Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C(O)C>[C:10]1([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1csc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1csc(-c2ccccc2)c1

Procedure:
5-Bromo-thiophene-3-carboxylic acid (2.07 g, 10 mmol) was dissolved in dimethoxyethane (15 mL) and ethanol (15 mL). Phenyl boronic acid (14 mmol), [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II) (0.5 mmol) and caesium carbonate (14 mmol) were added and the reaction mixture refluxed under nitrogen overnight. The solvent was evaporated under vacuum, and the residue dissolved in ethyl acetate. The organic solution was washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was dissolved in hot ethyl acetate, filtered and the solvent evaporated to give the title compound as a pale brown solid. LCMS m/z 203.20 [M−H]−R.T.=3.23 min (Analytical Method 5).
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[CH3:7][C:8]1[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][CH:9]=1>O>[Br:1][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[N:13]=1
Reactant: Br
Reactant: Cc1cccc(CO)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cccc(CBr)n1

Procedure:
To a flask containing a mixture of 15 ml of 48% hydrobromic acid and 11 ml of sulfuric acid was added 5 g of 6-methyl-2-pyridinemethanol dropwise under nitrogen. The mixture was heated to 90 C for 4 hours, and poured into 25 ml of water. After neutralization with sodium carbonate, the product was extracted with 100 ml ethyl acetate and washed with 30 ml of water. Following solvent removal, the product was purified by silica gel chromatography using 25% ethyl acetate in hexane, resulting in 6.3 g of a pink oil which solidified on storage at −5 C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[C:4]([C:17]([O:19]C)=[O:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][C:28]1[O:32][CH:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=2)[NH2:36])[CH:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CC(N(C)C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[C:33]([C:30]3[CH:29]=[C:28]([CH3:27])[O:32][CH:31]=3)[CH:34]=2)=[O:15])=[C:4]([CH:3]=1)[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Cc1cc(-c2cccc(N)c2)co1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
380 mg (2.2 mmol) of (2-[(4-chloro-2-(methoxycarbonyl)phenyl)amino]-2-oxoethoxy)acetic acid was dissolved in 7 mL of THF. 361 mg (2.9 mmol) of oxalyl chloride and a catalytic quantity of DMF were added thereto under ice-cooling, and stirred at room temperature for 2 hours. Thereafter, the solvent was distilled off under reduced pressure. The DMA solution of 380 mg (2.2 mmol) of 3-(5-methylfuran-3-yl)aniline was added to the resulting residue, and stirred for 1 hour. After completion of the reaction, an aqueous sodium bicarbonate solution (was added dropwise, and extraction was carried out using ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give 5-chloro-2-([(2-([3-(5-methylfuran-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 32%).
Reaction SMILES: ClC1N=C(Cl)C([N+]([O-])=O)=CN=1.[N+:12]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-])=O>[Pd]>[NH2:12][NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)N[N+](=O)[O-]
Agent: [Pd]
Agent: O=[N+]([O-])c1cnc(Cl)nc1Cl
Product: NN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
2,4-dichloro-5-nitropyrimidine is first coupled to a nitrophenylalanine derivative and the product is allowed to react with a dialkylamine, either directly or utilizing “Buchwald” palladium catalyzed coupling conditions. The resulting product is then hydrogenated yielding an aminophenylalanine derivative. This is coupled to 2-chloro-3-nitropyridine followed by reduction of the nitro group. Cyclization with CDI followed by alkylation with methyl iodide or other alkylating agent gives the imidazolone. Reduction of the pyrimidine nitro group followed by the introduction of the N-isopropyl group through reductive amination followed by sulfonylation with a sulfonyl chloride (or alternatively acylation with an acid chloride) gives the ester. Hydrolysis with formic acid affords the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25]C(C)([O-])C.[K+].CI.C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[C:19](=[O:24])[N:20]([CH3:25])[CH:21]=[CH:22][N:23]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: O=C(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccnc(CN2CCC(C(=O)Cc3ccccc3F)CC2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
After dissolving 300 mg of 3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 5 ml of N,N-dimethylformamide, 113 mg of potassium tert-butoxide was added, the mixture was stirred for 30 minutes while cooling on ice, 0.063 ml of methyl iodide was added and the stirring was continued for 1 hour. Ice water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order 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 (solvent: ethyl acetate/methanol). Diisopropyl ether was added and the mixture was filtered to obtain the title compound (61 mg, 20% yield).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3cc(F)ccc3F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cc(F)ccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 25.2 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,5-difluorobenzyl)-1-piperidinecarboxamide formate (0.50 g, 1.15 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.465 g, 1.15 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.238 g, 0.29 mmol).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)=[C:13]([CH3:25])[CH:12]=1>ClCCl>[ClH:10].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:23][C:22]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:18][C:19]([OH:21])=[O:20])=[C:13]([CH3:25])[CH:12]=1
Reactant: Nc1ccc(I)cc1N
Reactant: Cc1cc(Cl)ccc1C1CC(=O)OC(=O)C1
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(CC(=O)O)Cc1nc2ccc(I)cc2[nH]1
Product: Cl
Temperature: 25 °C
Yield: 125.5 %

