Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([CH:17]([OH:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Li+].I[CH2:38][CH3:39]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([CH:17]([O:24][CH2:38][CH3:39])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CCI
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCOC(c1ccccc1)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-(hydroxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (276 mg, 0.585 mmol) in NMP (3 mL) was added lithium hydroxide (28.0 mg, 1.170 mmol) and iodoethane (142 μL, 1.754 mmol), and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/0-50% EtOAc) to afford racemic 4-(5-chloropyridin-3-yl)-2-(ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak OJ-H, 21×250 mm, MeOH in CO2) to afford 4-(5-chloropyridin-3-yl)-2-(R)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 4-(5-chloropyridin-3-yl)-2-((S)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C29H30ClN5O [M+H]+ 500. found 500. 1H NMR (600 MHz, CD3OD) δ 8.75 (d, J=2.3, 1H), 8.70 (d, J=1.6, 1H), 8.27 (s, 1H), 8.23 (t, J=2.0, 1H), 7.49 (d, J=7.2, 2H), 7.38 (t, J=7.3, 2H), 7.36-7.31 (m, 1H), 5.94 (s, 1H), 4.01-3.85 (m, 2H), 3.68-3.59 (m, 2H), 1.44-1.36 (m, 2H), 1.27 (t, J=7.0, 3H), 1.07-0.98 (m, 1H), 0.89-0.78 (m, 1H), 0.76-0.66 (m, 5H), 0.64-0.54 (m, 1H), 0.54-0.46 (m, 1H), 0.46-0.36 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=1)[CH:5]=2.[C:17](O)(=O)[CH3:18]>CCOCC>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]3([C:18]4[CH:17]=[CH:8][CH:7]=[CH:6][C:5]=4[C:4]4[C:3]3=[CH:2][CH:14]=[CH:13][CH:12]=4)[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Solvent: CCOCC
Product: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1cc(Br)ccc1-2
Temperature: 25 °C
Yield: 60 %

Procedure:
According to a method similar to that of synthesis example 3, 2,7-dibromofluorenone (0.1 mol) and 2-biphenyl magnesium bromide are agitated in ether for 3 hr, followed by cooling to room temperature, further followed by slowly adding 50 ml of acetic acid. Ether is distilled away under reduced pressure, followed by adding thereto substantially 5 ml of HCl. Thereafter, the solution is refluxed for 1 hr, followed by filtering precipitate by suction, further followed by washing with water and recrystallizing with methanol. Thereby, 2,7-dibromo-9,9′-spirobifluorene is obtained (yield: 60%).
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C[NH2:30]>CO.O>[C:1]1([C:7]2[CH:12]([C:11](=[O:18])[CH:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:30]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Reactant: CN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1C(=O)C=C(c2ccccc2)N=C1c1ccccc1

Procedure:
3.5 gms of 2,6-diphenyl-3-ethoxycarbonyl-4-pyrone was dissolved in 33 mls of methanol. 2 mls of glacial acetic acid was added. 13.3 mls of 40% aqueous methylamine was then added very slowly at room temperature. After 6 hours the reaction mixture was diluted with 200 mls of water and extracted with methylene chloride. Evaporation yielded 3.5 gms of ethyl 2,6-diphenyl-4-oxonicotinate which was recrystallized from methylene chloride/ether. mp=177°-179°
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21]C(=O)C)=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[OH-].[Na+]>Cl>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1
Reactant: CC(=O)NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Yield: 63.2 %

Procedure:
N-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide (4.0 g) was dissolved in 10% hydrochloric acid (50 ml) and the solution was refluxed under heating for 12.5 hr. To the reaction mixture was added 10% aqueous sodium hydroxide solution to make it alkaline, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was crystallized from diisopropyl ether to give the title compound (2.2 g) as pale-yellow crystals, m.p.=70-72° C.
Reaction SMILES: C([O:8][C:9]([N:11]([CH3:14])[NH:12][CH3:13])=O)C1C=CC=CC=1.ClC(OC(Cl)(Cl)Cl)=O.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:25])[C:9]([N:11]([CH3:14])[NH:12][CH3:13])=[O:8]
Reactant: CNC
Reactant: CNN(C)C(=O)OCc1ccccc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNN(C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of N-benzyloxycarbonyl-N,N'-dimethylhydrazine (1.6 g) in toluene (30 ml) was added trichloromethyl chloroformate (0.553 ml). After the solution was refluxed for 30 minutes, dimethylamine (672 mg) and triethylamine (2.0 g) was added thereto at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 5% hydrochloric acid, 1 M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was dissolved in methanol (20 ml) and water (20 ml). The solution was hydrogenated over 10% palladium on carbon (100 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give N-(N,N-dimethylcarbamoyl)-N,N'-dimethylhydrazine (820 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:12]([CH:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)O)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:12](/[CH:13]=[CH:15]/[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(CCC(O)c2cccnc2Oc2ccc(F)cc2)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: c1ccccc1
Product: COc1ccc(C/C=C/c2cccnc2Oc2ccc(F)cc2)cc1
Yield: 43.1 %

