Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[CH2:11][O:10][C:9](=[O:13])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:14]=[CH2:15])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:1]1([C:4]2[C:12]3[CH2:11][O:10][C:9](=[O:13])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:14]2[CH2:15][O:24]2)[CH2:3][CH2:2]1
Reactant: C=Cc1ccc2c(c1C1CC1)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-cyclopropyl-5-vinyl-2-benzofuran-1(3H)-one (440 mg, 2.2 mmol) in 50 mL of DCM was slowly added mCPBA (1.14 g, 6.6 mmol) in 50 mL of DCM at 0° C. After warming to room temperature, the mixture was stirred for 12 hours. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers were combined, washed with brine and then concentrated. The residue was purified via prep-TLC to give product 4-cyclopropyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[OH:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OC1C=CC(C(Cl)=O)=CC=1)CCCCC>C(Cl)(=O)C(Cl)=O.ClCCl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:34][C:33]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][C:23]=3[N:22]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1ccc(O)c(N)c1
Agent: CCCCCCOc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCOc1ccc(-c2nc3cc(C(=O)OCC)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hexyloxybenzoic acid in oxalyl chloride (10 ml) and dichloromethane (10 ml) was added N,N-dimethylformamide (0.1 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give crude 4-hexyloxybenzoate chloride. To a suspension of Ethyl 3-amino-4-hydroxybenzoate (733 mg) and triethylamine (1.38 ml) and 4-dimethylaminopyridine (DMAP, 10 mg) in methylene chloride (10 ml) was added the solution of 4-hexyloxybenzoyl chloride obtained above in dichloromethane (5 ml) dropwise at 10° C. The reaction mixture was stirred at 10° C. for 1.5 hours and diluted with dichloromethane (20 ml). the solution was washed with H2O (20 ml), 1N HCl aq. (20 ml×2), H2O (20 ml) and brine (20 ml) successively. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. To the residue was added toluene (15 ml) and p-toluenesulfonic acid (10 mg). The mixture was refluxed for 6 hours and the solvent was removed under reduced pressure. The residue was triturated with acetonitrile, and precipitate was collected with filtration and dried over PO5 to give 2-(4-Hexyloxyphenyl)-5-ethoxycarbonylbenzoxazole (0.60 g).
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH2:10])=[O:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14](O)=[O:15])#[N:12].C(OC(=O)C)(=O)C>O>[NH2:12][C:11]1[N:7]([CH2:1][C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:9])[NH:10][C:14](=[O:15])[CH:13]=1
Reactant: NC(=O)NCc1ccco1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Nc1cc(=O)[nH]c(=O)n1Cc1ccco1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A solution of furfurylurea (7.0 g, 50.0 mmol), cyanoacetic acid (4.7 g, 55.0 mmol), and acetic anhydride (50 ml) was heated to 95° C. for 3 hours. After cooling to ambient temperature the solution was concentrated under reduced pressure to give a crude intermediate that was stirred with water (30 ml). After concentrating, the residue was dissolved in water (100 ml) and treated with a 50% aqueous sodium hydroxide solution (10 ml) to give a pH of 13. This solution was heated at 70° C. for 30 minutes, cooled and filtered. The wet solids were stirred in boiling ethanol for 15 minutes, cooled to ambient temperature and filtered. The filtrate was evaporated under reduced pressure to give 6-amino-1-furfuryluracil (5.5 g, 53% yield) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:25]=[C:26]=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:26]([NH:25][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([Cl:16])[CH:18]=3)=[O:27])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COc1ccc(N=C=O)cc1Cl
Product: COc1ccc(NC(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1Cl

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(3-chloro-4-methoxyphenyl)urea was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 3-chloro-4-methoxyphenyl isocyanate in a similar manner as described above to give a tan solid (42% yield). 1H-NMR (DMSO-d6): δ 10.98 (s, 1H), 8.33 (s, 1H), 7.73 (d, 1H), 7.60 (d, 1H), 7.30 (d, 1H), 7.25-7.14 (m, 2H), 7.08 (d, 1H), 6.63 (d, 1H), 5.01 (m, 1H), 3.82 (s, 3H), 2.65 (m, 2H), 2.04 (m, 1H), 1.94-1.76 (m, 3H); MS m/z 448 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[C:22]1=[O:36])[CH2:16][C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[C:22]1=[O:36])[CH2:16][C:17]([OH:19])=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCOCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(CC(=O)O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Yield: 61.6 %

Procedure:
To a solution of methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate [Example 55] (0.010 g) in THF (2 ml) was added lithium hydroxide (0.003 g) in water (2 ml), and the resultant solution stirred for 16 h. The mixture was acidified to pH 5 using hydrochloric acid (2N), and then concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.006 g) as a white solid.
Reaction SMILES: ClCl.[C:3]([Cl:7])(Cl)(Cl)Cl.[CH:8]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=C(CO)[N:15]=1)([CH3:10])[CH3:9]>C(O)C>[CH:8]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:3]([Cl:7])[N:15]=1)([CH3:10])[CH3:9]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)c1nc(CO)c(CO)[nH]1
Agent: ClCl
Solvent: CCO
Product: CC(C)c1nc(Cl)c(CO)[nH]1
Reaction time: 1 h

