Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]1[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:6]([CH3:22])=[C:7]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:8]=1)C.Br[CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38].[OH-].[Na+]>C(#N)C.O>[CH3:22][C:6]1[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:4](=[O:3])[N:8]([CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:7]=1[C:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CCOc1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CCCS(C)(=O)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 12.6 %

Procedure:
A mixture of 4-(5-{2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (intermediate 5) (66 mg, 0.15 mmol) and 1-bromo-3-methanesulfonyl propane (201 mg, 1.0 mmol) in acetonitrile (0.20 mL) was heated at 120° C. for 6 h. The mix was cooled to RT and diluted with acetonitrile (2 mL) and water (1 mL) then treated with 1M sodium hydroxide (0.20 ml). The mixture was heated at 50° C. for 2 h. The cold mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by MDAP to afford the title compound (10 mg).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1>>[Cl:57][C:50]1[N:51]=[C:52]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCCCC1c1ccccc1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared according to method A as described in Example 1 was obtained as a solid (0.25 g, 26%) by the reaction of 1-amino-2-phenylpiperidine (Overberger, C. G. and Herin, L. P. Journal of Organic Chemistry, 1962, 27, 417) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine, followed by deprotection (as described in Example 5) to give the title nucleoside (a ca. 60:40 mixture of diastereoisomers): m.p. 186°-210° C.; 1H NMR (400 MHz, Me2SO-d6) δ 3.47-3.20 (2H, m, 5'-CH2), 3.82-3.97, 4.04-4.14 (2H, 2m, H-3' and H-4'), 4.46-4.56 (1H, 2q, H-2'), 5.33, 5.73 (1H, 2d, H-1'), 8.26, 8.48 (1H, 28, H-8).
Reaction SMILES: [N:1]([CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[NH2:1][CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1
Reactant: [N-]=[N+]=NC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g of 2-azido-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine (axial) is added to a suspension of 3 g of LiAlH4 in dry ether. The mixture obtained is heated for 1 hour, and after that cooled down. Then 12 ml of water are added to the mixture dropwise, whereby an inorganic precipitate is formed. The inorganic residue is removed by filtration after which the filtrate is evaporated to dryness.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH2:25])[C:22]([Cl:26])=[CH:21][C:17]=1[C:18]([OH:20])=O.[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH:40][CH3:41])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[CH3:41][N:40]([CH:37]1[CH2:36][CH2:35][N:34]([CH2:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:39][CH2:38]1)[C:18](=[O:20])[C:17]1[CH:21]=[C:22]([Cl:26])[C:23]([NH2:25])=[CH:24][C:16]=1[O:15][CH3:14]
Reactant: CNC1CCN(CC2CCCCC2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N(C)C1CCN(CC2CCCCC2)CC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Triethylamine (4.2 ml; 0.03 moles) and a solution of ethyl chloroformate (2.85 ml; 0.03 moles) in anhydrous tetrahydrofuran (35 ml) were added successively to a solution of 2-methoxy-4-amino-5-chlorobenzoic acid (6.04 g; 0.03 moles) in N,N-dimethylformamide (225 ml) whilst maintaining the temperature at -10° C. After stirring at this temperature for 2 hours, a solution of 1-cyclohexylmethyl-4-methylaminopiperidine (6.15 g; 0.03 moles) in anhydrous tetrahydrofuran (35 ml) was added, and the temperature was allowed overnight to reach room temperature. The mixture was poured into an aqueous solution of sodium bicarbonate, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give a solid which was recrystallized from a mixture of ethanol and diethyl ether. N-methyl-N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (9.6 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C:17]3=[N:20][CH:21]=[CH:22][N:16]3[C:15]=2[CH:23]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17]4=[N:20][CH:21]=[CH:22][N:16]4[C:15]=3[CH:23]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)-n1ccnc1CO2
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)-n1ccnc1CO2

Procedure:
In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine to produce 2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineamine. 1H NMR (DMSO-d6): 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 8.31 (s, 1H), 7.91 (d, 1H, J=2.3 Hz), 7.74 (d, 1H, J=1.2 Hz), 7.37 (dd, 1H, J=2.3 and 8.8 Hz), 7.16 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=1.2 Hz), 5.29 (s, 2H). LCMS: ret. time: 18.74 min.; purity: 99%; MS (m/e): 318 (MH+).
Reaction SMILES: [CH2:1]([C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>[Pd].C(O)(=O)C>[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC(=O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccc(O)cc1

