Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[NH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:8]=2[C:7]([O:17][CH3:18])=[CH:6][CH:5]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:3][C:4]1[C:12]2[N:11]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:10]([C:13]([F:14])([F:15])[F:16])=[N:9][C:8]=2[C:7]([O:17][CH3:18])=[CH:6][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(Br)c2[nH]c(C(F)(F)F)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(C(F)(F)F)nc3c(OC)ccc(Br)c32)cc1
Temperature: 90 °C

Procedure:
Sodium hydride (0.16 g; 60% dispersion in oil) was added to a solution of 4-bromo-7-methoxy-2-trifluoromethylbenzimidazole (1.0 g) in N,N-dimethylformamide (20 ml). The mixture was stirred at room temperature for 10 minutes before addition of 4-methoxybenzyl chloride (0.56 ml) and catalytic tetrabutylammonium iodide. The reaction was heated at 90° C. for 6 h, then poured into water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with water (100 ml) and brine (50 ml), dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 33% ethyl acetate in hexane to afford the title compound as a white solid (0.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1Cl
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Borane-methyl sulfide complex (10 M; 10 mL, 100 mmol) was added to a solution of 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 11.98 g, 55.8 mmol) in tetrahydrofuran (100 mL). The solution was heated at reflux for 2 h and then allowed to stand at room temperature overnight. It was poured into water and ethyl acetate (200 mL each). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), filtered, and evaporated to give 2-chloro-4-(hydroxymethyl)benzoic acid, methyl ester (11.09 g, 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([C:15](SC)=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:17]#[N:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:33][CH:34]([NH2:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C>C(#N)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([C:15]([NH:39][CH:34]([CH3:33])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:17]#[N:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NC(=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Temperature: 80 °C
Reaction time: 68 h
Yield: 43.1 %

Procedure:
To a solution of 3-[N-(3,5-Bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.58 mmol) in dry acetonitrile (2 ml) was added 1,2,2-trimethylpropylamine (0.12 g) and dry triethylamine (89 μl). The mixture was stirred for 68 h at 80° C. under nitrogen. The reaction mixture was concentrated. Purification by flash chromatography using ethyl acetate/heptane 1:4 and 1:3 as eluent gave a syrup (142 mg) which was crystallised in ethanol/water to give 110 mg (33%) of the title compound. Mp 151.5-154° C. 1H NMR (300 MHz, CDCl3): δ=0.9 (s, 9H), 1.10 (d, 3H), 3.10 (m, 1H), 3.30 (s, 3H), 7.10 (s, 2H), 7.46 (s, 1H), 7.55 (d, 2H), 7.85 (d, 2H), 8.1 (br d, 1H); MA calc for C24H24ClF6N3O2S: C, 50.75%; H, 4.26%; N, 7.40%; Cl, 6.24%. Found: C, 50.79%; H, 4.28%; N, 7.24%; Cl, 6.19%.
Reaction SMILES: C(O)(=O)C=CC(O)=O.[NH:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].[O:20]1[CH:22]2[CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[CH:21]12.[OH-].[Na+]>O>[N:9]1([C@@H:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][C@H:22]2[OH:20])[CH2:13][CH:12]=[CH:11][CH2:10]1
Reactant: C1=CCNC1
Reactant: c1ccc2c(c1)CC1OC21
Agent: O=C(O)C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O[C@@H]1Cc2ccccc2[C@H]1N1CC=CC1
Temperature: 70 °C

