Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13](O)=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN.C1C=CC2N(O)N=[N:36][C:34]=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH:36][CH3:34])=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)c1ccc(N=NC(C(=O)O)=C2NC(C)(C)Cc3ccccc32)cc1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)C(N=Nc1ccc(C(C)=O)cc1)=C1NC(C)(C)Cc2ccccc21
Temperature: 25 °C

Procedure:
(4-acetyl-phenylazo)-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetic acid, methylamine, HOBt (Advanced ChemTech Corp., USA) and triethylamine are dissolved in DMF, and a dichloromethane solution of HBTU (Advanced ChemTech Corp., USA) is added thereto. The mixture is then stirred at room temperature. The mixture is washed with a saturated aqueous sodium chloride solution and a 5% aqueous sodium hydrogen carbonate solution. The reaction product is dried with anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:12])[CH3:2].[C:13](Cl)(=O)[CH3:14].C(O[C:21](=O)[CH3:22])(=O)C.[OH-].[Na+]>O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:4]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:21][CH3:22])[C:13]=2[CH3:14])=[CH2:12])=[C:4]1[CH3:12])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Cl
Reactant: CCn1c(C)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(c1c(C)n(CC)c2ccccc12)c1c(C)n(CC)c2ccccc12
Temperature: 51 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-2-methylindole (15.9 g, 0.1 mole), acetyl chloride (2.0 g, 0.025 mole) and acetic anhydride (15 ml) was stirred at 50-52° C. for 8 hours. Then, the reaction mixture was cooled to room temperature and poured into ice, water and sodium hydroxide (10%, 50 ml). After stirring for 20 minutes, the precipitated solid was filtered off, washed with water, refluxed with methanol for 1 hour and cooled. The solid was filtered, washed with methanol and dried. Yield of the product: 16.5g (96%), pale yellow powder, m.p.: 179-182° C. IR(KBr) spectrum was identical to that of the product in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:23]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:36][CH:35]=1
Reactant: COc1ccc(C(Nc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 45.6 %

Procedure:
The procedure is as in Example 1, but 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.14 g of tert-butyl (RS)-2-anilino-2-(4-methoxyphenyl)acetate and 0.72 cm3 of thionyl chloride are used as starting materials. The residue obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: cyclohexane/ethyl acetate (70/30 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from a mixture of diisopropyl ether/acetonitrile (50/50 by volume). 2.3 g of tert-butyl (RS)-2-(4-methoxyphenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 206° C. are then obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[C:10]([F:23])[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2ccnc(N)c2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2ccnc(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((2-aminopyridin-4-yl)methyl)-3-fluorophenylcarbamate as a TFA salt (73 mg, 0.17 mmol) in DCM (4.0 mL) was added TFA (1.0 mL). The solution was stirred at room temperature for 2 h and the solvent was removed in vacuo to give 4-(4-amino-2-fluorobenzyl)pyridin-2-amine, bis-trifluoroacetic acid (70 mg, 93% yield). MS (ESI+): m/z 218.12 (M+H)+.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33](=[N:3][OH:2])[NH2:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(-c3ccccc3)[nH]c2c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 105.6 %

Procedure:
To a solution of hydroxylammonium chloride (891 mg) in dimethylsulfoxide (5 mL) was added sodium hydrogen carbonate (1.29 g), and this mixture was stirred at 50° C. for 75 minutes. Then, a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbonitrile (435 mg) in dimethylsulfoxide (1.4 mL) was added dropwise thereto, followed by stirring at 50° C. for 24 hours. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (504 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.40 (2H, s), 5.63 (2H, br s), 6.43-6.69 (1H, br), 6.77 (1H, dd, J=2.2, 8.8 Hz), 6.91 (1H, d, J=2.2 Hz), 7.09-7.15 (1H, m), 7.31-7.40 (2H, m), 7.40-7.49 (2H, m), 7.49-7.60 (3H, m), 7.66-7.74 (1H, m), 8.06 (1H, br s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1.N1C=CC=C[C:21]=1C(N)=O.IC>CN(C)C=O.O>[F:10][C:8]1[CH:7]=[C:6]([N:11]([CH3:21])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: NC(=O)c1ccccn1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccn1)c1cc(F)cc(F)c1
Temperature: 65 °C
Yield: 56 %

