Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[NH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:26]1([CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:18][C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:8])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiidmidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days. The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][C:18]([NH:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:19][CH:20]=3)[N:15](COCC[Si](C)(C)C)[N:14]=2)[CH:10]=[CH:9][CH:8]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][C:18]([NH:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[N:19][CH:20]=3)[NH:15][N:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3cccc(Cl)c3)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (110 mg, 0.185 mmol) in dichloromethane (2.5 mL) was added TFA (2.5 mL). The reaction mixture was stirred for 2 hours at room temperature. The pH of the mixture was adjusted to about 8 with saturated NaHCO3 solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane:MeOH, 20:1), then further purified by prep-HPLC to give {3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-(2-morpholin-4-yl-ethyl)-amine. (Yield 23 mg, 26%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1B(O)O>>[CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:18]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: OB(O)c1ccc2ccccc2c1
Product: c1ccc2cc(-c3cccc4cc[nH]c34)ccc2c1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-naphthylboronic acid: ESMS m/e: 244.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](O)=[O:15])=[CH:10]2)[CH3:3].O[N:29]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[OH-].[NH4+]>O.CN(C)C=O>[CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:29])=[O:15])=[CH:10]2)[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A mixture of 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (4.0 g), 1-hydroxybenzotriazole (2.07 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.93 g) and N,N-dimethylformamide (50 mL) was stirred at 50° C. for 30 min, and then cooled to room temperature. An aqueous solution of ammonium hydroxide (10%, 10 mL) was added to the mixture. The whole was stirred at room temperature for 12 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound (2.26 g, 57%) as brown crystals. MS 390 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][CH2:12][CH2:11][N:10]=2)=[CH:5][CH:4]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][C:11]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:12][N:13]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(C2=NCCN=C2c2ccc(OC)cc2)cc1
Reactant: O=Cc1ccccc1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ncc(Cc3ccccc3)nc2-c2ccc(OC)cc2)cc1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-bis(p-methoxyphenyl)-5,6-dihydropyrazine and benzaldehyde. 2,3-Bis(p-methoxyphenyl)-5-benzylpyrazine was obtained as colorless prisms, m.p. 107°-109° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (X).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[N:15]=[CH:14]2)[NH:6][N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([NH:39][CH2:40][CH3:41])[CH:32]=1.CNCCNC>O1CCOCC1.[Cu](I)I.O.C(Cl)(Cl)Cl>[CH2:40]([NH:39][C:33]1[CH:32]=[C:31]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][C:11]([N:13]4[CH:17]=[C:16]([C:18]5[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=5)[N:15]=[CH:14]4)=[C:12]3[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:38]=[CH:37][C:34]=1[C:35]#[N:36])[CH3:41]
Reactant: CC(C)c1n[nH]c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Reactant: CCNc1cc(Br)ccc1C#N
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: CCNc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cnn(C)c5)c4)ccnc32)ccc1C#N
Temperature: 150 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
Compound (100b) (1.00 g), copper iodide (0.248 g), cesium carbonate (2.12 g), and 4-bromo-2-(ethylamino)benzonitrile (0.932 g) were suspended in 1,4-dioxane (10 mL), and N,N′-dimethylethylenediamine (0.560 mL) was added to the suspension, followed by stirring at 150° C. for 20 hr. The reaction solution was distributed between chloroform and water. The organic layer was washed with a 2 N aqueous sodium hydroxide solution and dried over magnesium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (1.13 g, 77%) as a white solid. 2-(Ethylamino)-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.700 g) was dissolved in DMSO (10 mL), and a 30% hydrogen peroxide solution (0.310 mL) and a 4 N aqueous sodium hydroxide solution (1.16 mL) were added to the resulting solution, followed by stirring at room temperature for 10 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (109) (0.655 g, 90%) as a white solid.
