Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[C:40]([CH2:42][NH2:43])[CH:39]=[C:38]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=3)[N:37]=2)[CH2:32][CH2:31]1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:43][CH2:42][C:40]1[CH:39]=[C:38]([C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:49]=2)[N:37]=[C:36]([N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH:41]=1)=[O:7])[CH3:2]
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCOCC2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCOCC2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of acid 4B (0.40 g, 1.46 mmol) in THF (20 mL) was added with DEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27B (530 mg, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (6/4 EtOAc/Petroleum ether) to afford a white solid (95 mg) after crystallization from ethyl ether. Yield=12%. 1HNMR (DMSO, 200 MHz) δ 1.087 (t, 3H, J=7.8), 3.39 (q, 2H, J=7.6), 3.55 (m, 4H), 3.71 (m, 4H), 4.42 (d, 2H, J=6.2), 5.13 (s, 1H), 6.12 (s, 1H), 6.85 (s, 1H), 7.35 (s, 1H), 7.47 (t, 2H, J=8), 7.83-7.90 (m, 4H), 8.26 (d, 2H, J=8), 8.80 (bt, 1H). [M+1] 592.33 (C28H28F4N4O4S requires 592.60).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[N:33]=[C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:31]=[CH:30][CH:29]=1)(C(C)(C)C)(C)C.O>C1COCC1>[N:34]1([C:32]2[N:33]=[C:28]([CH2:27][OH:26])[CH:29]=[CH:30][CH:31]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCOCC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A solution of tetrabutylammonium fluoride (1.44 mmol) in THF (1.0 M, 1.44 ml) was added to a stirred solution of 4-[6-(tert-butyldimethylsilanyloxymethyl)-pyridin-2-yl]morpholine (370 mg, 1.2 mmol) in THF (10 ml) at room temperature under N2 and the reaction mixture was stirred at room temperature for 1 h. H2O (30 ml) was added and the organic were extracted with EtOAc (150 ml), then washed with brine (50 ml), dried and concentrated under reduced. The mixture was purified by column chromatography on silica using 100% Et2O as eluent to yield the desired hydroxymethylpyridine (192 mg, 82%). 1H NMR (360 MHz, CDCl3) δ 7.49 (1H, dd, J=8.4, 7.4 Hz), 6.57 (1H, d, J=7.4 Hz), 6.51 (1H, d, J=8.4 Hz), 4.62 (2H, s), 3.83 (4H, t, J=4.9 Hz), 3.50 (4H, t, J=4.9 Hz).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21]>C1C=CC=CC=1>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=2)[CH3:11])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Solvent: c1ccccc1
Product: CC(c1ccccc1)n1c(=O)n(O)c(=O)c2oc3ccccc3c21

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 1-bromoethyl)benzene and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 1.98 (d, J=7 Hz, 3H); 6.32 (br s, 1H); 7.25-7.43 (m, 7H); 7.59 (dd, J=8 Hz, 1H); 7.81 (d, J=8 Hz, 1H); Ret. time=2.54 min., m/z=323.0.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al](C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:22]([C:30](OCC)=[O:31])[N:21]=[C:20]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>ClCCl.CCCCCCC>[CH:1]1([NH:7][C:30]([C:22]2[N:21]=[C:20]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])[N:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[C:23]=2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Part C: Cyclohexylamine (0.91 ml, 8 mmol) is dissolved in dichloromethane (20 ml) and (CH3)3Al (4 ml of a 2 M solution in heptane, 8 mmol) is added. The resulting mixture is stirred for 10 minutes at room temperature and ethyl 1-(4-chlorophenyl)2-(2,4-dichlorophenyl)-5-(pyrolidin-1-ylmethyl)-1H-imidazole4-carboxylate (1.8 gram, 3.8 mmol) is added. The resulting mixture is stirred at room temperature for 16 hours, poured into an aqueous NaHCO3 solution, stirred for 30 minutes and filtered over hyflo. The filtrated is twice extracted with dichloromethane. The organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (dichloromethane/methanol=98/2 (v/v)) gives N-cyclohexyl-1-(4-chlorophenyl )-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide, compound 1 (1.06 gram, 53% yield). Melting point: 155-157° C.
Reaction SMILES: C([N:5]([S:10](=[O:19])(=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](=[NH:9])[O:7][CH3:8])(OC)=O.[H-].[Na+].O.C1C[O:26][CH2:25]C1>>[CH:12]1([N:11]2[C:25](=[O:26])[NH:9][C:6]([O:7][CH3:8])=[N:5][S:10]2(=[O:18])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=N)N(C(=O)OC)S(=O)(=O)NC1CCCCC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC1=NS(=O)(=O)N(C2CCCCC2)C(=O)N1

