Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1)[CH2:21][CH3:22].C(C1C=CC(CCO)=CC=1)CC.CC(C)([O-])C.[K+].[CH2:50]([CH:55]1[CH2:60][CH2:59][CH:58]([CH:61]2[CH2:66][CH2:65][CH:64]([CH2:67][CH:68]=O)[CH2:63][CH2:62]2)[CH2:57][CH2:56]1)[CH2:51][CH2:52][CH2:53][CH3:54]>C1COCC1.CCOCC.C1(C)C(C)=CC=CC=1>[CH2:20]([C:23]1[CH:31]=[CH:30][C:26](/[CH:27]=[CH:28]\[CH2:68][CH2:67][CH:64]2[CH2:65][CH2:66][CH:61]([CH:58]3[CH2:57][CH2:56][CH:55]([CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:60][CH2:59]3)[CH2:62][CH2:63]2)=[CH:25][CH:24]=1)[CH2:21][CH3:22]
Reactant: CCCc1ccc(CCBr)cc1
Reactant: CCCCCC1CCC(C2CCC(CC=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: CCCc1ccc(CCO)cc1
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(CC/C=C\c3ccc(CCC)cc3)CC2)CC1
Yield: 50 %

Procedure:
Into a flask, were placed triphenylphosphine (2.3 g, 8.8 mmol) and 4-propylphenethylbromide (2.0 g, 8.8 mmol) prepared from 4-propylphenethyl alcohol, followed by adding and dissolving xylene (10 ml), heating under reflux for 10 hours, filtering off white crystals of 4-propylphenethyltriphenylphosphoniumbromide deposited after the completion of reaction, drying the obtained white crystals (4.3 g, 8.8 mmol), dissolving the white crystals in THF (10 ml), stirring under ice cooling, adding potassium-t-butoxide (984 mg, 8.8 mmol) to the reaction solution slowly, stirring the solution at room temperature for 2 hours after the completion of dropping, adding a THF solution of 4-(4-pentylcyclohexyl)cyclohexylacetoaldehyde (2.45 g, 8.8 mmol), further stirring for 5 hours, adding ether after completion of reaction, filtering off white solid deposited, concentrating the filtrate under reduced pressure, and purifying the obtained brown oil by means of silica gel column chromatography, to obtain a mixture (1.8 g, 4.4 mmol) of 1-(4-propylphenyl)-4-(4-(4-pentylcyclohexyl)cyclohexyl)-2Z-butene and its E-isomer.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].Cl[CH2:12][CH2:13][N:14]=[C:15]=[S:16]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH:10][C:15]1[S:16][CH2:12][CH2:13][N:14]=1
Reactant: Cc1cccc(NN)c1C
Reactant: S=C=NCCCl
Solvent: Cc1ccccc1
Product: Cc1cccc(NNC2=NCCS2)c1C
Temperature: 0 °C

Procedure:
13.6 g (0.1 mol) of 2,3-dimethylphenylhydrazine were dissolved in 50 ml of toluene, and a solution of 12.8 (5% excess) of 2-chloroethyl isothiocyanate in 25 ml of toluene was added in the course of 15 minutes, while stirring and cooling with ice water, and the mixture was further stirred for 2 hours at room temperature and for 2 hours under reflux. The product was filtered off with suction when cold and was recrystallised from isopropanol. Mp. 220° to 221° (decomposition) (hydrochloride), 13.5 g (52.5% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[Cl:13]C1C=CC=C(C(OO)=O)C=1.CCOC(C)=O.P(Cl)(Cl)(Cl)=O>ClCCl.CCCCCC>[Cl:13][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=1
Reactant: COc1cccc2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COc1cccc2nc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
After 5-methoxyquinoline (104.3 mg, 0.655 mmol) was dissolved in dichloromethane (3 mL), meta-chloroperbenzoic acid (mCPBA; 195 mg, 1.13 mmol) was added thereto at 0° C., and the resulting mixture was stirred for 30 min. After the stirring for 30 min, the reaction temperature was increased from 0° C. to room temperature, followed by further stirring for 3 hr. The completion of the reaction was confirmed by TLC (EtOAc/MC/Hexane=1:2:4). When the reaction was completed, the reaction mixture was extracted with an aqueous solution of 4 N NaOH and dichloromethane, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure, to thereby generate a white solid. The thus generated solid was dissolved in dichloromethane (2.5 mL) and added with phosphorous oxychloride (POCl3; 0.09 mL, 0.992 mmol). The resulting mixture was subjected to distillation under reflux at 60° C. for 3 hr. The completion of the reaction was confirmed by TLC (EtOAc/CHCl3/Hexane=1:2:10). When the reaction was completed, the reactant was cooled down to room temperature, followed by further cooling down with the gentle addition of ice. The pH of the resulting mixture was then adjusted to 10 by dropwise addition of an aqueous solution of 4 N NaOH. When the pH was adjusted to 10, the reaction mixture was extracted with distilled water and dichloromethane, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/CHCl3/Hexane=1:2:10, R.f: 0.6), to thereby obtain 2-chloro-5-methoxyquinoline (40.1 mg, 32%) as a white solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([O:9][C:10]([C@@:12]1([CH2:26][CH:27]=[CH2:28])[CH2:16][C:15](=[O:17])[N:14]([C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1.O>[C:5]([O:9][C:10]([C@@:12]1([CH2:26][CH:27]=[CH2:28])[C@@H:16]([CH2:3][CH:2]=[CH2:1])[C:15](=[O:17])[N:14]([C@@H:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: C=CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H]1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CC=C)C(=O)OC(C)(C)C
Yield: 44.4 %