Procedure:
26.3 Grams (15.6 mmol) of a 4.2% chlorine-carbon tetrachloride solution was dropwisely added to a solution consisting of 2.52 g (14.8 mmol) of the 2-isopropyl-4,5-bis(hydroxymethyl) imidazole and 200 ml of ethanol maintaining a temperature of 40° C. with stirring. After the dropwise addition has been finished, the stirring was continued at 40° C. for one hour and, then, the solvent was distilled off under reduced pressure. After the residual brown oil was dissolved in water, sodium carbonate was added thereto to make the mixture alkaline. The mixture was evaporated again under reduced pressure. The obtained resulting solid product was extracted with ethanol, the extract was evaporated under reduced pressure, and the resulting solid product was extracted with cold water. 0.71 Grams of the starting 2-isopropyl-4,5-bis(hydroxymethyl) imidazole was recovered as the extraction residue, and the extract after evaporate under reduced pressure was subjected to the column chromatography (silica gel-acetone) to obtain a 2-isopropyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.56 g (yield, 30.3% with respect to the starting material consumed). By using acetonitrile, the compound was further refined. The TLC and spectra of this compound were measured to be the same as those of Example 4.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:2][CH2:3]1)=[O:26]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 1 h

Procedure:
3.0 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 4.0 ml of tiethylamine were suspended in 20 ml of dichloromethane, and to the suspension was added dropwise 3.5 g of 3,4-dimethoxybenzoylchloride in 20 ml of dichloromethane under ice-cooled condition with stirring. Then the reaction was continued for additional 1 hour at a room temperature. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with chloroform. The chloroform layer was washed with water and a saturated sodium chloride aqueous solution in this order and was dried with anhydrous sodium sulfate, and the solvent was removed by distillation. The residue thus obtained was recrystallized from ethanol-chloroform to obtain 4.1 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:30])[C:16]([NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([OH:30])[CH2:16][NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: OCCN(CCO)CCO
Product: Oc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Yield: 59.9 %

Procedure:
(2R)-2-(4-Benzyloxyphenyl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (605 mg) was dissolved in tetrahydrofuran (7.5 ml), and 2M borane-dimethyl-sulfide complex in tetrahydrofuran (2.25 ml) was added to the solution at room temperature with stirring. After the mixture was heated under reflux for 3 hours, a solution of triethanolamine (1.12 g) in tetrahydrofuran (2.5 ml) was added to the reaction mixture and the mixture was heated under reflux for 15 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Recrystallization of the residue from ethyl acetate gave (1R)-1-(4-benzyloxyphenyl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-amino]ethanol (350 mg) having a melting point of 132-134° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:21]4[N:25]=[C:24]([CH:26]5[CH2:29][N:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:27]5)[O:23][N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][N:35]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[N:36]1.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([C:21]2[N:25]=[C:24]([CH:26]3[CH2:27][N:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:29]3)[O:23][N:22]=2)=[CH:15][C:14]=1[NH:13][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:38]=[CH:39][N:35]([CH3:34])[N:36]=3)=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:12]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(Br)ccn45)c3)no2)C1
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: [K+]
Solvent: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(-c6ccn(C)n6)ccn45)c3)no2)C1
Temperature: 80 °C