Procedure:
A solution of 10 g of 2,5-dihydro-1H-pyrrole (2-butenedioate) and 6 g of sodium carbonate in 20 ml of water was added at 20° C. to a solution of 7.4 g of 1a,6a-dihydro-6H-indeno [1,2-b] oxirene in 5 ml of water and the mixture was heated at 70° C. for 4 hours and allowed to cool to room temperature. 15 ml of sodium hydroxide solution were added and the mixture was extracted with ethyl acetate. The organic phase was dried and evaporated to dryness under reduced pressure to obtain 8.62 g of raw product. The latter was chromatographed over silica and eluted with a 98-2 ethyl acetate-triethylamine mixtures to obtain the desired product.
Reaction SMILES: OC1C=CC(/C=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.C(I)C>>[CH2:10]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH3:9]
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Solvent: CCI
Product: CCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and ethyl iodide to produce the above.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][C:16](=[O:31])[N:17]([CH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:21]=1[S:27][CH:28]([CH3:30])[CH3:29])[CH3:18])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl.O>[C:5]1([O:4][C:2](=[O:3])[NH:26][C:24]2[CH:23]=[CH:22][C:21]([S:27][CH:28]([CH3:30])[CH3:29])=[C:20]([CH2:19][N:17]([C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:31])[CH3:18])[CH:25]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)Sc1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)Sc1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Phenyl chloroformate (0.204 mL, 1.62 mmol) was added dropwise to a solution of 16E (0.48 g, 1.55 mmol) in pyridine (0.193 mL, 2.38 mmol) and DCM (3.5 mL) at 0° C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to give 16F (0.609 g, 91%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][OH:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].O>ClCCl>[CH3:51][S:52]([O:32][CH2:31][C:18]1[CH:19]=[N:20][C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[C:16]([C:11]2[N:10]=[C:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=3)[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[N:14]=[C:13]([CH3:15])[N:12]=2)[CH:17]=1)(=[O:54])=[O:53]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CO)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(COS(C)(=O)=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A suspension of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methanol (1.0 g, 1.725 mmol) in dichloromethane (25 mL, 1.725 mmol) was stirred at 0° C. and treated in one portion with triethylamine (1.092 mL, 7.85 mmol) and methanesulfonyl chloride (0.497 mL, 6.42 mmol). The resulting solution was stirred under nitrogen for 30 min. The reaction mixture was diluted with dichloromethane (10 mL) and treated with water (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×50 mL) and dried over Na2SO4, filtered and concentrated in vacuo to give (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl methanesulfonate (0.935 g, 1.422 mmol, 82% yield). m/z (ESI, +ve ion) 658.2 (M+H)+
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:36]([CH:37]=O)=[C:30]2[CH:29]=1>CO.C1(C)C=CC=CC=1>[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:36]([CH:37]=[CH:2][O:3][CH3:4])=[C:30]2[CH:29]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2C=O)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC=Cc1c(-c2ccc(OC)cc2)nn2ccc(Br)cc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of methoxymethyltriphenylphosphonium chloride (298 mg, 0.87 mmol) in methanol (3 ml) was added a solution of sodium methoxide 25% wt. in methanol (0.20 ml, 0.87 mmol). The resulting white suspension was stirred at 20° C. for 30 minutes. The mixture was concentrated to dryness and azeotroped with toluene (6 ml) twice. The resulting solid was suspended in toluene (2 ml). A suspension of 5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (180 mg, 0.54 mmol) in toluene (4 ml) was added to the ylide suspension. Heated the resulting mixture to 85-90° C. and stirred for 1.25 h. Cooled to 20° C. and stirred 17.5 h. In a separate flask, to a solution of methoxymethyltriphenylphosphonium chloride (298 mg, 0.87 mmol) in methanol (3 ml) was added a solution of sodium methoxide 25% wt. in methanol (0.20 ml, 0.87 mmol). The resulting white suspension was stirred for 30 minutes, concentrated and azeotroped with toluene (6 ml) twice. The resulting solid was suspended in toluene (2 ml) and added to the reaction mixture which was heated to 90° C. for 2 h at which time monitoring the reaction by LC indicated all starting material had converted to the title compound. to the mixture was cooled to 20° C., filtered through a 0.45 μm filter and rinsed with toluene (2 mL). The filtrate was concentrated under reduced pressure to afford a residue that was purified by automated ISCO chromatography (ethyl acetate/hexane; 25/75). The title compound was obtained as a bright yellow solid (168 mg, 86%). LCMS m/z 359.0 (M+H)+, ret. time=2.31 (cis isomer) and 2.34 min (trans isomer).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[S:24][CH:23]=[N:22][CH:21]=1.C(NC(C)C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH4+].[Cl-]>O1CCOCC1.[Cu]I>[C:1]([N:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: C#CCOCCN(C(=O)C(=O)OCC)C(C)(C)C
Reactant: Brc1cncs1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(=O)N(CCOCC#Cc1cncs1)C(C)(C)C
Yield: 87 %

