Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.Cl[CH2:12][CH2:13][CH2:14][Si:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C1COCC1>[CH2:20]([O:19][Si:15]([O:22][CH2:23][CH3:24])([O:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH3:21]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: c1cc[nH]c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCO[Si](CCCn1cccc1)(OCC)OCC
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of butyllithium (1.6 M in hexane, 187 mL, 0.3 mol) is added in 1 hour to a solution of pyrrole (20 g, 0.3 mol) in THF (200 ml) cooled to −10° C. This solution is kept at 0° C. for 1 hour. 72.3 g of 3-chloropropyltriethoxysilane (0.3 mol) is added to this solution, then the temperature of the reaction mixture is raised to +65° C. for 8 hours. After the temperature of the reaction mixture has returned to 20° C., the THF is evaporated under vacuum. The raw product is taken up in cyclohexane (150 mL), the salts of lithium chloride are filtered and the aqueous solution is washed with 50 mL of distilled water. The organic phase is dried over magnesium sulfate and the solvent is evaporated under vacuum. The desired product (57.8 g) is then recovered.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[NH3:15]>C1COCC1.C(O)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:15])(=[O:11])=[O:10]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
To a solution of 2-(trifluoromethyl)benzenesulfonyl chloride (5 g; 20.44 mmol; 1.00 eq.) in anhydrous THF (5.00 ml) was added a solution of 71 ml Ammonia in Ethanol 2M under nitrogen at room temperature. The reaction mixture was shaken for 20 h at room temperature. The solvent was evaporated and the residue redissolved in EtOAc (150 mL) and then washed with NH4Cl saturated aqueous solution (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and the solvent evaporated to give the pure 2-(trifluoromethyl)benzenesulfonamide as a yellowish solid (4.6 g, 89% yield, 98.6% HPLC purity). This compound was utilized as such for the next reaction.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][N:17]=[CH:16][C:15]=2[C:19]([OH:21])=O)=[CH:10][CH:9]=1.[CH3:22][CH:23]1[NH:27][CH2:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:28])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:18][N:17]=[CH:16][C:15]=2[C:19]([N:27]2[CH:23]([CH3:22])[CH2:24][C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([OH:28])[CH2:26]2)=[O:21])=[CH:12][CH:13]=1
Reactant: CC1CC(O)(c2ccccc2)CN1
Reactant: O=C(O)c1cn[nH]c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CC(O)(c2ccccc2)CN1C(=O)c1cn[nH]c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
Pyridine (13 μL, 0.16 mmol, 4 equ.) was added to a solution of 5-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (8 mg, 0.04 mmol), 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol) and TBTU (15 mg, 0.048 mmol, 1.2 equ.) in DMF (0.3 mL) at rt. The reaction mixture was stirred at 60° C. overnight. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z: calcd for C21H20FN3O2: 365.1540, found 365.1541.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22]1[CH2:26]OC[CH2:23]1>O.CCOC(C)=O.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>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:22]([CH3:26])=[CH2:23])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: COC(=O)c1cc(Br)c(OC)cc1OC
Reactant: C1CCOC1
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(=O)OC)c(OC)cc1OC

Procedure:
To potassium isopropylidene trifluoroborate (4.87 g, 32.7 mmol) and 5-bromo-2,4-dimethoxybenzoic acid methyl ester (7.5 g, 27.3 mmol) in THF (195 ml) was added Cs2CO3 (26.6 g, 81.8 mmol) in water (39 ml). The reaction was degassed and Pd(PPh3)4 (1.58 g, 1.36 mmol) added. The reaction was heated at reflux for three days then quenched by adding water and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to leave an orange solid. The product was taken up in EtOAc again and the precipitate filtered. The filtrate was evaporated to dryness to yield 5-isopropenyl-2,4-dimethoxy-benzoic acid methyl ester (6.2 g). 1H NMR (Me-d3-OD) 7.68 (1H, s), 6.66 (1H, s), 5.10-5.08 (1H, m), 5.02-5.00 (1H, m), 3.93 (3H, s), 3.92 (3H, s), 3.84 (3H, s), 2.08-2.06 (3H, m). MS: [M+H]+ 237.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10](C1NC=CN=1)(C1NC=CN=1)=[O:11].C(Cl)(Cl)=O>>[CH3:1][C:2]1[C:3]2[C:4](=[N:8][C:10](=[O:11])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C(Cl)Cl
Product: Cc1cccc2c1=NC(=O)N=2