Reaction SMILES: [CH2:1]([NH:20][C:21]1[CH:31]=[CH:30][C:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCC.C(NC1C=CC(CCC(O)=O)=CC=1)CCCCCCCCCCCCC.C(NC1C=CC(CCC(O)=O)=CC=1)CCCCCCC.CC(NC1C=CC(CCC(O)=O)=CC=1)CCCCCCCCCCCCCC.CC(C)CCCCCCCCCCCCCNC1C=CC(CCC(O)=O)=CC=1.C(NC1C=CC(CCC(O)=O)=CC=1)CCCCCCCCC>>[CH2:1]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:30][CH:31]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Agent: CC(C)CCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Agent: CCCCCCCCCCCCCCC(C)Nc1ccc(CCC(=O)O)cc1
Agent: CCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1

Procedure:
Similarly prepared by hydrolysis of the corresponding ester are 4-(nonadecylamino)hydrocinnamic acid, 4-(tetradecylamino)hydrocinnamic acid, 4-(octylamino)hydrocinnamic acid, 4-[(1-methylpentadecyl)amino]hydrocinnamic acid, 4-[(14-methylpentadecyl)amino]hydrocinnamic acid, and 4-(decylamino)hydrocinnamic acid.
Reaction SMILES: [N:1]1[N:2]2[CH2:8][CH2:7][CH2:6][C:3]2=[CH:4][CH:5]=1.C([O-])(=O)C.[Na+].[Br:14]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:14][C:4]1[CH:5]=[N:1][N:2]2[CH2:8][CH2:7][CH2:6][C:3]=12
Reactant: BrBr
Reactant: c1cc2n(n1)CCC2
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnn2c1CCC2
Reaction time: 0.17 h

Procedure:
To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (47.2 g, 437 mmol) and sodium acetate (36.2 g, 440 mmol) in acetic acid (750 mL) at 0° C. was added bromine (22.4 mL, 435 mmol). After 10 minutes, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (5×200 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to afford 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:19][C:20]([NH2:22])=[NH:21]>CO>[NH2:21][C:20]([NH2:22])=[N:19][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[CH:11][C:2]=1[CH3:1]
Reactant: CCOc1cc(C)c(C(=O)OC)cc1S(C)(=O)=O
Reactant: N=C(N)N
Solvent: CO
Product: CCOc1cc(C)c(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
A solution of 1.4 g of methyl 2-methyl-4-ethoxy-5-methylsulfonylbenzoate (obtainable by reaction of 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodium ethoxide and subsequent esterification) and 1.5 g of guanidine in 50 ml of methanol is boiled for five hours and the solvent is then removed. The residue is treated with water, and the crystallizate which remains is filtered off with suction and treated with dilute sodium hydroxide solution. The solid residue is filtered off and recrystallized from ethanol, and N-diaminomethylene-2-methyl-4-ethoxy-5-methylsulfonylbenzamide is obtained, m.p. 201°-203°.
Reaction SMILES: [CH:1]1([C@@H:4]2[CH2:9][CH2:8][N:7](C(OCC3C=CC=CC=3)=O)[CH2:6][C@H:5]2[NH:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C@@H:4]2[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[NH:20][P:21](=[O:22])([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CC1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1C1CC1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of trans-benzyl 4-cyclopropyl-3-(diethoxyphosphorylamino)piperidine-1-carboxylate (1.84 g, 4.48 mmol) and 10% Pd/C (0.48 g, 0.45 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-cyclopropylpiperidin-3-ylphosphoramidate (1.24 g, 100%) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8]O)[O:6][CH:7]=1.OS(O)(=O)=O.[BrH:16].[OH-].[Na+]>>[Br:16][CH2:8][C:5]1[O:6][CH:7]=[C:2]([OH:1])[C:3](=[O:10])[CH:4]=1
Reactant: Br
Reactant: O=c1cc(CO)occ1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(CBr)occ1O
Temperature: 4 °C
Reaction time: 18.5 h

Procedure:
In a 250 mL round-bottomed flask 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (10.0 g, 70.36 mmol) was added to concentrated H2SO4 (30 mL). The solution was cooled to 4° C. and bromohydric acid (40 mL) was added dropwise for 1.5 h. HBr vapors were trapped using a NaOH 0.5 N solution. The reaction was stirred at 70° C. for 18.5 h. After cooling ice (220 g) was added with continuous stirring for for 1.5 h to obtain a white precipitate. The solid was filtered off and dissolved in ethyl acetate and the solution was dried with MgSO4, filtered and evaporated. 2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one 21 was obtained as a pale yellow solid (9.1 g, 63% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)O1.I[C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O.C(O)C>[CH3:39][C:38]1[C:20]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:21][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])=[CH:36][CH:37]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
