Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:9]([CH:10]=[O:11])[C:8]([OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:14]Br.CC(=O)OCC.CCCCCCC>C(O)(=O)C>[Br:14][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[C:9]([CH:10]=[O:11])[C:8]=1[OH:13]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: BrBr
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a stirred solution of 5-tert-butylsalicylaldehyde (3.03 g, 16.97 mmol) in acetic acid (3.5 mL) was added a solution of bromine (0.90 mL, 17.56 mmol) in acetic acid (8.5 mL) dropwise within 15 min. The reaction mixture was stirred at room temperature for 3 h at 50° C. and was monitored by TLC (EA/heptane:1:4) and analytical HPLC analysis. Analytical HPLC analysis of the reaction mixture after 2.5 h shows the desired product ˜68% and the unreacted starting material ˜32%. A second batch of bromine (0.15 mL) in acetic acid (3 mL) was added and the reaction mixture was stirred at 50° C. for another 15 h. Analytical HPLC analysis of the reaction mixture after overnight stirring shows the desired product ˜96% and still shows the starting material ˜4%. The reaction mixture was diluted with dichloromethane (50 mL) and the organic layer was washed with 39% sodium bisulfite solution (1×10 mL), water, saturated NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the crude desired product as a pale yellow crystalline solid (4.6150 g). Purification of the crude product by Silica-gel flash chromatography on silica gel column and elution with 0-5% ethyl acetate in n-heptane afforded the desired product as a pale yellow crystalline solid (4.07 g, 93% yield). 1H NMR (400 MHz, CDCl3): δ 1.33 (s, 9H, t-Bu-), 7.49 (s, 1H, H-4), 7.81 (d, 1H, H-6), 9.85 (s, 1H, —CHO), 11.41 (s, 1H, —OH). 1H NMR of the isolated product was identical with that of a previously reported sample of the product (Girsch et al., 2008) LC-MS analysis of the product in negative mode shows the desired product's mass: m/z 255 (79BrM+−H) and m/z 257 (81BrM+−H). GC-MS analysis of the product in CI mode (Methane) shows the desired product's mass: m/z 256 (79BrM+) and m/z 258 (81BrM+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[C:16]1([S:13]([NH:12][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])=[O:11])(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Yield: 79.7 %

Procedure:
A suspension of the foregoing nitro compound (14.8 g, 48 mmol) in ethanol (240 ml) was hydrogenated over 10% palladium on carbon (1.4 g) at 45 psi for 1.5 hours. The reaction mixture was filtered then evaporated and the crude product recrystallised from hot ethanol to afford 3-(phenylsulphonylaminocarbonyl)aniline (10.57 g, 80%) as a colourless crystalline solid, mp 138° C. Rf=0.42 in dichloromethane/methanol (9:1) on silica plates.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:13]=[C:12]([Cl:14])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of 125 g of nitric acid in 153 g of sulfuric acid which had been prepared with ice-cooling at (−5)° C. was added dropwise to a solution of 262.5 g (1.5 mol) of 2,4-dichlorobenzaldehyde in 560 ml of sulfuric acid. After the reaction mixture had been stirred for 2 hours at 10° C., it was poured onto 4 kg of ice. The resulting solids were subsequently separated off, washed with water and dissolved in 2 l of dichloromethane. The resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution, then dried over magnesium sulfate and finally concentrated. Yield: 329.5 g; m.p.: 61-63° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:14])=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)(=[O:3])[CH3:2].[CH3:15][O:16]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[C:5]([OH:14])=[C:6]([CH:15]=[O:16])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(cc1O)CCCC2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(C=O)c1O)CCCC2
Temperature: 0 °C

Procedure:
To a solution of 5,6,7,8-tetrahydro-3-acetyl-2-naphthol (9.5 g) in dry dichloromethane (50 ml), cooled in an ice bath, was added titanium tetrachloride (38 g) over a period of three minutes. After fifteen minutes stirring dichloromethyl methyl ether (8.05 g) was added over a period of five minutes. The mixture was retained in the ice bath for a further ten minutes, then stirred without cooling for thirty minutes, and finally warmed to 35° for twenty minutes.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:25]>CO>[ClH:25].[ClH:25].[ClH:25].[N:19]1([CH2:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CO
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCC2)c1