Procedure:
A solution of 390 mg of 11d, 290 mg of 5-bromothiazole, 400 μl of diisopropyl amine, 40 mg of PdCl2(PheCN)2, 20 mg of CuI and 300 μl of a 1M solution of tri-tert-butyl phosphine (in toluene) in 4 ml of degassed dioxane, was stirred under N2 for 16 hr. The mixture was poured into 20 ml of 5% aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was dried, concentrated and the product was chromatographed over silica gel, using a gradient of heptane/ethyl acetate, to give 450 mg of 11e as a colorless oil; Rf 0.40 (heptane/ethyl acetate 1/1);
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:20]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Product: Cc1cn(CCS(=O)(=O)c2ccc(C#N)cc2)cn1

Procedure:
270 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with 4-methylimidazole to yield 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzonitrile. 320 mg of 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzoic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19](OCC)=[O:20])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:7]1([CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:24][CH:25]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(OC(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of LAH (3.2 g, 0.084 mmol) in THF (400 ml) under N2 was added dropwise a solution of 1-3 (21 g, 0.063 mol) in THF (100 ml). After stirring overnight at room temperature, saturated Na2SO4 was added to the reaction until a white suspension was observed. The mixture was filtered and the filtrate was combined with H2O and CHCl3, separated, and extracted further with CHCl3 (2×). The combined organic extracts were dried, filtered and concentrated to dryness. The residue was triturated with hexane to yield 1-4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[Cu](C#N)[C:14]#[N:15].C(OCC)(=O)C.CCCCCC>CN(C=O)C.[Hg]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:14]#[N:15]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: N#C[Cu]C#N
Agent: [Hg]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: N#Cc1cc(C(F)(F)F)ccc1N
Temperature: 100 °C
Yield: 105 %

Procedure:
In a 2-liter flask equipped with a septum inlet, magnetic stirring bar, and condenser leading to a mercury bubbler was placed 100 g (0.348 mol) of 4-amino-3-iodobenzotrifluoride in 1 liter DMF. To this reaction flask with stirring was added 37.4 g (0.416 mol) of copper cyanide and the contents were heated to 100° C. under nitrogen for fourteen hours. Afterwards, TLC analysis revealed minor starting material (20/80) ethyl acetate/hexane. The contents were cooled to 40° C. and filtered through a pad of Celite. The solids were washed with ether and the filtrate transferred to a separatory funnel and washed with about 5% aqueous ammonium hydroxide. The aqueous layer was back-extracted with ether and the organics were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated to yield a black oil. The oil was chromatographed on a Biotage 75L cartridge with ethyl acetate/hexane to obtain 68 g 2-amino-5-(trifluoromethyl)benzonitrile as a black solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1>C(=S)=S>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: BrBr
Reactant: COc1ccc(O)cc1
Solvent: S=C=S
Product: COc1ccc(O)c(Br)c1
Yield: 57.1 %

Procedure:
A solution of 2.6 mL (100 mmol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes to a solution of 12.4 gm (100 mMol) 4-methoxyphenol in 20 mL carbon disulfide at 0° C. After 30 minutes an additional 1 mL of bromine in 10 mL carbon disulfide are added dropwise. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in diethyl ether. This solution was washed sequentially with 100 mL water and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 11.6 gm (57%) of the desired compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[Cl-].[NH4+].C(O)C.CO>[Fe].O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[NH2:8]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2F)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: Nc1ccc(OCc2ccccc2F)c(Cl)c1
Temperature: 68 °C