Procedure:
To a solution of 4-iodo-1,2-phenylenediamine (0.47 g) in dichloromethane (2 ml) the solution of 3-(4-chloro-2-methylphenyl)glutaric anhydride (0.48 g) in dichloromethane (2 ml) was added with stirring at rt. Almost instantaneously an resinous precipitate is formed. After 1 h the mixture was cooled in an ice bath and the solvent was removed by decantation. The residue is dissolved in acetic acid (3 ml). Conc. HCl (1 ml) is added and the resulting solution is heated to reflux for 1 h. All volatiles are removed at the water aspirator and the residue is triturated with acetic acid and acetone to leave 3-(4-chloro-2-methylphenyl)-4-(5-iodo-2-benzimidazolyl)butanoic acid HCl (0.62 g) as light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:21])([CH3:20])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2].[CH3:24][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:20])([CH3:21])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:18])[CH3:24])=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(C=O)cc2=O)c2cc(C#N)ccc2O1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Reaction time: 0.33 h

Procedure:
In 4 ml of anhydrous tetrahydrofuran, is dissolved 355 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-formyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 25. Then, 1.73 ml of 0.94 M solution of methylmagnesium bromide in tetrahydrofuran is added at 0° C. and reacted first at that temperature for 50 minutes and then at room temperature for 20 minutes. After stopping the reaction by adding a saturated aqueous solution of ammonium chloride, the reaction mixture is extracted with ethyl acetate, and the organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/1 mixture of methylene chloride/ethyl acetate as a developing solvent. Thus, 281 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy)ethyl-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[N:20]([CH3:22])[CH3:21].ClC1C=CC=C(C(OO)=[O:31])C=1>C(OCC)(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:11]1[CH:16]=[C:15]([N:17]([CH3:18])[CH3:19])[CH:14]=[CH:13][C:12]=1[N:20]([CH3:22])[CH3:21])=[O:31]
Reactant: CN(C)c1ccc(N(C)C)c(Sc2nc3ccccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(N(C)C)c(S(=O)c2nc3ccccc3[nH]2)c1
Reaction time: 1 h