4,4,5,5-Tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborolane (1.4 g, 5.6 mmol) was mixed with 3-iodo-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide (2.00 g, 4.94 mmol), potassium carbonate (1.4 g, 9.9 mmol), toluene (40 mL), ethanol (6.0 mL), and water (4.0 mL). The mixture was degassed and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.24 mmol) was added. The resulting mixture was heated to reflux for 16 hours. The reaction was then cooled and was extracted with ethyl acetate. The organic extracts were washed with water, brine, dried (Na2SO4) and concentrated. The product was purified by flash column chromatography, eluting with a gradient of 20-50% ethyl acetate in hexanes (1.92 g, 91%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[C:12]([F:19])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[K+].O.Cl[CH2:27][C:28]([C:30]1[N:31]([CH:35]([CH3:37])[CH3:36])[N:32]=[CH:33][N:34]=1)=O>C1COCC1.[Na+].[Cl-]>[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[NH:16][CH:27]=[C:28]([C:30]3[N:31]([CH:35]([CH3:37])[CH3:36])[N:32]=[CH:33][N:34]=3)[N:15]=2)=[C:12]([F:19])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)c1ccc(OCc2ccccc2)cc1F
Reactant: CC(C)n1ncnc1C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(OCc3ccccc3)cc2F)n1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 4-benzyloxy-2-fluoro-benzamidine hydrochloride (74.5 g, 0.265 mol) in THF (705 mL) was treated with potassium hydrogen carbonate (106 g, 1.06 mol) and H2O (150 mL). The resultant mixture was heated to reflux to give a white suspension. Whilst maintaining gentle reflux and mechanical stirring (500 rpm) a solution of 2-chloro-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (50 g, 0.265 mol) was added dropwise over 40 min. The resultant suspension gradually dissolved giving a dark red mixture that was refluxed for 18 h. The mixture was cooled to RT, diluted with saturated aqueous NaCl solution (500 mL) and extracted with EtOAc (500 mL). The organic extract was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to give a pink solid The solid was triturated in a mixture of MTBE/pentane (1:1 by volume, 300 mL), collected by filtration, washed with a MTBE/pentane mixture and dried in vacuo to give 5-[2-(4-Benzyloxy-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole as a pale pink solid (84 g, 84%). 1H NMR (400 MHz, d6-DMSO): 7.95-7.93 (2H, m), 7.76 (1H, s), 7.44-7.42 (5H, m), 7.12 (1H, dd, J=13.10, 2.52 Hz), 7.03 (1H, dd, J=8.74, 2.47 Hz), 5.90 (1H, m), 5.21 (2H, s), 1.46 (6H, d, J=6.60 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:32])[C:13]([C:15]1[C:23]3[C:18](=[C:19]([N:26]4[CH:30]=[N:29][C:28]([CH3:31])=[N:27]4)[N:20]=[CH:21][C:22]=3[O:24][CH3:25])[NH:17][CH:16]=1)=[O:14])[CH2:7]2.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:25][O:24][C:22]1[CH:21]=[N:20][C:19]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:18]2[NH:17][CH:16]=[C:15]([C:13](=[O:14])[C:12]([N:6]3[CH2:5][CH2:4][C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:7]3)=[O:32])[C:23]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(Br)cccc4C3)c12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccc4)C3)c12
Temperature: 85 °C
Yield: 48.5 %

Procedure:
To a sealable vial containing 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (0.05 g, 0.101 mmol) was added phenylboronic acid (0.018 g, 0.151 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.016 g, 0.020 mmol), K2CO3 (0.06 g, 0.434 mmol), 1,4-dioxane (2 mL), and water (0.5 mL). The vessel was flushed with N2, then the vial was sealed and heated to 85° C. After 2 h the mixture was cooled to rt, and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with dichloromethane (3×30 mL). The organic solution was dried with Na2SO4, the drying agent was removed by filtration, and the organic solution was concentrated under reduced pressure. The residue was purified by prep HPLC. Some impurities were still present by LC/MS, so the mixture was further purified by flash chromatography using a 0-5% MeOH in dichloromethane gradient. The expected product, 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (0.024 g, 0.049 mmol, 48.3% yield), was isolated as an off-white solid. LC/MS: m/z 493.25 (M+H)+, 2.12 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 11.01 (br. s., 1H) 9.14 (s, 1H) 8.19-8.27 (m, 1H) 7.67-7.72 (m, 1H) 7.01-7.50 (m, 8H) 4.74-5.00 (m, 2H) 3.67-3.87 (m, 5H) 2.79-2.98 (m, 2H) 2.55-2.61 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([NH2:14])=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1.[CH3:26][O:27][CH2:28][CH2:29]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[C:10]([O:11][CH2:29][CH2:28][O:27][CH3:26])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([NH2:14])=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: COCCO
Reactant: CS(=O)(=O)c1ccc(Oc2cc3cc(C(N)=O)[nH]c3c(O)c2F)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
A mixture of 6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.98 g), 2-methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.35 g) in tetrahydrofuran (130 ml) was stirred at 50° C. for 6 h under argon atmosphere. To the mixture were added 2-methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.35 g) and the mixture was stirred at 50° C. for 15 h under argon atmosphere. Furthermore, 2-methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.35 g) were added to the mixture. After stirred at 50° C. for 18 h under argon atmosphere, the mixture was concentrated in vacuo. The resulting insoluble materials were filtered off and the filtrate was concentrated in vacuo. The residue was purified by basic silica gel chromatography (ethyl acetate:hexane=30:70 to 100:0, volume ratio) to give the title compound (0.61 g, 54%) as a pale pink amorphous solid. MS 424 (MH+).
Reaction SMILES: [CH:1](/[CH:9]([S:19]([CH:22](/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=1)(=[O:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.NN.[H][H].[O-]S(S([O-])=O)=O.[Na+].[Na+]>[Pd]>[CH:1](/[CH:9]([S:19]([CH:22](/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)(=[O:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(C(/C=C/c2ccccc2)S(=O)(=O)C(/C=C/c2ccccc2)c2cccc([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Product: Nc1cccc(C(/C=C/c2ccccc2)S(=O)(=O)C(/C=C/c2ccccc2)c2cccc(N)c2)c1

Procedure:
According to the Scheme 1 below, the benzyl thioacetic acid C is formed by the reaction of sodium thioglycollate and a benzyl halide B. The benzyl thioacetic acid C is then oxidized with 30% hydrogen peroxide to give a corresponding benzylsulfonyl acetic acid D. Condensation of the benzylsulfonyl acetic acid D with an aromatic aldehyde E via a Knoevenagel reaction in the presence of benzylamine and glacial acetic acid yields the desired (E)-styryl-3-nitrobenzylsulfone F. The (E)-styryl-3-nitrobenzylsulfone F is then reduced via either palladium catalyzed hydrogenation with hydrazine hydrate as the hydrogen source or with Na2S2O4, and subsequently alkylated to give the desired (E)-styryl-3-aminobenzylsulfone IIIa.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:22](OCC)(=[O:25])[CH:23]=[CH2:24]>CCO.C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:24][CH2:23][C:22](=[O:25])[NH:17]2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)OCC
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCN(c2ccc(OCc3ccccc3)cc2)N1
Temperature: 85 °C

Procedure:
To a mixture of 2.5 g of 4-benzyloxyphenylhydrazine HCl and sodium ethoxide (1.6 g) in 10 ml of EtOH and 10 ml of toluene are added 1.08 of ethyl acrylate at room temperature. The reaction mixture is then heated at 85° C. overnight. The reaction mixture is evaporated to dryness under vacuum and water added to the residue and the pH adjusted to pH 6 by 1N-HCl solution. Extraction with ethyl acetate and drying the organic solution and evaporating to dryness yields 2.8 g of crude product. Purification by dry column chromatography gives 0.3 g of product; mp. 130°-134° C.