Procedure:
To a suspension of 80% sodium hydride (1.22 g, 41 mmol) in anhydrous dimethylformamide (90 mL), was added dropwise a solution of N-(3,5-difluorophenyl)-2-pyridinecarboxamide, prepared by a process of Example 1, difluorophenyl)-2-pyridinecarboxamide, prepared by the process of Example 1, Step 1 (8.71 g, 37 mmol) in dimethylformamide (30 mL). The reaction mixture was warmed to 65° C. for 1 hour and then treated with iodomethane (2.60 mL, 42 mmol) at room temperature. After 2.5 hours the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with 75% brine, dried, preabsorbed onto silica gel, and flash chromatographed (300 g, elution with 40% ethyl acetate in petroleum ether) to yield pure N-(3,5-difluorophenyl)-N-methyl-2-pyridinecarboxamide (5.16 g, 21 mmol, 56%, m.p. 102°-104° C.), which was reacted with Lawesson's reagent (4.36 g, 11 mmol) in anhydrous toluene (65 mL) at reflux temperature for 1.5 hours. The toluene was evaporated and the residue was dissolved in dichloromethane, preadsorbed onto silica gel, flash chromatographed (300 g, elution with 10% ethyl acetate in petroleum ether), and recrystallized from ethyl acetate in petroleum ether to afford a yellow solid (2.36 g, 24%), m.p. 131°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7](OC)[N:6]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:4].[CH2:23]([Si](C)(C)C)[CH:24]=[CH2:25].O>C(Cl)Cl.[Cl-].[Na+].O.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:25][CH:24]=[CH2:23])[N:6]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[O:4]
Reactant: COC(=O)C1CCCC(OC)N1C(=O)OCc1ccccc1
Reactant: C=CC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCC1CCCC(C(=O)OC)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
6-Methoxy-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Compound 233, 1.04 g, 3.39 mmol) was dissolved in CH2Cl2 (10 mL), and the solution was cooled to −78° C. using dry ice-acetone bath. 1M TiCl4 solution in CH2Cl2 (3.7 mL) was added dropwise over a 1-minute period, followed by allyltrimethylsilane (1.61 mL, 10.14 mmol). The bath was changed to water, and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into brine (50 ml) and extracted with CHCl3 (2×50 mL). The combined organic layers were washed with saturated NaHCO3 solution (50 mL) and finally dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography (1:5 EtOAc/hexanes) to give Compound 234 (0.91 g, 84%). Rf=0.78 (1:2 EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([O:17]CC)=O)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:21]([NH:30][NH2:31])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([NH:31][NH:30][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O

Procedure:
Reagents: Comp 40 (0.5 mmols, 0.15 g); octanoyl hydrazine (0.55 mmols, 0.09 g). Yield: 0.06 g (29%), white solid, m.p.=161° C.-162° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccnc2Cl)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
2-Chloro-3-pyridinol (1.3 g), 1.88 g of p-methoxybenzyl chloride, and 1.4 g of potassium carbonate were added to 10 ml of dimethylformamide, followed by stirring at 60° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and a saturated sodium chloride aqueous solution. After drying, the solvent was removed by evaporation, and the residue was subjected to silica gel column chromatography using a 1:4 (by volume) mixture of ethyl acetate and hexane as a developing solution. The fraction containing the desired compound was concentrated to afford 2.18 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][N:4]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:29])[C:23](=[CH:27][CH:28]=1)[C:24](O)=[O:25]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]2[C:24](=[O:25])[N:2]=[C:1]([C:3]3[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][N:4]=3)[S:29][C:22]=2[CH:21]=1
Reactant: CCOP(=O)(CCc1ccnc(C#N)c1)OCC
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: CCOP(=O)(CCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1)OCC
Yield: 15.3 %