Procedure:
16.75 g of dodecyl chloride was dropwise added to 7.0 g of phenol and the resulting mixture was subjected to reaction at 90° C. for 30 minutes. And then, 12.0 g of AlCl3 powder was added thereto mixture was further subjected to reaction at 100° C. for 4 hours. The reaction mixture was cooled and added to dilute hydrochloric acid. The resulting mixture was then subjected to extraction with two 50-ml portions of ethyl acetate. To the resulting solution of the reaction product in the ethyl acetate was added 80 ml of 3% aqueous sodium hydroxide solution, and the aqueous layer was then separated. To the aqueous layer was added conc hydrochloric acid to adjust the pH to 2, and the crystal, thus precipitated was filtered and washed with water to obtain 9.35 g of 4-hydroxyphenyl undecyl ketone. Subsequently, 8.0 g of the 4-hydroxyphenyl undecyl ketone thus obtained was mixed with 650 mg of a 5% active carbon-supported palladium and 100 ml of acetic acid, and the resulting mixture was subjected to reaction in a hydrogen gas stream at 50° C. for 15 hours to reduce the ketone. The reaction mixture was cooled and filtered, and acetic acid was distilled off to obtain 7.50 g of white, solid 4-dodecylphenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)=[N:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:22])#[N:26]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: COc1ccc(CN(CCN(C)CCCN)c2ccccn2)cc1
Product: COc1ccc(CN(CCN(C)CCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.52 g (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil that crystallises from ether at -20° C.; MS (+FAB method): m/z (rel. int. [%])=610 ([M+H]+, 1), 121 (100); IR (KBr): 2161 cm-1 (C≡N); m.p.: 54° C. (ether).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[C:6]([OH:11])(=[O:10])[C:7]([OH:9])=[O:8].[CH2:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28](O)=[C:27]([OH:32])[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC(=O)C)(=O)C>[C:6]([OH:11])(=[O:10])[C:7]([OH:9])=[O:8].[CH2:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([O:3][C:1](=[O:4])[CH3:2])=[C:27]([O:32][C:7](=[O:8])[CH3:6])[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(C2CCCN(Cc3ccccc3)C2)cc1O
Reactant: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C2CCCN(Cc3ccccc3)C2)cc1OC(C)=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 224.9 %

Procedure:
9.8 g of anhydrous sodium acetate were added to a mixture of 9.8 g of N-benzyl-3-(3',4'-dihydroxyphenyl)-piperidine oxalate and 120 ml of acetic acid anhydride and the mixture was stirred for 3 hours at 20° C and was filtered. The filter was washed with ethanol and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in water and ethyl acetate and the solution was made alkaline with an aqueous solution saturated with sodium bicarbonate. The organic phase was decanted, dried and evaporated to dryness. The residue was dissolved in 50 ml of isopropanol and a solution of 4 g of oxalic acid in 30 ml of isopropanol was added thereto. The mixture was refluxed until dissolution occurred and after cooling to 20° C, the mixture was vacuum filtered to obtain 13.5 g of N-benzyl-3-(3',4'-diacetoxyphenyl)-piperidine oxalate melting at 145° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:4]=2[N:3]=1.[C:22]([C:30](OCCC)=[O:31])#[C:23][C:24]([O:26][CH2:27][CH2:28][CH3:29])=[O:25]>C(O)CC>[C:24]([C:23]1[N:3]2[C:4]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=3[C:6]([C:9]3[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=3[F:16])=[N:7][CH2:8][C:2]2=[N:1][C:30](=[O:31])[CH:22]=1)([O:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: NC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Reactant: CCCOC(=O)C#CC(=O)OCCC
Solvent: CCCO
Product: CCCOC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 27, 2-amino-7-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine was heated in propanol with dipropyl acetylenedicarboxylate to give 1-carbopropoxy-9-chloro-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35]Br)/[C:27]([O:29]CC)=[O:28])[N:25]=1)([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.[SH:37][C:38]1[S:39][C:40]([CH3:43])=[N:41][N:42]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][S:37][C:38]2[S:39][C:40]([CH3:43])=[N:41][N:42]=2)/[C:27]([OH:29])=[O:28])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1nnc(S)s1
Product: Cc1nnc(SCCO/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)s1

