Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].CN(C=O)C.[Cl:21]N1C(=O)CCC1=O>O>[Cl:21][C:8]1[CH:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a mixture of methyl-(2-nitro-4-trifluoromethylphenyl)-amine (4.40 g) and DMF (20 ml), N-chlorosuccinimide (3.67 g) was added under ice-cooling, and stirred for 3 hours. The mixture was heated to room temperature, and allowed to stand. Water was poured thereinto under ice-cooling, and then the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 3.96 g of (2-chloro-6-nitro-4-trifluoromethylphenyl)-methylamine.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.C1COCC1>[Br:1][C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[N:7]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C)c2c(c1Br)c1ccsc1c(=O)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a suspension of 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (2.2 g, 6.8 mmol) in a mixture of DMF (15 mL) and THF (15 mL) at 0° C. was added sodium hydride (60%, 0.54 g, 13.6 mmol). The reaction mixture was stirred at 0° C. for 30 min before (2-(chloromethoxy)ethyl)trimethylsilane (3.4 g, 20 mmol) was added. The resulting mixture was stirred at rt overnight and then poured into ice-water (50 mL). The resulting precipitate was filtered and purified by column chromatography (silica, heptane/ethyl acetate) to afford the desired product (2.7 g, 87%) as a light yellow solid: ESI MS m/z 454 [C19H24BrNO3SSi+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=[N+]=[N-].[H][H]>C(O)C.O.[C].[Pd]>[NH2:1][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15]
Reactant: [N-]=[N+]=NCCn1c(=O)[nH]c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: NCCn1c(=O)[nH]c2ccccc21
Yield: 89.1 %

Procedure:
In 150 ml of ethanol was dissolved 1.3 g (6.4 mmol) of Compound i followed by addition of a suspension of 65 mg (5 w/w%) of 10% palladium-carbon in 2 ml of water. The mixture was stirred at room temperature for 4.5 hours, with hydrogen gas being bubbled into the mixture. The reaction mixture was then filtered and the filtrate was concentrated to give 1.01 g (89.1%) of 1-(2-aminoethyl)-2,3-dihydro-2-oxo-1H-benzimidazole (Compound j) as white crystals.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[CH2:11]=O.Cl.[CH3:14][NH:15][CH3:16]>CCO>[ClH:1].[CH3:14][N:15]([CH3:11])[CH2:16][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CC(=O)c1ccccc1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.5 mL concentrated aqueous HCl in 40 mL EtOH, acetophenone (30.0 g), paraformaldehyde (10.0 g) and dimethylamine hydrochloride (26.5 g) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature, and the precipitate was filtered, washed with acetone and dried in vacuo to obtain 37.2 g of white crystalline material. 1H NMR (200 MHz, DMSO-d6) δ 2.84 (s, 6H), 3.38-3.55 (m, 2H), 3.57-3.74 (m, 2H), 7.48-7.73 (m, 3H), 7.97-8.10 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:10]=[CH:9][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 90 °C
Yield: 61 %

Procedure:
First, into a 200-mL three-neck flask were placed 9.7 g of 4-bromoiodobenzene, 3.1 g of 2-naphthylboronic acid, and 0.35 g of tri(ortho-tolyl)phosphine (P(o-tolyl)3), to which 30 mL of toluene, 6 mL of ethanol, and 10 mL of a 2.0M aqueous potassium carbonate solution were added. The mixture in this flask was degassed under reduced pressure, and the air in the flask was replaced with nitrogen. To this mixture was added 0.037 g of palladium(II) acetate, and the mixture was refluxed under a nitrogen stream at 90° C. for 6 hours. After the reflux, organic substances were extracted from the aqueous layer of this mixture with toluene. The solution of the extract was combined with the organic layer of the mixture. The resulting mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and then saturated brine. After the washing, anhydrous magnesium sulfate was added for drying. The obtained mixture was separated by gravity filtration, and the filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography. In the column chromatography, hexane was first used as a developing solvent, and then a mixed solvent in which a hexane/ethyl acetate ratio was 20:1 (v/v) was used. The obtained fractions were concentrated to give a solid. The obtained solid was recrystallized using a mixed solvent of toluene and hexane to give 2-(4-bromophenyl)naphthalene (as a white solid in 61% yield). The synthesis scheme of Step (a-2) is illustrated below.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.S(Cl)([Cl:28])=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:28][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-ylamino)pentan-1-ol (40.24 g, 114.6 mmol) in dichloromethane (350 mL) was cooled to 0° C. Thionyl chloride (12.5 mL, 172 mmol) was added dropwise, and the reaction was heated at reflux for one hour. The reaction was cooled to 0° C., and water (200 mL) was slowly added followed by solid sodium bicarbonate until the pH of the solution was basic. The solvent was partially removed under reduced pressure, and the aqueous solution was extracted with ethyl acetate (500 mL). The combined organic solutions washed with saturated aqueous sodium bicarbonate (3×50 mL), water (1×50 mL), and brine (2×20 mL), and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a yellow oil, which crystallized overnight. The solid was dried for one hour in a vacuum oven at 70° C. to provide 40.1 g of (5-chloropentyl)-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-yl)amine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[C:3]#[N:4].B.C1COCC1>C1COCC1>[CH3:5][C:2]([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)Sc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)Sc1ccccc1
Reaction time: 18 h