Procedure:
A mixture of 0.97 g (2.7 mmol) 2-(4-Fluorophenoxy)-a-[2-(4-methoxyphenyl)ethyl]-3-pyridinemethanol, 0.93 g (3.9 mmol) of Burgess Reagent, and 20 mL of benzene was heated to reflux for 4 h. The cooled mixture was partitioned between 300 mL of EtOAc and 100 mL of saturated aqueous sodium hydrogencarbonate solution, and the separated organic layer was washed with 100 mL of brine, dried (Na2SO4), and evaporated to 1.10 g of an oil. Purification by flash chromatography using 15% EtOAc-hexane as eluant gave 0.39 g (42% yield) of the title compound as an oil. 1H NMR (CDCl3) d 3.60 (2H, d, J=7 Hz), 3.82 (3H, s), 6.48 (1H, dt, J=7, 16 Hz), 6.78 (1H, d, J=16 Hz), 6.86-7.18(9H, m), 7.79 (1H, dd, J=2, 8 Hz), 7.99 (1H, dd, J=2, 5 Hz).
Reaction SMILES: [C:1]([C:4]([C:6]1[C:15]([F:16])=[C:14]([F:17])[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([F:18])[C:7]=1[F:19])=C)(O)=O>CN(C)C=O>[F:17][C:14]1[C:15]([F:16])=[C:6]([CH:4]=[CH2:1])[C:7]([F:19])=[C:8]([F:18])[C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=C(C(=O)O)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Solvent: CN(C)C=O
Product: C=Cc1c(F)c(F)c(C(=O)OC)c(F)c1F
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 3.0 g of methyl 4-(1-carboxyvinyl)-2,3,5,6-tetrafluorobenzoate. The resulting solution was stirred at 130°-140° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/n-hexane=1/1) to obtain 2.0 g (yield: 79.1%) of methyl 2,3,5,6-tetrafluoro-4-vinylbenzoate.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4](=[O:7])[NH:5][N:6]=1.C([O-])(O)=O.[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCOCC>CN(P(N(C)C)(N(C)C)=O)C.[Na+].[I-]>[C:23]([O:22][C:20](=[O:21])[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:6]1[NH:5][C:4](=[O:7])[S:3][C:2]1=[O:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=c1[nH]nc(O)s1
Reactant: CC(C)(C)OC(=O)CCCCCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C=CCCCCn1[nH]c(=O)sc1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 21.9 %

Procedure:
A solution of 11.8 g (0.1 mole) of 1,3,4-thiadiazoline-2,5-dione (1) (Example 1A) in 75 ml of HMPA was stirred with 9.24 g (0.11 mole) of NaHCO3 at room temperature for 18 hrs and then 0.3 g NaI was added followed by 26.5 g (0.1 mole) of tert-butyl 7-bromoheptanoate which was added dropwise over a period of 2 hr. The reaction mixture was stirred at room temperature for 5 days then poured with stirring into 500 ml of ice-cold 5% HCl topped with 200 ml of ether. The ether phase was washed with water and then with three 100-ml portions of 2.5% NaHCO3. The combined NaHCO3 solutions were washed with fresh ether, topped with 200 ml of fresh ether, and while being cooled in ice, acidified by dropwise addition of conc. HCl to pH 2-3. The ether layer was drawn off, two more ether extractions of the aqueous layer were made, and the combined ether extract was washed once with satd. NaCl, dried over Na2SO4, and evaporated. 2,5-Dioxo-1,3,4-thiadiazoline-3-heptanoic acid tert-butyl ester (6.58 g, 22%) was obtained as an oil, IR, (neat) νmax 1735 and 1725 (CO2 t-Bu), and 1675 cm-1 (amide), pmr, (CDCl3, TMS) δ 8.70 (s,1H,OH,NH), 3.75 (t, 2H, NCH2), 2.22 (t, 2H, CH2CO2), and 1.45 ppm (s, 9H C(CH3)3).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH:22]=1
Reactant: ClCc1cccnc1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cccnc2)c(=O)[nH]c1=O
Yield: 33 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (120 mg, yield: 33.0%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:14])=[CH:5][CH:4]=1.Cl[S:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:18])=[O:17]>ClCCl>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][S:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:18])=[O:17])=[CH:7][CH:8]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Cc1ccc(CCOCCN)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(C)cc1
Yield: 46.6 %