Procedure:
The 5-amino-5,6-dihydro-4H-imidazo(4,5,1-ij)quinolin-2-ones of the invention may also be prepared by the route shown in Scheme 6. 3-Methyl-1,2-benzenediamine is reacted with carbonyl diimidazole or phosgene to give 4-methylbenzimidazolone (XXXVI). This is refluxed with phosphorus oxychloride to give XXXVII which is protected and reacted with N-bromo-succinimine to give compound XXXIX. This is coupled with VIIb and the resulting adduct LX is hydrolyzed to LI. Reduction with lithium aluminum hydride alcohol LXlI which was treated with carbon tetrabromide/triphenylphosphine to give compound 51. Compound 51 was refluxed in acetic acid to effect conversion to compound 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32](C(OCC4C=CC=CC=4)=O)[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:29])[F:28])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCNC2)CC1
Yield: 98.2 %

Procedure:
Hydrogenate a solution of 4-[1-((R)-1-benzyloxycarbonyl-piperdin-3-yl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.71 mmol; 1.08 g) in methanol (20 mL) with 10% Palladium on carbon (100 mg) and 1 atmosphere of hydrogen gas for 60 min. Add Celite® and filter, rinse with DCM and evaporate to provide the title compound (834.3 mg; 1.68 mmol; 98%). MS (ES+): m/z=497 (M+H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Br[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[O:8]([CH2:7][CH2:6][NH:4][CH2:1][CH2:2][CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCOc1ccccc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Product: CCCNCCOc1ccccc1

Procedure:
47.2 g. Propylamine was dissolved in 100 ml. absolute alcohol with cooling and 40.2 g. β-bromophenetole was added portionwise to the solution formed. After completion of the addition the reaction mixture was allowed to stand at room temperature for one week with occasional agitation. The excess of amine and solvent were then removed under vacuum from the steam bath and the residual colourless solid obtained on cooling was treated with an excess of 5N aqueous sodium hydroxide. An oil was liberated which was then extracted with ether, washed with water and dried over anhydrous sodium sulphate. After removal of the solvent the residual oil was distilled under vacuum to give N-2-phenoxylethyl-N-propylamine, boiling point 90°-92° C./0.2 mm.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O.CS(O)(=O)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CS(C)=O>[F:1][C:2]1[C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: C1CNCCN1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A suspension of 2 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 2.8 g of piperazine and 40 cm3 of dimethyl sulphoxide is stirred for 15 minutes at a temperature close to 40° C. After cooling to about 20° C., the reaction mixture is poured into 150 cm3 of water and 27.75 cm3 of 2N methanesulphonic acid are added. A very small amount of insoluble matter is removed by filtration through diatomaceous silica. 15 cm3 of 2N aqueous potassium hydroxide solution are added to the solution obtained. The precipitate formed is drained, washed with 3 times 15 cm3 of water and taken up in 100 cm3 of dimethylformamide and the mixture is heated, with stirring, for 10 minutes at a temperature close to 150° C. The suspension is cooled to about 100° C.; the insoluble matter is drained and taken up in 100 cm3 of ethanol and the mixture is heated at a temperature close to 75° C. for 1 hour. The insoluble matter is drained at about 50° C. and washed with 40 cm3 of the same solvent at the same temperature as above. 1.8 g of 7-fluoro-1-methoxy-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a brown solid melting at 298°-300° C., solvated by 2.4% of water.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([CH3:19])([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:20])[CH:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:19][C:11]([N:8]1[CH2:9][CH2:10][CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:7]1=[O:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC1CCN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)N1CCC=C(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
4.2 g (0.012 mol) of 4-acetoxy-1-(α,α-dimethylbenzyl)-3-phenyl-2-piperidone prepared by the method of Reference Example 20, was dissolved in 100 ml of toluene, and 2.7 g (0.018 mol) of DBU was added thereto. The mixture was refluxed under heating for 10 minutes. The reaction solution was cooled to room temperature and washed with water. Then, the solvent was distilled off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 3.0 g (yield: 75.0%) of the desired compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=1)[CH:2]([CH3:4])[CH3:3].[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:24])[N:20]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(OCC(C)C)c1
Reactant: COCCN
Product: COCCNC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2OCC(C)C)n1
Yield: 62 %