Procedure:
Diethyl 2-(2-cyano-4-pyridyl)ethylphosphonate (1.7 g, 6.4 mmol) and 4-chlorothiosalicylic acid (2.4 g, 12.8 mmol) were dissolved in pyridine (30 ml), and the mixture was refluxed for 13 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-chloroform (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.43 g, 15%) as white crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:28][CH:29]([CH3:39])[CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][OH:38])[CH:34]=[CH:35][CH:36]=1.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[OH:38][CH2:37][C:33]1[CH:32]=[C:31]([CH2:30][CH:29]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:16]4=[N:17][C:18]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:19][C:20](=[O:21])[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:39])[CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)c1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Reactant: CC(N)Cc1cccc(CO)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Temperature: 100 °C

Procedure:
A mixture of 9-(2-methanesulfonyl-pyrimidin -4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (344 mg, 0.90 mmol), [3-(2-amino-propyl)-phenyl]-methanol (371 mg, 2.25 mmol), and N-methylmorpholine (8 mL) was heated to 100° C. for 20 h. Reaction was diluted with dichloromethane (15 mL) and ethyl acetate (40 mL), washed three times with water (50 mL) then saturated sodium chloride (10 mL). Organic dried over magnesium sulfate then concentrated to a oil under vacuum. Product purified on silica and isolated as a white solid. M+1=469.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[CH:12]([CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([O-:17])=[O:16])=O.Cl.[C:25]1(C)C=CC=C[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH:5]/[CH:12]=[C:14](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)\[C:15]([O:17][CH2:25][CH3:26])=[O:16]
Reactant: O=CC(C(=O)[O-])c1ccccc1
Reactant: COc1ccc(OC)c(N)c1
Reactant: Cc1ccccc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1cc(OC)ccc1OC)c1ccccc1
Yield: 72 %

Procedure:
A solution of 2,5-dimethoxyaniline (1.76 g, 11.49 mmol) and ethyl ∀-formylphenylacetate (2.43 g, 1.1 eq) in toluene (20 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (10 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The isolated residue is crystallized from methanol and then filtered through a sinter funnel to give 2.71 g (72%) of compound 10.
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[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=1.[CH3:18][C:19]1([CH3:27])[CH2:26][C:24](=O)[CH2:23][C:21](=[O:22])[CH2:20]1.Cl.[NH2:29][C:30]1[CH:34]=[CH:33][NH:32][C:31]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)C(C)C)(C)C>C(O)C.ClCCl>[CH2:38]([O:37][C:35]([C:31]1[NH:32][CH:33]=[C:34]2[CH:16]([C:14]3[O:15][C:11]([S:10][C:2]4[NH:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][CH:13]=3)[C:23]3[C:21](=[O:22])[CH2:20][C:19]([CH3:18])([CH3:27])[CH2:26][C:24]=3[NH:29][C:30]=12)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=Cc1ccc(Sc2nc3ccccc3[nH]2)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 46.7 %

Procedure:
430 mg (1.76 mmol) of 5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde are combined to 197 mg (1.405 mmol) of dimedone, 335 mg (1.76 mmol) of 3-amino-2-ethoxycarbonylpyrrole hydrochloride, 742 mg (5.741 mmol) of N,N-diisopropylethylamine in 10 ml ethanol. The stirred reaction mixture is refluxed overnight. Upon cooling to room temperature, reaction mixture was half concentrated under reduced pressure and then diluted with water and extracted with ethyl acetate. The organic layer is washed with water and with brine and then dried on magnesium sulfate, filtered and concentrated under reduced pressure giving crude product. The resulting oily residue is dissolved in 10 ml of dichloromethane and purified by chromatography on a prepacked 120 g 15-40 μm silica gel cartridge (eluting solvent: cyclohexane/ethyl acetate from 100/0 to 70/30 v/v; rate: 50 mL/min, in 50 min, from 70/30 to 50/50 v/v in 10 min, and then from 50/50 to 40/60 v/v in 30 min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure giving 330 mg of expected compound with 47% yield.
Reaction SMILES: B(F)(F)F.CCOCC.CO[C:12]1[C:13](=[O:27])[C:14]2[C:23]([C:24](=[O:26])[CH:25]=1)=[CH:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:15]=2.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[CH:28]([O:31][C:25]1[C:24](=[O:26])[C:23]2[C:14]([C:13](=[O:27])[CH:12]=1)=[CH:15][C:16]1[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:22]=2)([CH3:30])[CH3:29]
Reactant: COC1=CC(=O)c2cc3ccccc3cc2C1=O
Reactant: CC(C)O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)OC1=CC(=O)c2cc3ccccc3cc2C1=O
Reaction time: 8 h