Procedure:
The subtitle compound (2.49 g) was prepared according to the procedure in example 5 part d using 2-[2-(4-methylphenyl)ethoxy]ethanamine hydrochloride (3.5 g) triethylamine 4.74 ml) methyl 3-(chlorosulphonyl)propanoate (3.08 g), and dichloromethane (80 ml).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]\[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC=CC=1/C=C/C1C=CC(C(O)=O)=C(OC)C=1)C1C=CC=CC=1.C(OC1C=CC=CC=1CCCC1C=CC(C(OC)=O)=CC=1)C1C=CC=CC=1.C(OC1C=CC=CC=1CCCC1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]\[C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(/C=C\c2ccccc2OCc2ccccc2)cc1OC
Agent: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: COc1cc(/C=C/c2ccccc2OCc2ccccc2)ccc1C(=O)O
Agent: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Product: COc1cc(/C=C\c2ccccc2OCc2ccccc2)ccc1C(=O)O

Procedure:
Methyl 4-[2-(2-benzyloxyphenyl)-(Z)-ethenyl]-2-methoxy-benzoate (obtained from methyl 4-[2-(2-benzyloxyphenyl)-(Z)-ethenyl]-2-hydroxybenzoate as described in Example 14) was converted to 4-[2-(2-benzyloxyphenyl)-(E)-ethenyl]-2-methoxybenzoic acid (containing 15% of the (Z) isomer and obtained as a gum; negative FAB mass peak 359) using the method described in Example 1 for the conversion of methyl 4-[3-(2-benzyloxyphenyl)propyl]benzoate to 4-[3-(2-benzyloxyphenyl)-propyl]benzoic acid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.CS(O[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([F:37])[CH:31]=1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:19]2[CH:20]=[CH:21][C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH:6]4[CH2:7][CH2:8][O:3][CH2:4][CH2:5]4)[N:15]=3)=[CH:17][C:18]2=[O:22])=[CH:31][C:32]=1[F:37]
Reactant: CS(=O)(=O)OCCc1ccc(Cl)c(F)c1
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1CCc1ccc(Cl)c(F)c1
Reaction time: 0.25 h

Procedure:
NaH (11.1 mg, 0.277 mmol; 60% oil dispersion) neat as a solid was added to a stirred suspension of 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (75.4 mg, 0.277 mmol) in DMF (700 μL) at room temperature under nitrogen. After 15 minutes, a clear solution had formed. A solution of 4-chloro-3-fluorophenethyl methanesulfonate (105 mg, 0.416 mmol) in of DMF (700 μL) was then added dropwise. After stirring overnight, the reaction was quenched by addition of saturated ammonium chloride solution (1 mL). The mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organics were isolated and washed with water (3×30 mL) and with brine (30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12M column with 2.5/97.5 methanol/ethyl acetate and eluted. The undesired O-alkylated product eluted first and was not collected. Product containing fractions then eluted and were pooled and concentrated to an oil that eventually solidified, 1-(4-chloro-3-fluorophenethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 7.30 (dd, 1H), 7.18 (br s, 1H), 7.02 (d, 1H), 6.98 (dd, 1H), 6.90 (m, 2H), 6.66 (dd, 1H), 5.17 (br d, 1H), 4.16 (t, 2H), 4.12 (m, 1H), 4.00 (m, 2H), 3.57 (m, 2H), 3.08 (t, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=430.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH2:48])[CH:46]=2)[N:41]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[N:40]=1>CN(C=O)C>[NH:32]1[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N:30]=[C:31]1[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH:48][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[CH:46]=2)[N:41]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[N:40]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
3-Fluorobenzoic acid (10 mg, 0.029 mmol), HOBt (6 mg, 0.044 mmol), EDC (9 mg, 0.045 mmol) and sodium bicarbonate (2.5 mg, 0.029 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.029 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (8 mg) as a off white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=1.6 Hz), 8.15-8.13 (m, 2H), 7.95 (s, 1H), 7.58 (m, 2H), 7.52 (d, 1H, J=9.6 Hz), 7.42-7.36 (m, 2H), 7.21 (m, 2H), 5.69 (dd, 1H, J=2.4 and 9.2 Hz), 3.99 (m, 1H), 3.72 (m, 1H), 2.55 (m, 1H), 2.06 (m, 2H), 1.67 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[O:14])[N:12]=1.OO.C([O-])(O)=[O:31].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:16][CH2:17][S:18](=[O:31])[CH2:19][CH2:20]2)=[O:14])[N:12]=1
Reactant: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCSCC1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 54 %