Procedure:
Methyl 3-(3-(3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (42) (40 mg, 0.078 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.6 mg, 0.094 mmol) and Pd(PPh3)4 (9 mg, 0.0078 mmol) were added to a flask equipped with a stir bar. The flask was evacuated and backfilled with nitrogen several times. DMF (1 mL) and 1.8 M K2CO3 (0.094 mmol) were added by syringe. The flask was sealed and heated at 80° C. for 12 hours. The reaction was filtered and directly purified by preparative reverse phase HPLC to afford methyl 3-(3-(4-methyl-3-(7-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F56). MS m/z 513.2 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccnc2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of the title compound from Step B (4.0 g, 14.32 mmoles) in DMF (120 mL) was added to a stirred solution of NaH (0.52 g, 21.66 mmoles) and imidazole (1.46 g, 21.47 mmoles) in DMF (20 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% cone NH4OH in methanol)-CH2Cl2 as eluant to give the title compound (0.94 g, 26%). FABMS (M+1)=252; δH (CDCl3) 1.4 (s, 9H), 1.6-1.8 (m, 2H), 2.0 (dd, 2H), 2.8 (dt, 2H), 4.05 (m, 1H), 4.2 m, 2H), 6.9 (s, 1H), 7.0 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[C:12]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:5]1=[O:37].Cl>CO.O1CCCC1.O>[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:12]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:5]1=[O:37]
Reactant: COC(=O)CCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)c(Cc3cccc4ccccc34)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
Aqueous sodium hydroxide solution (1M, 4 ml) was added to a solution of methyl 4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate (0.382 g) in methanol (8 ml) and tetrahydrofuran (4 ml). The mixture was stirred at room temperature for 4 hours, diluted with water (50 ml), acidified with hydrochloric acid (2M) and extracted with an ether/ethyl acetate mixture (5:3, 80 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual solid was recrystallised from ethyl acetate/hexane to give the title compound (0.19 g).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH2:24]O)[CH:21]=[N:22][CH:23]=2)=[CH:14][CH:13]=1>ClCCl>[Cl:3][CH2:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:27])([F:26])[F:10])=[CH:13][CH:14]=2)[CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
177 mg (0.11 ml, 1.49 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.1 ml N,N-dimethylformamide (DMF) and 196 mg (0.74 mmol) [5-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in 6 ml dichloromethane and stirred for 1.5 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (174 mg, 81%) used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:18])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2].IC.[CH3:21]COC(C)=O.CCCCCC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:21])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1c(O)nc2cc(F)ccc2c1C
Solvent: ClCCl
Solvent: CI
Solvent: CCCCCC
Product: CCOC(=O)c1c(OC)nc2cc(F)ccc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a stirred solution of 2.30 g (9.24 mmol) 7-fluoro-2-hydroxy-4-methylquinoline-3-carboxylic acid ethyl ester in DCM (60 ml) were added 6.36 g (23.1 mmol) Ag2CO3 and 1.44 ml (23.1 mmol) iodomethane at RT. The reaction mixture was stirred at RT for 16 h. Then the mixture was filtered through celite and the filtrate was concentrated in vacuum. After CC (EtOAc/hexane 1:4) of the residue, 1.50 g (5.70 mmol, 62%) 7-fluoro-2-methoxy-4-methylquinoline-3-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.[C:28]1([N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][N:18]([C:35]([N:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:36])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCN(C(=O)N(c4ccccc4)c4ccccc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
In 10 ml of dimethylformamide was dissolved 400 mg (1.46 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained according to the method described in South African Patent No. 67 06512 (1968), and 1.02 ml (7.32 mmol) of triethylamine was added thereto. To the resulting mixture was added 406 mg (1.75 mmol) of diphenylcarbamoyl chloride, followed by overnight stirring at room temperature. After the reaction mixture was poured into water, the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 680 mg of the desired compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][CH:15]1[CH2:18][NH:17][CH2:16]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH:15]([F:14])[CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: FC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CC(N2CC(F)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.14 g, 0.82 mmol), 3-fluoroazetidine hydrochloride (0.1 g, 0.9 mmol) in DCE (3 mL), trimethoxymethane (0.88 mL, 8.5 mmol) and acetic acid (0.046 mL, 0.81 mmol). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.26 g, 1.22 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water; the organic phase was washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 40:60 to 100:0) to give 3-Fluoro-[1,3]biazetidinyl-1′-carboxylic acid tert-butyl ester as a colourless oil (0.109 g, 59%). 1H NMR (CDCl3, 400 MHz) δ 5.15 (dt, J=57.1, 5.3 Hz, 1 H); 3.93 (dd, J=9.1, 7.0 Hz, 2 H); 3.74-3.59 (m, 4 H); 3.45-3.38 (m, 1 H); 3.31-3.25 (m, 1 H); 3.23-3.17 (m, 1 H); 1.43 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH:26]1([N:23]2[CH2:22][CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]4[N:13]=[CH:12][N:11]([C@@H:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[CH3:10])[C:15]=4[CH:16]=3)[CH2:25][CH2:24]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C1CCCCC1
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCNCC3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C4CCCCC4)CC3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole (prepared from Example 4 step d, 0.047 g, 0.13 mmol) and cyclohexanone (0.0.038 g, 0.38 mmol) in dichloromethane (1 mL) was added sodium triacetoxyborohydride (NaBH(OAc)3, 0.11 g, 0.52 mmol) and acetic acid (3 drops). The reaction mixture was stirred at room temperature for 18 h, and quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude material was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give a white solid (0.015 g, 0.032 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1 H), 7.69 (d, J=8.4 Hz, 1 H), 7.44 (d, J=2.4 Hz, 1 H), 7.32 (dd, J=1.2, 8.4 Hz, 1 H), 7.12 (dd, J=2.4, 8.4 Hz, 1 H), 7.06 (s, 1 H), 6.82 (d, J=8.4 Hz, 1 H), 5.99-5.94 (m, 2 H), 3.30 (d, J=2.8 Hz, 2 H), 2.81-2.78 (m, 2 H), 2.58-2.48 (m, 2 H), 2.38-2.36 (m, 1 H), 1.97 (d, J=6.8 Hz, 3 H), 1.94-1.82 (m, 4 H), 1.67-1.64 (m, 1 H), 1.31-1.26 (m, 4 H), 1.15-1.11 (m, 1 H); MS: (ES) m/z calculated for C26H30Cl2N3 [M+H]+ 454.2, found 453.