Procedure:
A solution of Example 266A (0.5 g, 2.82 mmol) in THF at room temperature was treated with 1M BH3.THF (15 mL), stirred for 18 hours, quenched with methanol (5 mL), and concentrated. The concentrate was treated with 2M HCl (50 mL) and concentrated. The concentrate was partitioned between dichloromethane and saturated sodium bicarbonate, and the organic phase was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI(+)) m/e 182 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:10][CH2:11]O)[CH2:3][CH2:2]1.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:10][CH2:11][Cl:15])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCCN1CC1CC1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCC1CCCN1CC1CC1
Temperature: 10 °C

Procedure:
172 g of 1-cyclopropylmethyl 2-[2-hydroxyethyl]pyrrolidine (1.02 mole) and 510 ml of chloroform are introduced into a 3 liter balloon flask provided with a stirrer, a reflux condenser, a thermometer and a dropping funnel. The solution is cooled to 10° C. then 151.5 g of thionylchloride (1.02 mole+25%) is dropped in while keeping the temperature between 10° and 15° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6])=[CH:14][CH:13]=1
Reactant: CC(C)C(C)(C)C(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(C)(C)C(=O)COc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 87.4 %

Procedure:
461.5 9 (2.84 mols) of 1-chloro-3,3,4-trimethylpentan-2-one are added with stirring over the course of 1 hour to a mixture of 364.9 g (2.84 mols of 4-chlorophenol and 392 g (2.84 mols of potassium carbonate heated to 100° C. in 2,700 ml of N,N-dimethylformamide. After heating at 100° C. for ten hours, the mixture is cooled to 20° C., precipitated potassium chloride is removed by filtration, and the filtrate is evaporated under reduced pressure. The residue is taken up in 1,500 ml of dichloromethane and washed twice with 750 ml of 5% strength aqueous sodium hydroxide solution and 750 ml of water each time. After drying the organic phase over anhydrous sodium sulphate, the solvent is removed by distillation under reduced pressure and the oily residue is distilled in vacuo. 632 g (87.4% of theory) of 1-(4-chlorophenoxy)-3,3,4-trimethylpentan-2-one of boiling point 147°-148° C./0.15 torr are thus obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].N([O-])=O.[Na+]>O.C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:24]([O-:26])=[O:25])[CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)cc1

Procedure:
To 8.7 g of N-(2, 6-diisopropylphenyl)-p-toluenesulfonamide (8.7 g) were added 6.3 ml of 60% nitric acid, 50 ml of water and 50 ml of acetic acid, then 0.18 g of sodium nitrite, and the resultant mixture was stirred under refluxing and heating for 5 hours. After cooling, the reaction mixture was mixed with 200 ml of water, and the precipitated crystals were filtered and recrystallized from 50 ml of ethanol to give 4.7 g of N-(2, 6-diisopropyl-4-nitropheyl)-p-toluenesulfonamide. This compound was hydrolyzed in aqueous sulfuric acid to give 2.7 g of 2, 6-diisopropyl-4-nitroaniline.
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[Br:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>CO.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]2[NH:18][C:2](=[O:3])[NH:19][C:14]=2[CH:13]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 33.9 %

Procedure:
Add phenyl chloroformate (922 mg, 5.89 mmol) to a suspension of 4-bromo-benzene-1,2-diamine (1.00 g, 5.35 mmol) and NaHCO3 (483 mg, 5.89 mmol) in methanol (20 mL) and H2O (10 mL). Stir at room temperature for 3.5 h and add 1.00N aqueous NaOH (6 mL, 6.00 mmol). Stir overnight at room temperature and filter. Wash the filter cake with H2O and dry in-vacuo overnight to obtain 386 mg (34%) of the title compound as a brown powder. MS (ES) 213,215 (M+H), 211,213 (M−H); HPLC shows 95% purity.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:12]([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][O:19][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:17]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 40 °C
Yield: 65.1 %