Procedure:
2-{2-[3-(2-Isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-N-(2-methoxy-ethyl)-acetamide (130 mg, 62%) was prepared from {2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (181 mg, 0.5 mmol) and 2-methoxyethylamine following the general procedure K.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH3:10].C[O-].[Na+]>>[C:3]([CH:2]([CH2:9][CH3:10])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: CCBr
Agent: C[O-]
Agent: [Na+]
Product: CCC(C(C)=O)C(=O)OC
Yield: 56.8 %

Procedure:
465 g of methyl acetoacetate and then 458 g of ethyl bromide were added under nitrogen to 720 g of 30% sodium methylate solution. The reaction mixture was subsequently boiled at reflux. After distilling off the methanol the residue was poured onto ice-water, the mixture was then extracted with n-hexane and water. The organic phases were combined and dried. After evaporation of the solvent and distillation there were obtained 328 g of methyl 2-acetylbutyrate, b.p. 77°-79°/15 Torr.
Reaction SMILES: [N:1]([CH:4]1[C:11](=[O:12])[N:10]2[CH:5]1[CH2:6][CH2:7][O:8]C2(C)C)=[N+:2]=[N-:3]>FC(F)(F)C(O)=O.O>[N:1]([CH:4]1[CH:5]([CH2:6][CH2:7][OH:8])[NH:10][C:11]1=[O:12])=[N+:2]=[N-:3]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC1C(=O)NC1CCO

Procedure:
7-Azido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]-octane (0.2 mol) is dissolved in 2:1 trifluoroacetic acid -H2O (200 ml) and the solution is kept at room temperature (25° C.) for 10 minutes. The solution is concentration under vacuum to a syrup which is taken up in ethylacetate, washed with 5% sodium bicarbonate and brine, dried with sodium sulfate, and filtered. Evaporation of the solvent provides 3-azido-4-(2-hydroxyethyl)-azetidin-2-one.
Reaction SMILES: [C:1]([C:4](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])(=O)[CH3:2].[NH2:26][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:28][C:29]([O:31][CH2:32]C)=[O:30]>>[CH3:2][C:1]1[NH:26][C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=C(N)c1ccccc1
Product: COC(=O)C1=C(c2ccccc2)NC(C)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
More specifically a mixture of 330 mg (1 mmol) of t-butyl 2-[N-[2-acetyl-3-(3-nitrophenyl)-2-propenoyl]-amino]acetate and 191 mg (1 mmol) of ethyl 3-amino-3-phenyl-2-propenoate was stirred under a light-shielding condition at 110° C. overnight. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 98 mg (22%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nc3ccccc3s2)cc1
Yield: 112.7 %

