Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:16]=[C:15]([N:17]3[C:21]4=[N:22][CH:23]=[CH:24][C:25]([C:26]5[CH:27]=[N:28][C:29]6[C:34]([CH:35]=5)=[CH:33][CH:32]=[CH:31][CH:30]=6)=[C:20]4[C:19]([C:36]([F:39])([F:38])[F:37])=[N:18]3)[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH2:4][CH2:3]1.C([OH:42])C.[OH-].[Na+].OO>CS(C)=O.O.C(OCC)(=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:16]=[C:15]([N:17]3[C:21]4=[N:22][CH:23]=[CH:24][C:25]([C:26]5[CH:27]=[N:28][C:29]6[C:34]([CH:35]=5)=[CH:33][CH:32]=[CH:31][CH:30]=6)=[C:20]4[C:19]([C:36]([F:39])([F:38])[F:37])=[N:18]3)[CH:14]=[CH:13][C:10]=2[C:11]([NH2:12])=[O:42])[CH2:6][CH2:7]1
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1N[C@H]1CC[C@H](O)CC1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1N[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
Compound (1f) (0.450 g) was dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO, 2 mL) and ethanol (4 mL). An aqueous sodium hydroxide solution (4 M, 0.851 mL) and a 30% hydrogen peroxide solution (0.193 mL) were added to the resulting solution in this order at room temperature, followed by stirring for 30 min. Water was added to the reaction solution, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1) (0.300 g, 65%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[CH3:10]I>>[CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[N:5]([CH3:10])[C:4]1=[O:9])[CH3:2]
Reactant: CI
Reactant: CCC1NC(=O)NC1=O
Product: CCC1NC(=O)N(C)C1=O

Procedure:
Using 5-ethylimidazolidine-2,4-dione (1.00 g) and methyl iodide (0.51 mL) and by the reaction and treatment in the same manner as in Preparation Example 214, the title compound (0.52 g) was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11](C=O)C>CO.O.[C-]#N.[C-]#N.[Zn+2].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>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([C:10]#[N:11])=[N:7][C:6]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1nc(Br)ccc1N
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]
Solvent: CO
Solvent: O
Product: Cc1nc(C#N)ccc1N
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-2-methylpyridin-3-amine (compound 1, 500 mg, 2.69 mmol) in DMF (10 mL) was added Zn(CN)2 (943 mg, 8.06 mmol) and Pd(PPh3)4 (288 mg, 0.3 mmol) at room temperature. The reaction was stirred at 110° C. in microwave reactor for 1 h. After it was cooled to room temperature, the mixture was filtered and purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% MeOH in water with 10 mmol NH4HCO3 modifier) to afford the compound as an oil.
Reaction SMILES: [ClH:1].[NH:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:24])[C@@H:15]([NH2:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.[NH:25]1[C:29]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])=NN=[N:26]1>>[Cl:1][C:36]1[CH:30]=[CH:31][C:32]([N:33]2[CH:6]=[N:2][N:3]=[N:4]2)=[C:34](/[CH:16]=[CH:15]/[C:14]([NH:23][C@H:15]([C:14](=[O:24])[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[NH:2][N:3]=[N:4][N:5]=3)[CH:8]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:24])[CH:35]=1.[NH2:33][C:32]1[CH:31]=[C:30]2[C:36](=[CH:35][CH:34]=1)[NH:26][N:25]=[CH:29]2
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2nnn[nH]2)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cl
Product: Nc1ccc2[nH]ncc2c1
Product: O=C(/C=C/c1cc(Cl)ccc1-n1cnnn1)N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2nnn[nH]2)c1
Yield: 49 %