Procedure:
Reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-bromoethoxyimino)acetate (UK patent application 2017702A) with 2-mercapto-5-methyl-1,3,4-thiadiazole and hydrolysis of the ester gave 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-(5-methyl-1,3,4-thiadiazol-2-ylthio)ethoxyimino]acetic acid; n.m.r. in solvent C: 2.7 (s,3H); 3.65 (t,2H); 4.51 (t,2H); 6.65 (s,1H); 7.34 (s,15H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:29][CH2:30][CH:31]1OCC[O:32]1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Na+].O>[CH:31]([CH2:30][CH2:29][CH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1)=[O:32]
Reactant: BrCCC1OCCO1
Reactant: Cc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
a 100 mL three necked RB flask, equipped with a rubber septum, a teflon coated stir bar and a gas inlet adaptor was flushed with N2. 4′-methyl-2,2′:6′,2″-terpyridine (18) (0.494 gm., 2 mmol), prepared by literature methods (see K. T. Potts, et al, J. Am. Chem. Soc., 1987, 109, 3961-3967) was dissolved in dry THF (10 mL) and was syringed into the flask. The reaction mixture was cooled to −78° C. and LDA (1.6 mL, 2.4 mmol) was added via syringe. The resulting dark brown mixture was stirred for 2 hr. at −78° C. 2-(2-bromoethyl)-1,3-dioxolane (0.434 mL, 2.4 mmol) was syringed into the reaction mixture, stirred for 1 hr. at −78° C. and allowed to warm to room temperature overnight. The mixture was poured over 10 ml brine and the aqueous layer was extracted with CH2Cl2. The extracts were dried over MgSO4 and evaporated to dryness to yield the crude acetal. The acetal was hydrolyzed with 1M HCl (10 mL) by heating to 50-60° C. for 2 hours. The solution was then neutralized with aqueous NaHCO3 and extracted with CH2Cl2. The extracts were dried over MgSO4 and evaporated to dryness to yield the crude aldehyde. Purification by flash chromatography (neutral alumina, CH2Cl2 elution) gave pure aldehyde (19) (0.339 gm., 1.12 mmol, 56%).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:28]3[CH:27]=[C:26]4[C:31](=[CH:30][CH:29]=3)[N:23]([CH3:22])[CH:24]=[CH:25]4)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc4c(ccn4C)c3)CCC2)CCN(C)C1
Temperature: 90 °C

Procedure:
To a degassed solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 1-methylindole-5-boronic acid pinacol ester (149 mg, 0.579 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-indol-5-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR, (CD3OD, TFA salt) δ (ppm): 7.21-7.38 (m, 2H), 7.2 (s, 1H), 7.04 (m, 2H), 6.9 (d, 1H), 6.8 (d, 1H), 6.21 (s, 1H), 4.62 (m, 1H), 4.35 (m, 1H), 3.65 (s, 3H), 3.58 (m, 2H), 3.01 (s, 3H), 2.81 (m, 2H), 2.6 (m, 4H), 2.41 (s, 3H), 2.21 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].Br[C:36]1([C:41]([O:43][CH3:44])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:36]4([C:41]([O:43][CH3:44])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C1(Br)CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OC3(C(=O)OC)CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in N,N-dimethylacetamide (10 mL) were added methyl 1-bromocyclopentanecarboxylate (1.4 g) and cesium carbonate (2.2 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature. The insoluble material was filtered off, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.94 g, 77%) as a pale-yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])=O)C1C=CC=CC=1>CO.[Pd]>[N:18]1([C:16]([C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C([C@H]1CCCN1C(=O)OCc1ccccc1)N1CCCC1
Agent: [Pd]
Solvent: CO
Product: O=C([C@H]1CCCN1)N1CCCC1

Procedure:
A mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDC (2.3 g, 12 mmol), HOBt (800 mg, 6 mmol), TEA (1.5 mL) and pyrrolidine (853 mg, 12 mmol) in DMF (20 mL) was stirred at rt for 18 hr. The reaction was diluted with water and sodium bicarbonate, extracted with dichloromethane (3×). The combined DCM was concentrated and purified on a silica gel column to give (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester. (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester was hydrogenated using Pd/C in methanol at ambient temperature for 20 hr to provide pyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone. To a solution of pyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone (1.2 g, 7.1 mmol) in THF (10 mL) at 0° C. was added B2H6 (10 mL, 10 mmol). The mixture was heated to reflux for 16 hr. The reaction was acidified with HCl and concentrated. The residue was basified to pH 10 with 2N NaOH and extracted with 5% methanol in DCM. The organic layer was concentrated and purified on a silica gel column to give 800 mg (73%) of (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)#[N:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:24][C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: N#Cc1cccc(CBr)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: COCCOC
Product: N#Cc1cccc(Cc2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
A mixture of 2-benzyloxy-5-chlorophenylboronic acid (2.1 g), 3-cyanobenzyl bromide (1.57 g), sodium carbonate (1.7 g) and tetrakis(triphenylphosphine)palladium (0) (0.46 g) in ethylene glycol dimethyl ether (30 ml) was heated at 80° C. for 5 h. The mixture was cooled, partitioned between water/diethylether, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% ethylacetate/isohexane, yield 0.53 g.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:19]C1C=CC=CC=1)=[O:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>C(O)C>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[O:18])[N:19]=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2[nH]1

Procedure:
A stirred mixture of 7.02 g (0.02 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-phenylurea and 4.17 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of ethanol was refluxed for 22 hr, and then cooled. The suspended solid was collected on a filter, washed with ethanol, and dried in air to give 3.82 (70%) of 6-chloro-4-phenyl-2(1H)-quinazolinone as yellow crystals; mp 267°-269°.