Procedure:
The product of step (b) above (1.5 g) was dissolved in ethyl acetate (120 ml) and cooled to -10°. A solution of m-chloroperbenzoic acid (980 mg of 85%) in ethyl acetate (30 ml) was added in one portion and the mixture stirred for 1 hr. The mixture was filtered and the residue taken up in dichloromethane. The dichloromethane was washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine and then dried and evaporated. Flash chromatography afforded the title compound as an off white solid (857 mg) mp 213°-215° NMR (CDCl3) delta 7.7 (broad), 7.4 (2H)broad, 7.20 (2H)m, 7.12 (2H)m, 6.69 (1H)d.o.d., 2.79 (6H) 2.60 (6H)s.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([C:13]([F:16])([F:15])[F:14])=O.[CH3:18][NH:19][NH2:20]>C(O)(=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:19]([CH3:18])[N:20]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cc(F)ccc1F
Reactant: CNN
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(F)ccc2F)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
34.5 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)-propane-1,3-dione was dissolved in 250 ml of acetic acid and 9.5 mL of methylhydrazine slowly added. The mixture was heated at 100° C. for 5 minutes then cooled and diluted with ether. The ether solution was washed with water and potassium carbonate solution, then dried with magnesium sulfate, filtered and concentrated. The residue was chromatographed to give 9.5 g of 3-(2,5-difluorophenyl)-1-methyl-5-(trifluoro-methyl)-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16]C2C=C(C=CC=2O)C#N)[C:12]1=[O:26].[Cl:27][C:28]1[C:36]2[CH:35]=[C:34]([S:37](Cl)(=[O:39])=[O:38])[S:33][C:32]=2[CH:31]=[C:30](Cl)[CH:29]=1>>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:16][N:13]1[CH2:14][CH2:15][C@H:11]([NH:10][S:37]([C:34]2[S:33][C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[C:36]=3[CH:35]=2)(=[O:39])=[O:38])[C:12]1=[O:26]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1cc2c(Cl)cc(Cl)cc2s1
Reactant: N#Cc1ccc(O)c(CN2CC[C@H](N)C2=O)c1
Product: N#Cc1ccc(N)c(CN2CC[C@H](NS(=O)(=O)c3cc4c(Cl)cccc4s3)C2=O)c1

Procedure:
The title compound is prepared as described in EXAMPLE 17, Part G, substituting 3-[3-(S)-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-amino-benzonitrile for 3-[(3-(S)-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-hydroxy-benzonitrile and substituting 4-chlorobenzo[b]thiophene-2-sulfonyl chloride for 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is triturated with Et2O to give the product as a white solid. FAB MS, [M+H]+ =461, 463, Cl pattern.
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:18]1([NH:17][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH:7]4[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]4[CH2:5][C:4]=3[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccccc3)nc2CC2CCCCC12
Yield: 6 %

Procedure:
To a solution of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.4 g, 1.7 mmol) and aniline (0.204 g, 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.223 g, 2.2 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.085 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.03 g, 6%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16][C:15]=2[N:14]=[CH:13][C:12]=1[C:22](OCC)=[O:23]>C1(C)C(C)=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22](=[O:23])[C:12]3=[CH:13][NH:14][C:15]4[CH2:16][CH2:17][CH:18]([CH3:21])[CH2:19][C:20]=4[C:11]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(C)CC2
Reactant: NNc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: CC1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 1.37 g of p-chlorophenylhydrazine and 2.4 g of ethyl 4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate in 75 mL of xylene is stirred and refluxed overnight, then cooled to room temperature and filtered. Collected solid is dissolved in hot ethanol, treated with decolorizing charcoal, and concentrated to a smaller volume to deposit a solid, which is recrystallized from ethanol containing hydrogen chloride to yield 2-p-chlorophenyl-2,3,6,7,8,9-hexahydro-8-methylpyrazolo[4,3-c]quinolin-3(5H)-one hydrochloride, m.p. 331°-333°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].O[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:13])([F:14])[F:15])[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC2CCN(C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.8 %

Procedure:
In a round bottom flask wrapped with foil, methyl 4-hydroxy-3-(trifluoromethyl)benzoate (500 mg, 2.13 mmol) was dissolved in methylene chloride (10 mL). 4-Hydroxy-1-methyl-piperidine (0.25 mL, 2.13 mmol), PPh3 (670 mg, 2.56 mmol), and DIAD (0.50 mL, 2.56 mmol) were added thereto, and the mixture was stirred at room temperature for 23 hours. DTAD (4.26 mmol) and PPh3 (1.12 g, 4.26 mmol) were added at 0° C. to the reaction mixture, which was stirred at room temperature for 24 hours. The resulting mixture was concentrated and then purified by silica gel chromatography (Hex/EA=1/1→DCM/MeOH=10/1) to obtain the title compound (512 mg, 76%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].Br[CH2:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C.CCOCC>C(O)C>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: OCCCBr
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Yield: 69.9 %