Procedure:
(S)—N-(3-(1H-tetrazol-5-yl)phenyl)-2-amino-3-phenylpropanamide hydrochloride: The title compound was prepared in a similar manner described for Examples 3 and 31 using 3-(1H-tetrazol-5-yl)aniline in place of 5-aminoindazole (49% yield). LCMS m/z 309 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[C:14]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:50]([O:54][C:55]([N:57]([CH:70]([CH3:72])[CH3:71])[CH2:58][C@H:59]([C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=1)[C:60](O)=[O:61])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:22]2[CH2:23][CH2:24][N:25]([C:60](=[O:61])[C@@H:59]([C:63]3[CH:64]=[CH:65][C:66]([Cl:69])=[CH:67][CH:68]=3)[CH2:58][N:57]([CH:70]([CH3:72])[CH3:71])[C:55](=[O:56])[O:54][C:50]([CH3:53])([CH3:51])[CH3:52])[CH2:26][CH2:27]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1
Reactant: Brc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0687 mL, 0.394 mmol) was added to 5-bromo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.050 g, 0.0986 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0380 g, 0.118 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0337 g, 0.0986 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 3-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was again concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-(isopropylamino)propan-1-one dihydrochloride (0.030 g, 53%). MS APCI (+) m/z 507.2 detected.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].C(O)(=O)C.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18]>C(O)C>[F:18][C:17]([F:19])([F:20])[C:16]([F:25])([C:21]([F:22])([F:23])[F:24])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:1][C:2]#[N:3]
Reactant: N#C[S-]
Reactant: FC(F)(F)C(F)(CCCCCCBr)C(F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CSCCCCCCC(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 97 %

Procedure:
In accordance with scheme (45) above, 8-Bromo-1,1,1,2-tetrafluoro-2-trifluoromethyl-octane (20 grams) can be dissolved in 30 mL of ethanol containing 7.6 grams of potassium thiocyanate. Acetic acid (0.2 mL) can be added to form a mixture and the mixture heated to reflux for 4 hours. The mixture can be allowed to cool to room temperature overnight, concentrated under vacuum, and partitioned between methylene chloride (200 mL) and water (100 mL). The organic layer can be dried over magnesium sulfate, filtered, and concentrated under vacuum to afford 18.2 grams (97%) 1,1,1,2-tetrafluoro-8-thiocyanato-2-trifluoromethyl-octane by NMR analysis.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=3)[N:4]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Yield: 88 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.500 g, 1.54 mmol) in 15 mL of ethylene glycol dimethyl ether, was added 3-aminophenyl boronic acid (0.358 g, 2.31 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.178 g, 0.098 mmol), and potassium phosphate (1.63 g, 7.7 mmol). The reaction mixture was heated to reflux temperature of the solvent for 18 hours. The solvent was then removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The title compound was purified by column chromatography (SiO2, 6% MeOH in CH2Cl2) (0.457 g, 88% yield): ES-MS (m/z) 337 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2
Reactant: COc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)cc2c1NC(=O)CC2
Yield: 98.3 %

Procedure:
6-Nitro-8-methoxy-3,4-dihydrocarbostyril (2 g) and 5% palladium-carbon (0.2 g) were added in ethanol (50 ml) and catalytic reduction was conducted at a hydrogen gas pressure of 3 kg/cm2 for 1 hour. Then, the reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from benzene to give 1.7 g of 6-amino-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](O)=O)=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:12]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:17][CH:18]=1)[CH2:11][CH2:10][CH3:9]
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(-c2nc3ccccc3[nH]2)nc1
Reaction time: 1.5 h

Procedure:
0.6 g. of o-phenylenediamine, 1 g. of fusaric acid and 10 g. of polyphosphoric acid were heated at 200°-250° C. under a nitrogen gas current with stirring for 1.5 hours. The reaction mixture was diluted with 200 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 1.2 g. of colorless needles of the product(86% of theory) was obtained. M.P. 138.0°-139.0° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].Cl.[NH2:14][CH:15]1[C:27](=[O:28])[C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16]1>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16][CH:15]1[NH:14][C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: NC1CCc2cc3c(cc2C1=O)OCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CCc2cc3c(cc2C1=O)OCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 ml of triethylamine and 5.7 ml of propionyl chloride are added in succession to 17 g of dl-7-amino-2,3,6,7-tetrahydro-5H-naphtho[2,3-b]furan-8-one hydrochloride suspended in 170 ml of methylene chloride. After 2 hours' stirring at room temperature, the reaction mixture is washed with water, decanted and concentrated to dryness. 20 g of the desired compound are obtained.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)(=[O:31])=[O:30]
Reactant: CCCCCCCCc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(4-Octylphenyl)ethanol (53 g) and dichloromethane (500 mL) are charged into a 1 liter three-neck round bottom flask equipped with guard tube and addition funnel. Triethylamine (83.5 g) is added, the mixture is stirred for 30 minutes, then it is cooled to 0° C. Methanesulphonyl chloride (35.2 mL) is added drop-wise at 0° C. and the mass is stirred for 3 hours at room temperature. The mass is diluted with water (700 mL) and the organic layer is separated and the aqueous layer is extracted with dichloromethane (2×250 mL). The combined organic layers is washed with saturated sodium bicarbonate (500 mL) and brine solution (500 mL). The organic layer is separated, dried with sodium sulphate, and concentrated under vacuum to obtain the title compound. Yield: 70 g.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].P(Br)(Br)[Br:14]>CCOCC>[Br:14][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1ccc(CBr)c(OC)c1