Procedure:
A suspension of 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (13.4 g; 38.3 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 350 mL of methanol was treated with 25.5 mL of concentrated HCl. The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave the product. The crystalline residue was triturated with 150 mL of absolute ethanol, filtered and dried to give 10.8 g of the title compound, m.p. 195°-203° C. (dec.).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].[CH3:26][C:27]1[S:31][CH:30]=[N:29][CH:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:30]4[S:31][C:27]([CH3:26])=[CH:28][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cncs1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4c(F)ccnc4F)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12j and 5-methylthiazole
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-methylpiperidin-4-ol (2.99 mmol, 344.4 mg) was added to a suspension of potassium tert-butoxide in THF (5 mL) and stirred at RT for 30 minutes. 2-fluoro-5-trifluoromethyl nitrobenzene (2.39 mmol, 500 mg) was then added and the reaction mixture was stirred an additional 5 h at RT, at which time LC-MS showed complete conversion to the desired product. The reaction mixture was concentrated and the dark brown residue was taken up in methylene chloride (25 mL). This was washed with water (3×20 mL), dried over sodium sulfate, filtered and concentrated to give the crude product as a yellow oil. Crude material (>90% purity) was taken to the next step without further purification LC-MS: 305.1 (M+H)
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:24])C=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[OH:24][CH2:3][CH:2]1[CH2:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[CH:13][C:14]=2[O:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of ethyl 3-allyl-4-hydroxybenzoate (6.74 g, 32.7 mmol) in chloroform (105 ml) was added with meta-chloroperbenzoic acid (11.40 g, 66.1 mmol) and the mixture was refluxed under stirring for 4 h. Afterwards, the solvent was evaporated, the crude was redissolved in ethyl acetate and washed with a 1M NaOH solution. After drying and removing the solvent, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 90:10, to recover 5.95 g of the title compound (82% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16](OC)=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.O.[NH2:28][NH2:29]>CO.CN(C=O)C>[O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH:28][NH2:29])=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1
Reactant: COC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: NN
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1

Procedure:
A suspension of 500 mg (1.34 mmol) of the product obtained in Step A and 978 μl (20.13 mmol) of hydrazine monohydrate in a mixture of MeOH (30 ml) and DMF (6 ml) is refluxed for 24 hours. The MeOH is evaporated off, water is added to the reaction mixture and the precipitate, which corresponds to the title product, is filtered off.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@@H:5]1[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:13][O:12][C:9]([C@H:5]1[C:6](=[O:8])[NH:7][C@@H:4]1[CH2:3][C:2]([OH:16])=[O:1])([CH3:11])[CH3:10]
Reactant: CC(C)=O
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)O

Procedure:
A solution of (3S, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (50.7 mg) in acetone (5.42 ml) was added to a solution of 2N Jones reagent (0.542 ml) in acetone (5.42 ml) at ambient temperature over a period of 30 minutes, and the mixture was stirred for an hour. After addition of an excess of isopropyl alcohol to the mixture, the solvent was removed. The residue was dissolved in chloroform and the resultant solution was washed with a saturated aqueous sodium chloride. The washings were extracted five times with chloroform. The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The crystalline residue was washed with isopropyl alcohol to give 2-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (25.1 mg). The mother liquor was concentrated and the crystalline residue was washed with hexane to give a second crop of the above product (19.4 mg). Total yield is 44.5 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[C:11]([O:18][CH3:19])[CH:10]=2)[CH:7]=1.Cl.[NH2:29][OH:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[C:15](=[N:29]/[OH:30])/[CH3:16])=[C:11]([O:18][CH3:19])[CH:10]=2)[CH:7]=1
Reactant: NO
Reactant: COc1cc(Sc2cc(F)cc(C3(OC)CCOCC3)c2)ccc1C(C)=O
Agent: Cl
Product: COc1cc(Sc2cc(F)cc(C3(OC)CCOCC3)c2)ccc1/C(C)=N/O
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 7, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2'-methoxyacetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2'-methoxyacetophenone oxime in 52% yield, m.p. 155° C.;
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[F:25])=[O:16])=[CH:10][CH:9]=1)#[N:2].C([O-])([O-])=[O:37].[K+].[K+]>CS(C)=O.OO.[Cl-].[Na+].O>[F:25][C:19]1[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[NH:17][C:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[S:6][N:5]=[C:4]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:3]=2[C:1]([NH2:2])=[O:37])=[CH:9][CH:10]=1)=[O:16]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(NCCCN4CCOCC4)c3C#N)cc2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(NCCCN4CCOCC4)c3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 1-(4-{4-cyano-3-[(3-morpholin-4-ylpropyl)amino]isothiazol-5-yl}phenyl)-3-(2-fluoro-5-methylphenyl)urea (5 mg, 0.011 mmol) in 0.8 mL DMSO at rt was added catalytic K2CO3, 1 drop 30% hydrogen peroxide and the reaction stirred at rt for 30 min. The reaction was added into a solution of dilute brine and the precipitant filtered and rinsed with water, then 20% EtOAc/hexane. The product was washed from the filter paper using 15% MeOH/CHCl3 and then evaporated to give the title compound as a white solid (5 mg, 85%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([CH2:9]Cl)=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>O1CCCC1>[Cl:2][C:3]1[C:8]([CH2:9][NH:20][CH2:19][CH2:17][OH:18])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: ClCc1c(-c2ccccc2)ccnc1Cl
Reactant: NCCO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCCNCc1c(-c2ccccc2)ccnc1Cl