Procedure:
To a solution of 4-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}thiomorpholine (Table entry 176) (30 mg, 0.072 mmol) in acetone (2 mL), was added 30% aqueous H2O2 (0.09 mmol). The resulting solution was stirred at rt for 36 h, diluted with water, neutralized with NaHCO3, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (20% MeOH in EtOAc) to give the product 4-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}thiomorpholine 1-oxide (17 mg, 54% yield): LC-MS m/z 434.5 (MH+), retention time 2.55 min (method 1); Rf=0.47 (17% EtOAc in hexane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].ClC1C=CC=C(C(OO)=[O:25])C=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH+:9]([O-:25])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[NH+]([O-])CCc1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
tert-Butyl 2-(2-pyridyl)ethylcarbamate (18.5 g, 83 mmol) and 3-chloroperbenzoic acid (77%, 24.5 g, 109 mmol) were dissolved in ethyl acetate (200 ml), and the mixture was stirred at room temperature for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:4, v/v) were collected and concentrated to give the titled compound (19.6 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:19].[Na+].Cl>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:19])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 4′-nitroacetophenone (5.00 g, 30.3 mmol) and ammonium acetate (28.4 g, 378 mmol) in MeOH (75 mL) was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (1.38 g, 21.2 mmol) was added and the resulting mixture stirred for 48 hours. Aqueous HCl (6 M, 40 mL) was added and the mixture was filtered. The filtrate was washed with Et2O (3×40 mL) then the aqueous phase was basified to pH 10 using KOH. The basified aqueous layer was extracted with DCM (3×30 mL) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo to give the title compound A129 as an amorphous orange solid (3.00 g, 60%); 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 4.27-4.33 (m, 1H), 2.20 (brs, 2H), 1.45 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:24])[C:14]2=[O:25])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:24])[C:14]2=[O:25])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCCC3)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)O)c3)c1=O)CCCC2
Reaction time: 1 h

Procedure:
A solution of 3.6 g of ethyl 2-chloro-5-[1,4,5,6,7,8-hexahydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-benzoate in 70 ml of ethanol is held at 60° C. for 10 minutes with 0.6 g of sodium hydroxide in 70 ml of water and subsequently stirred for 1 hour. The solution is substantially evaporated down under reduced pressure and the residue is brought to pH 1 with 2N hydrochloric acid. The precipatate is shaken five times with 50 ml amounts of diethyl ether and the organic phases are dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. 2-Chloro-5-[1,4,5,6,7,8-hexahydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-benzoic acid is obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[O:22][CH2:21][CH2:20][O:19]2)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[O:19][CH2:20][CH2:21][O:22]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: Fc1ccc(Br)cc1F
Reactant: Ic1ccc(C2OCCO2)cc1
Agent: Cl[Pd]Cl
Agent: [Mg]
Agent: c1ccc([PH](CCC[PH](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc(C3OCCO3)cc2)cc1F
Reaction time: 72 h

Procedure:
A Grignard reagent solution prepared from 1.0 g of magnesium, 7.6 g of 1-bromo-3,4-difluorobenzene and 75 ml of tetrahydrofuran was added dropwise to a mixture of 9.0 g of 2-(p-iodophenyl)dioxolane, 100 ml of tetrahydrofuran, 0.025 g of palladium(II) chloride and 0.16 g of 1,3-bis(triphenylphosphino)propane. The reaction mixture was heated to boiling for 3 days and, after cooling, extracted with 200 ml of diethyl ether and 120 ml of 0.5N ammonium chloride solution. The organic phase was washed with three 80 ml portions of water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) gave pure 2-(3',4'-difluoro-4-biphenylyl)dioxolane; m.p. 89°-91° C.