Procedure:
Allyl bromide (1.36 mL, 16.1 mmol) was added to a solution of (3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.05 g, 12.3 mmol) in tetrahydrofuran (41.0 mL) with stirring under salt ice cooling. A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (16.0 mL, 16.0 mmol) was added dropwise with stirring under salt ice cooling, and the mixture was stirred under salt ice cooling for 15 minutes. A saturated ammonium chloride solution (40 mL) and water (20 mL) were added to the reaction solution, followed by extraction with ethyl acetate (40 mL×1, 20 mL×1). The organic layer was washed with brine (140 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→89:11→88:12→87:13→83:17→80:20→75:25) to give 2.02 g of the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=S)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[N:28]([CH2:31][C:32](=[O:34])[CH3:33])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]4[O:34][C:32]([CH3:33])=[CH:31][N:28]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Reactant: CC(=O)CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C)o3)nc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 25 %

Procedure:
To a solution of N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 121B, 45.7 mg, 0.120 mmol) in dioxane (343 μL) was added 1-azidopropan-2-one (14.28 mg, 0.144 mmol) and triphenylphosphine (37.8 mg, 0.144 mmol). The contents of the flask were immersed into a preheated oil bath for 35 min and cooled to room temperature. The residue was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on an Isco 12 g column eluting with 1-10% MeOH/CH2Cl2. The pale yellow solid was taken up in MeOH and further purified by preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(5-methyloxazol-2-ylamino)-1,6-dihydro imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide was isolated (10 mg, 25% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C@@H:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>C(Cl)Cl>[Cl:34][C:28]1[CH:27]=[C:26]([NH:25][C@H:16]([CH2:15][NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:31]=[CH:30][C:29]=1[C:32]#[N:33]
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (14.15 g, 64 mmol) in CH2Cl2 (50 mL) was added dropwise over 20 min to an ice cold solution of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (19.8 g, 64 mmol) and Et3N (6.5 g, 64 mmol) in CH2Cl2 (150 mL) and the reaction was stirred at room temperature for 30 min. The reaction was washed with H2O and cold 0.1 N HCl. The organic layer was dried over CaCl2, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[C:17]=1[O:26][CH3:27].[F-].[Cs+]>COCCOC.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:26][CH3:27])[C:18]=2[F:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(N)c1OC
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1OC
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
6-Amino-2-chloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (0.2 g, 0.9 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (0.29 g, 1.4 mmol), bis(triphenylphosphine)palladium(II)dichloride (65 mg, 0.1 mmol), and cesium fluoride (0.28 g, 1.9 mmol) were combined in 1 mL of 1,2-dimethoxyethane and 1 mL of water. The reaction mixture was heated in a CEM microwave at 100° C. for 15 min (other temperature/time pairs used in the subsequent examples were 110° C. for 15 min and 150° C. for 5 min). The cooled reaction mixture was diluted with ethyl acetate, washed with water, washed with brine, dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (162 mg, 51.1% yield): mp 155-158° C.; 1H NMR (CDCl3): δ 7.58 (dd, 1H), 7.20 (dd, 1H), 5.56 (br s, 2H) 4.00 (s, 3H), 3.99 (d, 3H), 3.94 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13](O)[CH2:14][OH:15].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(OCC)C>[O:15]1[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCCCC1=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCCC12OCCO2
Temperature: 25 °C