Procedure:
To a suspension of 2-chloro-3-(chloromethyl)-4-phenylpyridine hydrochloride (12.6 g) obtained in Reference Example 2C in tetrahydrofuran (150 ml) was added ethanolamine (14 ml), and the mixture was heated under reflux for 6 hrs. After cooling the reaction solution, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (13.4 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[C:20]([CH3:36])=[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH:14]3[CH2:18][CH2:17][O:16][CH2:15]3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:26]([NH:25][C:21]1[C:20]([CH3:36])=[C:19]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([O:13][CH:14]5[CH2:18][CH2:17][O:16][CH2:15]5)=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][CH:2]=2)[CH:24]=[CH:23][CH:22]=1)=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(OC3CCOC3)ccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(OC3CCOC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
To a solution of benzyl 3-(2-amino-1-(6-(tetrahydrofuran-3-yloxy)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (0.678 g, 1.396 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.554 mL, 2.79 mmol) at room temperature was added hydrogen chloride in 1,4-dioxane (4.0 M) (0.419 mL, 1.676 mmol). The mixture was stirred room temperature for 16 hr. The volatiles were removed under vacuum. The residue was diluted with water (50 mL), basified with NaHCO3 solution to pH 10, and extracted with ethyl acetate (4×50 mL). The combined extract was washed with brine (40 ml), dried over anhydrous MgSO4, and concentrated to dryness under vacuum. To the residue were added p-xylene (60 mL) and 10% Pd/C (0.46 g), and the mixture was heated at 125° C. under an ambient atmosphere for 4.5 hr. The solid phase was removed by suction filtration. The filtrate was diluted with ethyl acetate (120 ml), washed with brine (40 ml), and dried over anhydrous MgSO4. The desired product (0.240 g, 0.424 mmol, 30.4% yield) was isolated by ISCO (40 g silica gel, solid loading, 15-35% ethyl acetate/CH2Cl2).
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Br.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>CN(C)C=O>[Br:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:11]1[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]2[C:7]1=[O:17]
Reactant: BrC/C=C/CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Temperature: 50 °C

Procedure:
A mixture of trans-1,4-dibromo-2-butene (6.4 g, 30 mmol) and potassium phthalimide (5.6 g, 30 mmol) in anhydrous dimethyl formamide (200 ml) was heated at 50° C. for 24 h. Then the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with brine and the pure title product was obtained by flash chromatography on silica gel (ethyl acetate: hexane; 15:85) (3.2 g, 40%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:43])[C:10]([CH3:42])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][C:23](C)([CH3:25])[CH3:24])=[O:20])=[CH:15][C:14]=3[O:27][CH2:28][CH2:29]CC(NNC(OC(C)(C)C)=O)=O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:44]1([NH:47][C:48](=O)C2C=C(F)C(C)=C(B3OC(C)(C)C(C)(C)O3)C=2)CC1.C(=O)([O-])O.[Na+]>CC(O)C.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>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH:23]4[CH2:24][CH2:25]4)=[O:20])=[CH:15][C:14]=3[O:27][CH2:28][CH2:29][N:47]([CH3:48])[CH3:44])[C:10]([CH3:42])=[C:9]([F:43])[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)cc1OCCCC(=O)NNC(=O)OC(C)(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1OCCN(C)C