Procedure:
A solution of 0.537 g of 1-hydroxymethyl-2,4-dimethoxybenzene in 5 ml of ether is cooled to -10° C., under a nitrogen atmosphere, and a solution of 0.1 ml of phosphorus tribromide in 2 ml of ether is added dropwise. The 1-bromomethyl-2,4-dimethoxybenzene thus obtained is stored in solution at -30° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[CH3:27])[N:18]=[N:19][CH:20]=1>>[ClH:14].[CH3:27][C:23]1[N:22]([CH2:21][C:17]2[N:18]=[N:19][CH:20]=[C:15]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[CH:16]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1nccn1Cc1cc(-c2cccc(C(F)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=319.4 (M+H+), was prepared from 3-trifluoromethylbenzeneboronic acid (commercially available) and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:18][CH2:17]3)=[C:11](I)[CH:10]=2)[C:5]([Cl:33])=[CH:4][N:3]=1.[CH:34]([C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[N:40][CH:41]=1)=[CH2:35]>>[NH2:42][C:38]1[CH:37]=[C:36](/[CH:34]=[CH:35]/[C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:33])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][C:12]=2[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[CH:41]=[N:40][CH:39]=1
Reactant: C=Cc1cncc(N)c1
Reactant: O=C(OCc1ccccc1)N1CCC(Nc2ccc(Nc3nc(Cl)ncc3Cl)cc2I)CC1
Product: Nc1cncc(/C=C/c2cc(Nc3nc(Cl)ncc3Cl)ccc2NC2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 75 %

Procedure:
The desired compound was prepared according to the procedure of Example B334, step G, using benzyl 4-({4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenyl}amino)piperidine-1-carboxylate and 5-vinylpyridin-3-amine as the starting materials in 75% yield. LCMS for C30H30Cl2N7O2 (M+H)+: m/z=590.2, 592.1.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]([CH3:14])[CH:12]([CH2:15][CH2:16][CH3:17])[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[NH:19][C:20]([C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:21].C(O)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:14][C@@H:13]1[C:8]([C:6]2[CH:5]=[CH:4][C:3]3[N:19]=[C:20]([C:22]4[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[O:21][C:2]=3[CH:7]=2)=[N:9][NH:10][C:11](=[O:18])[C@H:12]1[CH2:15][CH2:16][CH3:17]
Reactant: CCCC1C(=O)NN=C(c2ccc(NC(=O)c3cccn3C)c(O)c2)C1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCC[C@@H]1C(=O)NN=C(c2ccc3nc(-c4cccn4C)oc3c2)[C@H]1C
Temperature: 200 °C
Reaction time: 1 h

Procedure:
150 mg (407 mmol) 1-methyl-1H-pyrrole-2-carboxylic acid[2-hydroxy-4-(4-methyl-6-oxo-5-propyl-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-amide are placed in 5 mL dioxane. 300 μL (5.19 mmol) acetic acid and 140 mg (814 μmol) p-toluenesulphonic acid monohydrate are added and the mixture is stirred for 60 min in the microwave at 200° C. The reaction mixture is extracted successively with 10% sodium carbonate solution, 1% acetic acid, 10% sodium carbonate solution and saline solution. Then the solv. of the organic phase is eliminated i.V. and the residue is purified through silica gel. (Cyclohexane/EA) The solv. of the corresponding fractions is eliminated i.V. and the residue is crystallised with diethyl ether/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[ClH:17]>C(C(C)=O)C(C)C.O>[Cl:17][CH:12]([CH2:11][C:10]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)=[O:16])[C:13]([OH:15])=[O:14]
Reactant: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Reactant: Cl
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1c(Cl)cc(C(=O)CC(Cl)C(=O)O)cc1Cl
Yield: 100 %