Procedure:
Ethyl 2-oxocyclohexane carboxylate (11.3 g) and ethylene glycol (11 mL) were dissolved in toluene (100 mL). To the reaction mixture camphorsulfonic acid (1.03 g) was added and refluxed for 8 hours with Dean-Stark apparatus. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with saturated aqueous sodium hydrogencarbonate solution. The extract washed with saturated brine, dried over anhydrous magnesium sulfate, and from which the solvent was distilled off to provide a crude product of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15])([O-:7])=[O:6].N1C=CC=CC=1.O>CN(C)C=O>[OH:4][CH2:3][CH2:2][NH:1][S:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])(=[O:15])=[O:16]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO
Temperature: -10 °C
Reaction time: 0.83 h
Yield: 78.1 %

Procedure:
2-Aminoethanol (4.0 mL, 66 mmol) was dissolved in N,N-dimethylformamide (50 mL). After the solution was cooled to −10° C., 2-nitrobenzenesulfonyl chloride (12 g, 52 mmol) and pyridine (4.7 mL, 58 mmol) were added dropwise thereto, followed by stirring for 50 minutes, while the temperature was raised to room temperature. To the reaction mixture was added water (0.20 L), and the mixture was extracted with ethyl acetate (0.10 L×6). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide (10 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[CH:10]=1)#[N:9]
Reactant: Cc1cncc(C(N)=O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cncc(C#N)c1
Yield: 100918.3 %

Procedure:
To a suspension of 5-methyl-nicotinamide from step 2 (10.5 g, 0.077 mmol) in triethylamine (23.3 g, 0.23 mmol) and 400 mL of methylene chloride was added trifluoroacetic anhydride (21.0 g, 0.100 mmol) rapidly at 0° C. The reaction was completed after a few minutes. Water was added and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to give 9.18 g of 3-cyano-5-methylpyridine crude, which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=O)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[NH:26][CH2:25][CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 34.3 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (143 mg, 0.42 mmol) in dry THF (4 mL) was added boron trifluoride diethyl etherate (91 μL, 0.73 mmol) and sodium borohydride (27 mg, 0.73 mmol) at 0° C. under nitrogen. The resulting mixture was stirred for 4 h at 0° C. AcOEt (5 mL) and a saturated solution of NaHCO3 (10 mL) were added. The aqueous phase was extracted with dichloromethane (3×) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 2% MeOH in DCM) to give the title compound as a white solid (66 mg, 48%). 1H NMR (500 MHz, CDCl3): 7.21-7.26 (7H, m), 7.14-7.12 (2H,m), 6.97 (1H, s), 4.48 (2H, t), 3.48 (2H, br s),2.55-2.25 (4H, m), 2.06-1.98 (1H, m), 1.82-1.73 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:14]>CC(N(C)C)=O>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:2]2[N:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:25]1)[CH3:14]
Reactant: Clc1nccc(-c2cccs2)n1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nccc(-c4cccs4)n3)CC2)ccc1OC
Yield: 18.1 %