Procedure:
To a solution of 6-chloro-9-β-D-ribofuranosylpurine (5.00 g, 17.4 mmol) and triphenylmethyl chloride (9.72 g, 34.8 mmol) in DMF (60 mL) was added DIPEA (2.7 mL, 19.1 mmol) dropwise. The reaction was heated to 40° C. overnight, cooled to r.t. and filtered. The yellow filtrate was diluted with chloroform and washed with water, 0.5 N HCl, and water. The organic layer was dried (Na2SO4), filtered and concentrated. The yellow foam was purified by flash chromatography (0 to 4% MeOH/CHCl3) to yield the product as a pale yellow foam (5.99 g, 65%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].O.Cl.[C:15](=[NH:23])([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[O:10]=[C:8]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=2)[N:22]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:23]1
Reactant: N=C(N)c1ccccc1
Reactant: N#Cc1ccc(F)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc2nc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A stirring solution of 5-cyano-2-fluorobenzoic acid (2.02 g, 12.2 mmol) and benzimidamide hydrochloride monohydrate (2.14 g, 12.2 mmol) in DMF (15 mL) was treated with DIEA (5.34 mL, 30.6 mmol) and HATU (4.65 g, 12.2 mmol). The reaction mixture was stirred at room temperature for 30 min then heated at 100° C. for 18 h. The reaction mixture was cooled to room temperature and water (200 mL) was added. A precipitate formed which was isolated by filtration and dried under vacuum to afford 1.66 g (54%) of 4-oxo-2-phenyl-3,4-dihydroquinazoline-6-carbonitrile INT-87 as a light powdery white solid. LCMS-ESI (m/z) calculated for C15H9N3O: 247; found 248 [M+H]+, tR=1.70 min (Method 10).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH3:2].[C:49]1([S:55]([OH:58])(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(C)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)=[O:9])[CH3:2].[C:49]1([S:55]([O-:58])(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
1.0 g (1.52 mmol) of 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and 0.24 g (1.52 mmol) benzenesulphonic acid were refluxed in 20 mL isopropanol. Then the solution was continuously cooled over three days from 50° C. to 25° C., during which time a crystalline precipitate was formed. The solid formed was filtered off, washed with isopropanol and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([F:54])=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)[CH:45]=1.C(N(CC)CC)C>C(Cl)Cl>[F:54][C:43]1[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)=[CH:45][C:40]([CH2:39][NH:38][C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])=[CH:41][CH:42]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 8 h

Procedure:
To 3-[(methyloxy)carbonyl]benzoic acid (0.18 g, 1 mmol) in CH2Cl2 (25 mL) was added HBTU (0.379 g, 1 mmol), followed by [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (0.231 g, 1 mmol), and triethylamine (0.278 mL, 2 mmol). The mixture was stirred under argon overnight. The reaction mixture was then concentrated to dryness, and taken up in EtOAc and H2O. The organic phase was washed 2× with H2O, 1× with brine, dried and concentrated. The residue was absorbed on Isolute® Sorbent, and CombiFlashed on a 12 g column eluted with 0-100% EtOAc/hexane to afford the title compound as a white solid. LC-MS m/z 393.8 (M+H)+, 1.98 min (ret time); analytical HPLC shows 97.2% purity, (ret time 7.205 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[CH2:7][C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(C)=O)=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[ClH:37]>>[ClH:37].[CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[CH2:7][C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1)CC2
Agent: Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(N)c([N+](=O)[O-])c1)CC2

Procedure:
1.0 gm (1.75 mmols) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{4-acetamino-3-nitro-phenyl}-ethyl)-amino]-propane was heated in 50 ml of methanolic hydrochloric acid for 2 hours at 45° to 50° C. The reaction solution was then concentrated by evaporation; the residue was dissolved in methylene chloride; the solution was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate, and the solvent was distilled off in vacuo. After the residue had been purified on silica gel with methylene chloride and 5% ethanol as the eluant, the hydrochloride was precipitated from acetone by the addition of ethereal hydrochloric acid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:7]([C:11]1[CH:16]=[C:15]([NH:17][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C(C)C(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)methacrylamide was prepared by adding a solution of 11.5 grams of methacryloyl chloride in 50 milliliters of benzene to the solution of 2,6-di tert.butyl-4-aminophenol to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 24° C. to 37° C. The mixture was stirred for 1 hour and the solid product was filtered off, washed thoroughly with 2% hydrochloric acid and dried. The yield was 10.0 grams of product which melted at 222° C. to 225° C.
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=2)[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N+:40]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)([O-:42])=[O:41]>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(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([C:47]4[CH:46]=[CH:45][CH:44]=[C:43]([N+:40]([O-:42])=[O:41])[CH:48]=4)=[CH:8][N:9]3[C:24]3[N:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=3)=[CH:14][CH:13]=2)=[CH:17][CH:18]=1
Reactant: CNc1cc(-n2cc(Br)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(-n2cc(-c3cccc([N+](=O)[O-])c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 31.6 %

Procedure:
DMF (5 mL) was added to a mixture of 6-(3-bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (200 mg, 0.49 mmol), K3PO4 (312 mg, 0.885 mmol) and 3-nitrophenylboronic acid (123 mg, 0.74 mmol) and then the dissolved gas was removed. After adding Pd(PPh3)4 (85 mg, 0.075 mmol), the mixture was stirred at 100° C. for 4 hours. After adding ethyl acetate and water and filtering using a diatomite pad, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4-1:1). The target compound (70 mg) was obtained as white solid.