 Hz, 1H), 7.60-7.53 (m, 2H), 7.49 (dd, J=4.3, 8.3 Hz, 1H), 2.97 (tt, J=3.8, 10.5 Hz, 1H), 2.67-2.63 (m, 1H), 2.63-2.59 (m, 1H), 2.54-2.35 (m, 4H), 2.29-2.16 (m, 2H). m/z (ESI) 269.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.O.O.Cl[Sn]Cl>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1ccnn1C
Yield: 33.1 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (2.11 g, 9.06 mmol) was treated with SnCl2.2H2O (8.341 g, 36.22 mmol, 4.0 equiv.) in EtOH (50 mL), in a similar manner as described in Example 1.1, providing 4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (1.592 g, 7.8 3 mmol, 87%) as an oil. LCMS m/z (%)=204 (M+H). 1H NMR (400 MHz, CDCl3) δ: 7.51 (d, J=1.8 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.76 (dd, J=2.8, 8.7 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.22 (d, J=1.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.24-3.55 (broad s, 2H).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[ClH:11].[CH2:12](O)C>>[ClH:11].[CH:2]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:12][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCO
Reactant: OCCCc1ccccn1
Agent: Cl
Product: OCCCC1CCCCC1
Reaction time: 16 h

Procedure:
To a stirred solution of compound 20 (5 g, 36.4 mmol) in ethanol (32 mL) was added concentrated HCl (3.2 mL) and the reaction mixture was degassed with N2 for 15 minutes. Platinum oxide (PtO2; 1 g) was then added and degassed for 5 minutes. Finally, the reaction mixture was hydrogenated at rt in a Parr apparatus for 16 hours under 45 psi H2 pressure. The reaction mixture was filtered through the Celite® reagent, and was washed with ethanol. The filtrate was concentrated to yield the crude product 21 which was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[NH:19]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[Cu]Br>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[N:19]2[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(c1cc2ccc(Cl)cc2[nH]1)N1CCOCC1
Reactant: COc1ccc(Br)cc1OC
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-n2c(C(=O)N3CCOCC3)cc3ccc(Cl)cc32)cc1OC
Temperature: 140 °C
Reaction time: 14 h

Procedure:
4-Bromoveratrole (5.7 g, 26 mmol), 6-chloroindole-2-carboxylic acid morpholide (1.7 g, 6.5 mmol), potassium carbonate (1.7 g), copper(I) bromide (0.2 g) in a mixture of pyridine (2 ml) and nitrobenzene was stirred at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture was applied onto a flash chromatography column (silica gel, 140 g), Elution with toluene, toluene/acetone [9:1] and toluene/acetone [8:2] (500 ml each) gave 6-chloro-1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid morpholide as brown oil. Yield: 2.1 g (81% of theoretical) Rf : 0.54 (toluene/acetone, 7:3). The H-NMR spectra was consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: N
Reactant: COC(=O)CC(=O)Nc1ccc(C=Cc2ccc(F)cc2)cc1
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(C=Cc2ccc(F)cc2)cc1
Yield: 89 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=89%. Colorless solid. MS: m/e=299.2 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:21]1[CH:22]=[C:23]2[C:28](=[N:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:3](=[O:6])/[CH:4]=[CH:5]/[C:21]1[CH:30]=[N:29][C:28]2[NH:27][C:26](=[O:31])[CH2:25][CH2:24][C:23]=2[CH:22]=1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1c(C)n(C)c2c(C)cccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cccc2c(CN(C)C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)c(C)n(C)c12
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide (256 mg, 1 mmole) and 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (227 mg, 1 mmole) in propionitrile (20 mL) was treated with DIEA (0.3 mL), Pd(OAc)2 (29 mg, 0.13 mmole), and tri-o-tolylphosphine (50 mg, 0.16 mmole). The reaction was heated at reflux under argon for 10 h, then was cooled to RT and filtered through supercel. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel to afford the title compound (100 mg, 25%) as an off-white solid: MS (ES) m/e 403.2 (M+H)+. Anal. Calcd for C24H26N4O2.2.75 H2O: C, 63.77; H, 7.02; N, 12.39. Found: C, 63.81; H, 7.25; N, 11.90.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.O>[Br:33][CH:25]([C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:27])[C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1)[CH3:26]
Reactant: BrBr
Reactant: CCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
In a 100 mL round bottom flask combined 4-[(3-chloro-2-methylphenyl)methyl]-5-ethyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.1 g, 10.13 mmol) (Example 75) and sodium acetate (1.246 g, 15.19 mmol) in acetic acid (30 mL). Bromine (0.782 mL, 15.19 mmol) in acetic acid (5 mL) was added dropwise over ˜3 min. The red colored reaction was stirred at room temperature for 16 hr. LC/MS indicated complete conversion to product. This reaction mixture was diluted with water (150 mL), producing a gummy yellow residue. The mixture was extracted with chloroform (100 mL), then concentrated to a thick yellow oil. This oil was triturated from ether (150 mL), to provide, after sonication a yellow solid that is consistent with 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.52 g, 9.34 mmol, 92% yield). The proton NMR is consistent for the desired product. LC/MS m/z MH+=484 (theoretical), found=484.9, 1H NMR (400 MHz, CHLOROFORM-d) S ppm 1.97 (d, J=6.57 Hz, 3H) 2.51 (s, 3H) 3.52-3.64 (m, 4H) 3.71-3.84 (m, 4H) 4.53-4.65 (m, 1H) 5.43 (d, J=17.43 Hz, 1H) 5.95 (d, J=17.43 Hz, 1H) 6.38 (d, J=7.83 Hz, 1H) 7.06 (t, J=8.08 Hz, 1H) 7.34 (d, J=7.83 Hz, 1H)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:31])[CH:26]1[O:30][CH2:29][CH2:28][CH2:27]1>CCO>[O:30]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][NH:31][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NCC1CCCO1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)cc2n(CCC)c1=O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(NCC4CCCO4)nc3)cc2n(CCC)c1=O
Temperature: 164 °C
Reaction time: 120 h
Yield: 82.1 %