Procedure:
A solution of 2-chloro-4-thiophen-2-yl-pyrimidine (29.5 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 220° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 11.5 mg (15%) of the title compound. MS (ISP): 425.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH3:27][O:28][C:29]([C:31]1[CH:48]=[CH:47][C:34]2[N:35]=[C:36]([NH:38][CH2:39][C:40]3([F:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[NH:37][C:33]=2[CH:32]=1)=[O:30].CO>CN(C=O)C.C(O)(=O)C>[CH3:27][O:28][C:29]([C:31]1[CH:48]=[CH:47][C:34]2[N:35]=[C:36]([NH:38][CH2:39][C:40]3([F:46])[CH2:45][CH2:44][N:43]([CH2:5][C:4]4[CH:7]=[C:8]([Cl:10])[CH:9]=[C:2]([Cl:1])[C:3]=4[OH:11])[CH2:42][CH2:41]3)[NH:37][C:33]=2[CH:32]=1)=[O:30]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: COC(=O)c1ccc2nc(NCC3(F)CCNCC3)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(NCC3(F)CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 3,5-dichloro-2-hydroxybenzaldehyde (57.3 mg, 0.3 mmol) and sodium triacetoxyborohydride (64 mg, 0.3 mmol) to a solution of 2-{[(4-fluoro-4-piperidyl)methyl]amino}benzimidazole-5-carboxylic acid methyl ester hydrochloride (30 mg, 0.1 mmol) in DMF-acetic acid (10:1) (1.0 ml), the mixture was stirred at room temperature overnight. Methanol (1.0 ml) was added to the reaction mixture to suspend the reaction, and after stirring for 1 hour, the solution was passed through SCX (Bond Elute SCX500MG: cationic ion-exchange resin, Varian). The SCX was washed with methanol and then with a mixed solution of chloroform/methanol (1/1), and elution was performed with a 0.5 N ammonia-dioxane solution to obtain 2-[({1-[(3,5-dichloro-2-hydroxyphenyl)methyl]4-fluoro-4-piperidyl}methyl)amino]benzimidazole-5-carboxylic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@:14]2([CH3:15])[C@@:9]([OH:23])([CH2:10]/[C:11](=[CH:16]\[CH2:17][CH:18]3OCC[O:19]3)/[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>CC1C=CC(S(O)(=O)=O)=CC=1.C(#N)C.O>[C:1]([O:4][CH2:5][C@@H:6]1[C@:14]2([CH3:15])[C@@:9]([OH:23])([CH2:10]/[C:11](=[CH:16]\[CH2:17][CH2:18][OH:19])/[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC[C@]2(O)C/C(=C\CC3OCCO3)CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)OC[C@H]1CC[C@]2(O)C/C(=C\CCO)CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of 1.80 g of (1S,3aS,7aR)-1-acetoxymethyl-5-((Z)-2-(1,3-dioxolan-2-yl)ethyliden]-7a-methylperhydroinden-3a-ol in 20 ml of 1N PTSA in acetonitrile/water 85:15 was kept at room temperature for 8 hrs. The mixture was then neutralised with 5% aqueous NaHCO3, concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in 5 ml of methanol and the solution cooled at 0° C. 0.33 g of NaBH4 were cautiously added and the mixture was stirred for 1 hr. It was then diluted with 10 ml of 5% aqueous NaH2PO4.H2O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 1.13 g of (1S,3aS,7aR)-1-acetoxymethyl-5-[(Z)-3-hydroxypropyliden]-7a-methylperhydroinden-3a-ol as a dense colourless off.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](=[O:10])[NH:2]1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:1][N:2]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=c1[nH]sc2ncccc12
Reactant: CC1CCN(C(=O)Cl)CC1
Product: CC1CCN(C(=O)Oc2nsc3ncccc23)CC1

Procedure:
In analogy to example 1, 60 mg (0.4 mmol) of isothiazolo[5,4-b]pyridin-3-one were reacted with 76 mg (0.47 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 29 mg (27%), M+H+: 278.13.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]3[C@@H:24]4[C@H:29]([CH2:30][CH2:31][C:22]=3[CH:21]=2)[NH:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:28]3[C@@H:29]4[C@@H:24]([C:23]5[CH:32]=[CH:33][C:20]([O:19][C:18]6[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:35][CH:34]=6)=[CH:21][C:22]=5[CH2:31][CH2:30]4)[CH2:25][CH2:26][CH2:27]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(Oc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)c2ccc3[nH]cnc3c2)cc1
Yield: 72 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-8-(4-methoxy-phenoxy)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 72% of theory; LC (method 1): tR=3.16 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: C[C:2](C1C=CC(O)=CC=1)([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=CC=1)C.C=O.[NH2:20][CH2:21][CH2:22][CH2:23][Si](OCC)(OCC)OCC>C(Cl)(Cl)Cl>[O:10]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:2][C:23]=2[CH:22]=[CH:21][NH:20]1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: C=O
Solvent: ClC(Cl)Cl
Product: C1=Cc2ccccc2ON1
Yield: 75 %

Procedure:
In FIG. 6A, BPA (10 g, 43.8 mmol), methanal (5.26 g, 175 mmol) and 3-aminopropyl-triethoxysilane (19.4 g, 87.6 mmol) are mixed in chloroform (100 mL) for reaction at 85 Celsius degrees (° C.) for 24 hours (hr). The product obtained after the reaction do not need to be further purified. The product is directly condensed to obtain an anticipated product Bz-BES (yield: 75%). Elemental analysis calcd (%) for C37H62N2O8Si2: C 61.83, H 9.63, N 3.89; found C 61.70, H 8.67, N 3.81.