Procedure:
14.1 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound b), 11.7 g of 3-bromo-1-propanol and 13 g of triethylamine were heated under reflux in 250 ml of ethanol for 20 hours to carry out reaction. After completion of the reaction, the resultant reaction mixture was then concentrated to dryness, and the resultant residue was dissolved in 300 ml of chloroform and then washed with 100 ml of water twice. The washed organic layer was dried over anhydrous magnesium sulfate and then treated with under reduced pressure, and the solvent was distilled off, thereby obtaining 20.5 g of a crude product. Next, ether was added to this crude product so as to achieve crystallization. The resultant crystals were recovered, washed and then dried to obtain 12.4 g (yield 69.8%) of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound a).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Br[CH:13]([OH:15])[CH3:14].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:1]([NH:4][N:5]([CH2:14][CH2:13][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(O)Br
Reactant: CC(=O)NNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)NN(CCO)c1ccccc1
Yield: 34.8 %

Procedure:
To a solution of 1-acetyl-2-phenylhydrazine (2 g, 13.3 mmol) in anhydrous toluene 20 ml was added bromoethanol (1.04 ml, 14.6 mmol), diisopropylethylamine (2.54 ml, 14.6 ml) at room temperature. The reaction mixture was refluxed under nitrogen for 40 hours. After cooling, the reaction was then quenched with 100 ml water, extracted with dichloromethane 2×100 ml. The organic was dried (MgSO4) and removed in vacuo. The residue was purified by flash column chromatography over silica using a gradient 50% mixture of ethyl acetate and hexane to 100% ethyl acetate as eluant. Appropriate fractions were combined and the solvent was removed in vacuo to give the product as a yellow oil 0.9 g (Yield 35%).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (90.00 mg, 0.418 mmol), N-methyl-4-(piperazin-1-yl)benzamide (115 mg, 0.523 mmol) and (cyanomethyl)trimethylphosphonium iodide (163 mg, 0.669 mmol) in Propiononitrile (Volume: 2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.364 mL, 2.091 mmol) at 23° C. The reaction was stirred at 95° C. for 2 hr. The suspension was cooled to 40° C., filtered warm, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.152 g, 0.365 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.58 (m, 4 H) 2.74 (d, J=4.55 Hz, 3 H) 3.20-3.31 (m, 4 H) 3.62 (s, 2 H) 6.71-6.77 (m, 1 H) 6.94 (d, J=8.84 Hz, 2 H) 7.08 (dd, J=3.54, 1.52 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.68 (dd, J=3.03, 1.77 Hz, 1 H) 7.70 (d, J=8.84 Hz, 2 H) 8.14 (q, J=4.21 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.61 (br. s., 1 H). ESI-MS: m/z 417.4 (M+H)+. mp=285.6-288.6° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1416 g, 0.70 mmol) is added to a slurry of pentane-washed NaH (0.0400 g, 0.0010 mol) in DMF (2 mL) and after stirring for 30 min, p-fluorobenzyl bromide (0.11 mL, 0.88 mmol) is added. After the mixture had stirred for 2.3 h, it is partitioned between aq. sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (100 mL) using first dichloromethane (100%) and then methanol/dichloromethane (2/98). The product fractions are combined and rechromatographed on silica gel (50 mL) using acetone/heptane/NH4OH (15/85/0.25) and then recrystallized using ethyl acetate/hexane to give 0.0932 g (43%) of the title compound; mp 177-178° C.; MS (ESI−) for C19H15F2NO m/z 310.1 (M−H)−; IR (drift) 1638, 1630, 1509, 1496, 1459, 1436, 1413, 1361, 1249, 1222, 1194, 1158, 1125, 830, 790 cm−1; 1H NMR (CDCl3) δ2.24, 2.58, 2.86, 5.47, 6.89-7.02, 7.16, 8.06. Anal. Calcd for C19H15F2NO: C, 73.30; H, 4.86; N, 4.50. Found: C, 73.40; H, 4.83; N, 4.50.