Procedure:
17 ml of cold borontrifluoride etherate was added to a suspension of 7 g of 2-methoxy-1,4-anthraquinone in 120 ml of isopropanol. The reaction was carried at 70°-80° C. overnight. After partially concentrated, the reaction mixture was left at room temperature and the crude product was obtained as dark brown precipitate. Recrystallization from isopropanol yielded 5 g of pure yellow needles of IPAQ.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 2-naphthoyl chloride (164 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (175 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][CH:6]=[C:5]4[CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[O:29])=[CH:31][CH:32]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(-c5ccccc5)cc4)cc23)CC1

Procedure:
Reacting 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 20.0 mg (0.10 mMol) 4-phenylbenzoic acid at 70° C., 10.0 mg (49%) of the title compound were recovered.
Reaction SMILES: [I-:1].[Na+].[CH2:3]([N:7]([CH3:17])[S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6]>C(C(C)=O)C>[CH2:3]([N:7]([CH3:17])[S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][I:1])(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: [I-]
Reactant: CCCCN(C)S(=O)(=O)CCCCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCN(C)S(=O)(=O)CCCCCI
Yield: 93.8 %

Procedure:
526 mg of sodium iodide were added to a solution of 449 mg of the product of Step A in 4.5 ml of methyl ethyl ketone, and the mixture was stirred at reflux for 4 hours. After cooling, the methyl ethyl ketone was evaporated under reduced pressure and water was added. Extraction was carried out with ethyl acetate and the extracts were washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 572 mg of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][C:20]=4[O:32][CH3:33])[N:16]=[CH:17][C:12]=3[CH:11]=[CH:10][C:9]2=[O:34])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[CH3:33][O:32][C:20]1[CH:21]=[C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[CH:10][C:9](=[O:34])[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:44](=[O:47])[CH:45]=[CH2:46])[CH:7]=[CH:6][CH:5]=3)[C:13]=2[N:14]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b) (2.17 g, 4.74 mmol) in DCM (30 mL) and THF (30 mL) at 0° C. was treated with DIEA (1.66 mL, 9.49 mmol) and acryloyl chloride (0.46 mL, 5.69 mmol) dropwise over 15 min and stirred at 0° C. After 1.5 h, additional acryloyl chloride (0.20 mL) was added slowly over 10 min then the suspension was stirred at 0° C. for another 20 min. Additional acryloyl chloride (0.1 mL) was added and the reaction mixture stirred another 15 min. The reaction mixture was treated with a saturated solution of NaHCO3, extracted with DCM (5×100 mL), dried over Na2SO4, filtered and concentrated. Purification of the crude residue on a silica gel column (1-20% MeOH in DCM) afforded the desired product as a yellow solid. This material was treated with 20 mL of EtOH and the slurry was filtered through a medium porosity sintered glass frit and washed with additional EtOH (10 mL) and Et2O (3×10 mL) affording N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(71-1)-yl)phenyl)acrylamide (1) (680 mg, 1.33 mmol, 28% yield) as a yellow solid after drying overnight at 36° C. in a vacuum oven. m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.75 (1H, br. s.), 8.17 (1H, br. s.), 7.92 (2H, d, J=9.4 Hz), 7.59 (1H, br. s.), 7.52 (1H, t, 0.1=8.1 Hz), 7.29 (1H, d, J=9.0 Hz), 7.01 (1H, d, J=8.0 Hz), 6.54 (1H, br. s.), 6.37-6.50 (2H, m), 6.20-6.33 (1H, m), 6.03 (1H, br. s.), 5.77 (1H, d, J=10.0 Hz), 3.78 (3H, s), 3.07 (4H, br. s.), 2.43 (3H, s), 2.34 (4H, br. s.).