Procedure:
N-Cyclopropylmethyl-3-[2-(dimethylarnino)ethoxy]4-iodobenzamide (Intermediate 1) (42 mg), N-cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (38 mg), tetrakis(triphenylphosphine)palladium (2 mg) and aqueous sodiumhydrogen carbonate (1M, 0.3 ml) were reacted in propan-2-ol (2 ml) at 9° C. for 20 hours. The solvent was evaporated under vacuum and the residue purified by bond-elut (silica, 10 g) eluting with a methanol/chloroform gradient (1-10% methanol) to give, after evaporation of the solvents, N3-cyclopropyl-N4′-(cyclopropylmethyl)-2′-[2-(dimethylamino)ethoxy]-5-fluoro-6-methyl-1,1 ′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][C:12]#[N:13].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+].Br[C:67]1[CH:72]=[CH:71][C:70]([F:73])=[CH:69][CH:68]=1>O1CCOCC1>[F:73][C:70]1[CH:71]=[CH:72][C:67]([N:7]2[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:3]([CH3:2])[CH2:8]2)=[CH:68][CH:69]=1
Reactant: CC1CNCCN1CCCC#N
Reactant: Fc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1CN(c2ccc(F)cc2)CCN1CCCC#N
Temperature: 100 °C
Reaction time: 15 h
Yield: 50.7 %

Procedure:
To a stirred solution of 4-(2-methylpiperazin-1-yl)butanenitrile hydrochloride (1 g, 4.91 mmol) in 1,4 dioxane (25 ml) at 25° C. was added 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.306 g, 0.491 mmol), NaOtBu (1.415 g, 14.73 mmol), 1-bromo-4-fluorobenzene (0.648 ml, 5.89 mmol) and tris(dibenzyllideneacetone)dipalladium (0) [Pd2(dba)3] (0.225 g, 0.245 mmol). The resulting reaction mixture was purged with nitrogen for 10 min in sealed tube and stirred at 100° C. in seal tube for 15 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, filtered through a celite bed, and washed with ethyl acetate (2×20 ml). The filtrate was concentrated under reduced pressure to get crude compound. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 25% ethyl acetate in hexane as eluent to obtain title compound (0.65 g, 50.7).
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:27](=[O:29])[NH:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:33]3[CH2:32][CH2:31][CH:30]([N:26]4[C:25]5[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][C:24]=5[NH:28][C:27]4=[O:29])[CH2:35][CH2:34]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 5.5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5 parts of sodium carbonate and 63 parts of N,N-dimethylformamide is stirred and heated in an oil-bath at 50°-60° C for 2 hours. The reaction mixture is poured onto water. The precipitated product is filtered off, dried and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water. It is filtered off again and dissolved in a mixture of 4-methyl-2-pentanone and a small amount of N,N-dimethylformamide. The solution is filtered till clear and the filtrate is concentrated to a volume of about 10 parts. The concentrate is triturated in methanol. The precipitated product is filtered off and dried, yielding 1.27 parts of 5-chloro-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 229°-236° C.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([N:12]1[C:16]([NH2:17])=[N:15][N:14]=[N:13]1)[CH2:10][CH3:11]>>[CH2:9]([N:12]1[C:16]([NH:17][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:8])=[N:15][N:14]=[N:13]1)[CH2:10][CH3:11]
Reactant: CCCn1nnnc1N
Reactant: O=C(O)C1CCCC1
Product: CCCn1nnnc1NC(=O)C1CCCC1
Yield: 45 %

Procedure:
Employing 0.30 g (2.6 mmol) of cyclopentane carboxylic acid and 0.33 mg (2.6 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et3N (9.3:0.5:0.2) gave the product in 45% yield.