Procedure:
A solution of the isourea from Step 1. above (208.9 g) in anhydrous THF (500 ml) is added dropwise to a stirred suspension of 60% sodium hydride dispersion (57.0 g) in anhydrous THF (750 ml) and the reaction mixture is refluxed for 2 hours. Distilled water (450 ml) is added dropwise to the stirred mixture which is washed with diethyl ether. 20% sulfuric acid (400 ml) is added slowly to the stirred reaction mixture, which is extracted with methylene chloride, dried, filtered, and the filtrate evaporated and dried under high vacuum yielding the desired product as a crude solid which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH3:15][C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([OH:24])[CH:23]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:16]([C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][CH:19]=1)[O:24][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1)(=[O:17])[CH3:15]
Reactant: COC(=O)Cc1c(Cl)ncnc1OC
Reactant: CC(=O)c1cccc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C(C)=O)c1
Yield: 90.1 %

Procedure:
A mixture of methyl 4-chloro-6-methoxy-pyrimidin-5-yl-acetate (21.7 g, 100 mmol), 3-hydroxyacetophenone (13.6 g, 100 mmol), potassium carbonate (20.7 g, 150 mmol) and a catalytic amount of 18-crown-6 in dimethylformamide (50 ml) is heated to +120° C. for 1 hour. Addition of crushed ice, filtration and drying gives the methyl 4-(3-acetylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate (28.5 g) having a m.p. of 65°-67° C.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:11])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[I-:12].[Na+]>CC(C)=O>[CH:6]1([CH2:5][C:4](=[O:11])/[CH:3]=[CH:2]/[I:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [I-]
Reactant: O=C(/C=C/Cl)CC1CCCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)CC1CCCC1

Procedure:
A solution of 57 g. of 1-chloro-4-cyclopentyl-trans-buten-3-one (Example 32) in 360 ml. of acetone containing 55 g. of sodium iodide is stirred at the reflux temperature for 18 hours. The resulting mixture is cooled, filtered and and the water liquor is taken to dryness. The residual oil is dissolved in ether washed successively with water, dilute sodium thiosulfate solution, and saturated sodium chloride solution, dried with anhydrous magesium sulfate and taken to dryness to give 87 g. (99%) of orange oil. Vapor phase chromatography shows one peak.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:12](Cl)(=[O:16])[O:13][CH2:14][CH3:15].O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>>[C:19](=[O:21])([O:22][CH2:23][CH3:24])[O:5][CH2:4][CH2:3][N:2]([C:12]([O:13][CH2:14][CH3:15])=[O:16])[CH3:1]
Reactant: CCOC(=O)Cl
Reactant: CCOC(C)=O
Reactant: CNCCO
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)OCCN(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(methylamino)ethanol (100 g) in ethyl acetate (1000 mL) was added pyridine (222 mL), and added dropwise ethyl chlorocarbonate (240 mL) over 2 hrs under ice-cooling. After the addition, the reaction solution was stirred at room temperature for 18 hrs. To the solution was added water (300 mL), and the ethyl acetate layer was separated. The ethyl acetate layer was washed with 1 N hydrochloric acid (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate, followed by concentrating under reduce pressure. The residue was distilled under reduce pressure to give title compound (180 g) as colorless fraction having boiling point of 95-100° C. (pressure: 0.1-0.2 mmHg).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[C:28](Cl)(=[O:38])[C:29]1[CH:37]=[CH:36][CH:35]=[C:31]([C:32](Cl)=[O:33])[CH:30]=1.C(N(CC)CC)C.[CH3:47][OH:48]>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@:7]1([C:28](=[O:38])[C:29]1[CH:37]=[CH:36][CH:35]=[C:31]([C:32]([O:48][CH3:47])=[O:33])[CH:30]=1)[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reactant: CO
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cccc(C(=O)[C@]2(OCc3ccccc3)C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2COC(C)=O)c1
Yield: 69 %