Procedure:
A suspension of 5.18 g (0.02 mole) of 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid, prepared as described in Example 1(b), in 50 ml of methyl isobutyl ketone was saturated with dry hydrogen chloride gas, by blowing the gas through the suspension whilst ice-cooling and stirring it. The mixture was then stirred at room temperature for a further 1 hour, after which it was diluted with 30 ml of cold water and extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous sodium sulphate, after which the solvent was distilled off and the residue was washed with a small amount of hexane and then dried, giving 5.91 g (yield 100%) of the desired 2-chloro-4-(3,5-dichloro-4-methylphenyl)-4-oxobutyric acid, melting at 129°-132° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[C:7]([C:9]1[N:10]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:11](=[O:33])[N:12]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)[C:13]=1[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)#[N:8].[CH3:45][N:46]([CH:48]=[O:49])C>>[C:7]([C:9]1[N:10]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:11](=[O:33])[N:12]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)[C:13]=1[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C@H:9]2[CH2:13][CH2:14][C@H:45]([N:46]3[C:48](=[O:49])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:1]3=[O:4])[CH2:7]2)[CH:15]=1)#[N:8]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cn2c(C#N)c(-c3c[nH]c4ccccc34)n(-c3cn(C)c4ccccc34)c2=O)c(OC)c1
Reactant: CN(C)C=O
Agent: [Cs+]
Product: COc1ccc(Cn2c(C#N)c(-c3cn([C@H]4CC[C@H](N5C(=O)c6ccccc6C5=O)C4)c4ccccc34)n(-c3cn(C)c4ccccc34)c2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Two portions of totally 0.72 g (2.33 mmol) of 1(R)-O-Methanesulfonyl-3(S)-phthalimido-cyclopentane and two portions of totally 1.33 g (4.05 mmol) of cesium carbonate were added within 1.5 hours, to a stirred solution of 0.26 g (0.51 mmol) 4-cyano-3-(2,4-dimethoxybenzyl)-5-(3-indolyl)-1-(1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one in 3 ml of dry DMF at 70° C. After an additional 2 hours, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated brine. The aqeous phase was back-extracted with ethyl acetate and the combined organic extracts washed three times with saturated brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography on SiO2 (EtOAc-heptane, 3:2). The fractions containing the desired product were combined and crystallized (chloroform:ether) to give the sub-title compound (0.20 g, 54%).
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[CH:40]=[CH:39][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:38])=[CH:10][CH:9]=1)(=O)C.Cl>CO.C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]2=[O:38])=[CH:39][CH:40]=1
Reactant: CC(=O)Oc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.99 g of a 28% w/v methanolic solution of sodium methoxide in 10 ml of methanol was added dropwise, whilst ice-cooling, to a solution of 7.86 g of 5-(4-acetoxybenzyl)-3-triphenylmethyl-thiazolidine-2,4-dione [prepared as described in step (c) above] in 70 ml of toluene, and the resulting mixture Was stirred at room temperature for 1 hour, after which it was allowed to stand overnight at the same temperature. The pH of the reaction mixture was then adjusted to a value of 4 by the addition of 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the crystals which appeared in the residue were collected, washed with hexane and dried, to give the title compound.
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1.C1C[O:40][CH2:39]C1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:7][C:6]1([CH3:8])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=[C:2]1[C:39]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:40]
Reactant: C1COCCN1
Reactant: C1CCOC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1C(=O)N1CCOCC1
Temperature: 108 °C

Procedure:
A pressure tube was charged with (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (60 mg, 0.19 mmol), morpholine (48 mg, 0.56 mmol), Mo(CO)6 (49 mg, 0.19 mmol), palladium(II) acetate (4.0 mg, 0.018 mmol), DBU (85 mg, 0.56 mmol) and anhydrous THF (3 mL). The tube was immediately capped under nitrogen and heated in 108° C. bath for 1 hour. After cooling, the reaction mixture was filtered through a short celite pad. The filtrate was concentrated and purified by silica gel flash chromatography (5-10% MeOH in CHCl3) to give (3E)-3-[5,5-dimethyl-4-(morpholin-4-ylcarbonyl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 39 mg, 55%.