Procedure:
8a (154 mg) was suspended in tetrahydrofurfurylamine (2.0 g) in EtOH (5 ml) in a pressure tube and stirred at 164° C. for 5 days. After cooling to room temperature, the solid was filtered and washed with methanol to give the product (9b) (150 mg).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]1[O:30][C@@H:29]1[CH2:31][OH:32]>C(Cl)Cl>[C:2]1([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:32][CH2:31][C@@H:29]2[CH2:28][O:30]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CO1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
A 5 L 3-neck round bottom flask was charged with trityl chloride (133.8 g, 0.48 mol) and methylene chloride (400 ml). It was cooled to 0° C. under N2 and treated with triethylamine (70.7 g, 0.70 mol). After an hour of stirring at 0° C., a solution of (R)-glycidol (88% ee, 37.03 g, 0.5 mol) in methylene chloride (100 ml) was added over 0.75 hour. The resulting solution was allowed to warm to ambient temperature and was stirred for 3 hours. It was then filtered, and the filtrate was washed with water (2×500 ml) and brine (2×500 ml). The organic phase was dried over MgSO4 and concentrated to a foam, which on crystallization from isopropyl alcohol gave the title compound (116.2 g, 76.5%) as an off-white powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][N:8]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:7]1=[O:23]>C(#N)C.O>[N:1]([CH:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][N:8]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:7]1=[O:23])=[N+:2]=[N-:3]
Reactant: O=C1C(Br)CC(c2ccccc2)CCN1CC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=NC1CC(c2ccccc2)CCN(CC2CC2)C1=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Sodium azide (0.24 g, 3.72 mmol) was added to a solution of 3-bromo-1-(cyclopropylmethyl)-5-phenylazepan-2-one (0.3 g, 0.93 mmol) in acetonitrile (4 mL) and water (1 mL), and the mixture heated to 100° C. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with water (3×), saturated brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[Br:31][CH2:32][CH2:33][CH2:34][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14][C:15]=2[NH2:24]
Reactant: BrCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1

Procedure:
The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate (3.7 g) and 1,3-dibromopropane (2.85 ml) were added to dimethylformamide (5 ml), and the same manner to Example 2-13 step (i) was conducted to give the titled compound as a white solid. Yield: 1.0 g (50%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].CC([Mg]Cl)C.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH2:8][OH:9])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCc1ccncc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OCc1ccncc1C1(O)CCN(Cc2ccccc2)CC1
Yield: 15.8 %

Procedure:
To a solution of 1.9 g (10 mmol) (3-bromo-pyridin-4-yl)-methanol in 50 ml dry tetrahydrofuran were added 11 ml (21 mmol) 2-propylmagnesium chloride solution (2.0 M in tetrahydrofuran). The reaction mixture was heated at reflux for 2 h. A solution of 1.9 g (10 mmol) 1-benzyl-4-piperidone in 5 ml tetrahydrofuran was added dropwise at a temperature of approximately 65° C. The reaction mixture was heated at reflux for 2 h and then quenched with water. The tetrahydrofuran was evaporated. The aqueous layer was basified to pH 10 with aqueous 2 M sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash-chromatography gave the title compound (0.47 g, 16%) as a brown solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:16]2[C:11](=[C:12]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[CH:10]=[CH:9][N:8]4[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:19][CH2:20]2)[CH:25]=1)=[O:35]
Reactant: Ic1ccccn1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccn3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-iodopyridine and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[F:23][C:22]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[CH:3][C:4]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1ccc(F)c(Br)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: O
Solvent: COCCOC
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ccc(F)c(-c2ccc(C)cc2)c1
Yield: 97.1 %

Procedure:
A solution of 0.3 g of the product from Example 3 in 15 ml of dimethoxyethane was admixed with 0.2 g of 4-methylphenylboronic acid, 0.17 g of sodium carbonate, 2 ml of water and 40 mg of tetrakis(triphenylphosphine)palladium(0) and refluxed for 20 hours. The mixture was then poured into water and extracted with ethyl acetate, and the extract was washed with 1N aqueous sodium hydroxide solution and then with water and dried. Distillative removal of the solvent and silica gel chromatography (MtBE: cyclohexane=9:1) gave 0.3 g of the title compound.