Procedure:
A mixture of 2-(4-nitrophenyl)benzothiazole (105 mg, 0.40 mmol) and tin(II) chloride dihydrate (205 mg, 0.91 mmol) in ethanol (20 mL) was refluxed under N2 for 4 hrs. After removing ethanol by vacuum evaporation. The residue was dissolved into ethyl acetate (20 ml), and washed with NaOH solution (1N, 3×20 ml) and water (3×20 ml), dried and evaporated to dryness to give 102 mg (97%) of the product
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6][C:5]1[CH:13]=[C:14]([CH3:15])[C:2]([Br:1])=[C:3]([CH3:16])[CH:4]=1)(=[O:27])=[O:26]
Reactant: Cc1cc(OCC(C)(C)CO)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCC(C)(C)COS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled (0° C.) solution of 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropan-1-ol (251 mg) and triethylamine (160 μL) in dichloromethane (3 mL) is added methanesulfonyl chloride (75 μL). The mixture is stirred for 2 days while warming to room temperature. Then the mixture is diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. Yield: 271 mg; LC (method 7): tR=1.18 min; Mass spectrum (ESI+): m/z=365 [M+H]+.
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[NH:21][C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.[CH2:29](I)[CH3:30].[H-].[Na+].O>CN(C=O)C>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH2:29][CH3:30])[C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2ccccc23)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(N3CCn4c3nc3ccccc34)cc2)c2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) and ethyl iodide (0.1 mL) in DMF (4.0 mL) was added sodium hydride (62 mg) (60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h, and then H2O was added. The precipitate was collected and washed with MeOH to give 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (23 mg) as white powder.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12](S(C)=O)[N:11]=[C:10]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)[CH:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C)C(=O)C>O>[F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:11]=[C:10]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)[CH:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1
Reactant: C1COCCN1
Reactant: CS(=O)c1nc(OCC2CCN(NC(=O)OC(C)(C)C)CC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NN1CCC(COc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfinyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (240 mg), morpholine (0.3 mL), and N,N-dimethylacetamide (2 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-50:50) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (246 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:35][CH3:36])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccccc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(6-benzylaminohexyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.3 g) as starting compound, acetaldehyde (0.16 ml) and sodium cyanoborohydride (0.37 g) were reacted and treated in the same manner as in Example 136 to give 0.25 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-benzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[C:11]([C:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]#[N:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:32])(C)(C)C>FC(F)(F)C(O)=O>[C:24]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:13]([C:11]1[CH:10]=[CH:9][C:8]([CH3:32])=[C:7]([CH:12]=1)[C:6]([OH:33])=[O:5])=[O:14])[C:16]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[CH:17]2)#[N:25]
Reactant: Cc1ccc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)cc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acid tert-butyl ester is dissolved in trifluoroacetic acid (3 mL), and stirred at room temperature for 1 h. After removing the solvent, the residue is purified by HPLC with an X-bridge Phenyl using acetonitrile-0.1% trifluoroacetic acid as an eluent to yield 5-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm (TFA salt) 2.59 (s, 3H), 7.32 (s, 1H), 7.39-7.44 (m, 2H), 7.71-7.75 (m, 1H), 7.76-7.79 (m, 1H), 7.81 (dd, J=7.8, 2.0 Hz, 1H), 7.92 (dt, J=8.0, 1.8 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.52 (dd, J=5.0, 1.5 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 382.1202 [(M+H)+ Calcd for C23H16N3O3: 382.1192].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.Cl[C:11]1[CH:23]=[C:15]2[N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:24])[N:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:11]2[CH:23]=[C:15]3[N:16]([CH:20]([CH3:21])[CH3:22])[CH2:17][CH2:18][CH2:19][N:14]3[C:13](=[O:24])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Cl)cc1
Product: CC(C)N1CCCn2c1cc(OCc1ccc(Cl)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-chlorophenyl)methanol and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13](=[O:22])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13](=[O:22])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:30](=[O:32])[CH3:31])=[CH:19][CH:20]=1)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)OC(=O)C(C(=O)Nc1ccc(O)cc1)=C1SC=CS1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(NC(=O)C(C(=O)OC(C)C)=C2SC=CS2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-[N-(4-hydroxyphenyl) carbamoyl]acetate (13.5 g) and triethylamine (6.7 ml) were dissolved in methylene chloride (100 ml) and cooled to 0° C. To the mixture was added acetyl chloride (3.16 ml) dropwise and then stirred for 1 hr. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solution was evaporated to dryness and the residue was triturated with n-hexane to give the titled compound. (12 g), 79.1%)