Procedure:
In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, —under nitrogen flow—25.0 g of 2-Chloro-[(2-fluorobenzyl)oxy]-4-nitrobenzene of formula (V), 14.9 g of powder iron (MW: 55.85, 3.0 mol. equiv.), 42.7 g of ammonium chloride (MW: 53.49, 9.0 mol. equiv.), 350 mL of Ethanol denatured with Methanol and 85 mL of purified water were introduced. The reaction mixture was stirred at reflux temperature (68° C.) for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:37][C:38]1[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=2)=[CH:4][CH:3]=1
Reactant: Cn1ccnc1CCl
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4nccn4C)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.9 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was stirred for 30 min. 2-(Chloromethyl)-1-methyl-1H-imidazole (23.7 mg, 181 μmol) was added and the mixture warmed to room temperature. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 24 g Analogix column, dichloromethane) to give 2-(6-chloro-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (106 mg) as a yellow solid. MS (M+H)+=579.
Reaction SMILES: CN(C(C1C(I)=C(N[C:18]([CH2:20][O:21][CH3:22])=[O:19])C(I)=C(C(NCC(O)CO)=O)C=1I)=O)CC(O)CO.[NH2:33][C:34]1[C:35]([I:48])=[C:36]([C:45]([Cl:47])=[O:46])[C:37]([I:44])=[C:38]([C:42]=1[I:43])[C:39]([Cl:41])=[O:40].COCC(Cl)=O>CN(C)C=O>[CH3:22][O:21][CH2:20][C:18]([NH:33][C:34]1[C:42]([I:43])=[C:38]([C:39]([Cl:41])=[O:40])[C:37]([I:44])=[C:36]([C:35]=1[I:48])[C:45]([Cl:47])=[O:46])=[O:19]
Reactant: COCC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Agent: COCC(=O)Cl
Solvent: CN(C)C=O
Product: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I

Procedure:
According to the above reaction scheme 1, iopromide of formula (1) is prepared through the steps of reacting 5-amino-2,4,6-triiodoisophthalic acid dichloride of formula (2) with methoxyacetyl chloride in dimethylformamide solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride of formula (3), and reacting the compound of formula (3) with 2,3-dihydroxypropylamine and in turn with 2,3-dihydroxy-N-methylpropylamine in dimethylformamide solvent in the presence of basic material.
Reaction SMILES: NC1C(C(O)=O)=CC(Cl)=NC=1.C(OC(=O)C)(=O)C.[Cl:19][C:20]1[N:38]=[CH:37][C:23]2[N:24]=[C:25]([CH3:36])[N:26]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:27](=[O:28])[C:22]=2[CH:21]=1.Br.Br[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[N:38]=[CH:37][C:23]2[N:24]=[C:25]([CH3:36])[N:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:33][CH:34]=3)[C:27](=[O:28])[C:22]=2[CH:21]=1
Reactant: BrCCCN1CCCCC1
Reactant: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(O)cc1
Agent: Br
Agent: Nc1cnc(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Using 5-amino-4-carboxy-2-chloropyridine and acetic anhydride as starting materials, 6-chloro-2-methyl-3-(4-hydroxyphenyl)pyrido[3,4-d]pyrimidin-4(3H)-one synthesized according to Example 1-(1) and -(2) (52 mg, 0.18 mmol), 1-(3-bromopropyl)piperidine hydrobromide (78 mg, 0.27 mmol) and potassium carbonate (100 mg, 0.72 mmol) were mixed in dimethylformamide (1 mL) and stirred at 80° C. for 1 hour. The solvent was distilled off under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with distilled water, and dried with anhydrous sodium sulfate. The title compound (45 mg, 60%) was obtained as colorless crystals by purifying with silica gel column chromatography (chloroform/methanol=30/1) and recrystallizing (ethanol).