Procedure:
To a solution of 3.00 g of 5'-O-acetyl-3'-O-benzyl-2'-deoxy-5-fluorouridine in 100 ml of dry dioxane were added 2.40 g of isophthaloyl chloride and 8.5 ml of triethylamine, and the mixture was refluxed for 2 hours. Then, to the reaction mixture were added 5 ml of methanol and a suspension of 9.60 ml of triethylamine in 100 ml of dry dioxane, and the mixture was refluxed for 2 hours. The insolubles were removed by filtration and the filtrate was concentrated. The residue was dissolved in 100 ml of ethyl acetate, and the solution was washed twice with 30 ml of saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was placed on a silica gel column to conduct a gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform. The fractions corresponding to the title compound were collected and concentrated to dryness, giving the title compound as a powder in a yield of 69%.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C@:7]23[CH2:14][C@@H:13]([NH:15][C:16](=[O:30])[C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=4)[CH2:12][N:11]2[C:10](=[O:31])[N:9]([C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)[C:8]3=[O:40])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C@:7]23[CH2:14][C@@H:13]([NH:15][C:16](=[O:30])[C:17]4[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=4)[CH2:12][N:11]2[C:10](=[O:31])[N:9]([C:32]2[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=2)[C:8]3=[O:40])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N[C@H]2CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(Cc3ccc(Br)cc3)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C(=O)N[C@H]2CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(Cc3ccc(Br)cc3)C2)cc1
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of Example 80 (0.161 g) in CH2Cl2 (4 mL) was added TFA (1 mL). After 3 hours at room temperature, the reaction mixture was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel: 80:20 CH2Cl2:MeOH, Chromatotron) to afford the titled compound (0.133 g). MS (m/z) 614 [M-H]−.
Reaction SMILES: C[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12]C(C)=O.C[O:17][C:18](=[O:21])[CH2:19]Br>O>[C:18]([O:21][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH3:2])=[CH:10][C:9]=1[CH3:12])(=[O:17])[CH3:19]
Reactant: CC(C)=O
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: COC(=O)CBr
Solvent: O
Product: CC(=O)OOc1ccc(C(C)=O)cc1C
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxypropiophenone (10.0 g, 60.24 mmol), CsCO3 (21.6 g, 66.3 mmol), and acetone (150.0 mL) under an N2 atmosphere was treated with methylbromoacetate (7.26 mL, 78.3 mmol) and the mixture heated to reflux for 4 h. The mixture was then allowed to cool to ambient temperature, diluted with H2O (150 mL) and extracted with CH2Cl2 (2×300 mL). The organic layers were combined, dried with Na2SO4, and the solvent removed in vacuo to provide the title compound (12.75 g, m.p. 64-66° C.). 1H NMR (400 MHz, DMSO-d6) δ9.35 (d, 2 H, J=8.9 Hz), 7.040 (d, 2 H, J=8.9 Hz), 4.920 (s, 2 H), 3.715 (s, 3 H), 2.981 (q, 2 H, J=7.2 Hz), 1.071 (t, 3 H, J=7.2 Hz).
Reaction SMILES: [H][H].[CH2:3]([CH:10]1[CH:15]2[CH2:16][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]([CH:13]=[CH:14]2)[NH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23](Cl)(=[O:25])[CH3:24]>[Pd].N1C=CC=CC=1>[C:23]([N:11]1[CH:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:15]2[CH2:16][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]1[CH:13]=[CH:14]2)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CC2C=CC1NC2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: CCOC(=O)C1CC2C=CC1N(C(C)=O)C2Cc1ccccc1

Procedure:
Reduction of the ethyl 2,3-dibenzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylic described in Example 1AE in the form of the hydrochloride salt with one molar equivalent of hydrogen over a palladium-on-charcoal catalyst at ambient temperature and reaction of the resulting ethyl 3-benzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate with acetyl chloride in the presence of pyridine affords ethyl 2-acetyl-3-benzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[CH:20][CH:19]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: c1c[nH]cn1
Reactant: Cc1ccc2ccc3c(C#N)cc(C(=O)c4ccc(F)cc4)n3c2c1
Product: Cc1ccc2ccc3c(C#N)cc(C(=O)c4ccc(-n5ccnc5)cc4)n3c2c1

Procedure:
The title compound was prepared as described for Example 21, using 3-cyano-1-(4-fluoro-benzoyl)-8-methyl-pyrrolo[1,2-a]quinoline (54 mg, 0.164 mmol) and imidazole, and yielded 50.1 mg (81%). 1H NMR (CDCl3): 8.20 (dt, J=8.7, 2.1 Hz, 2H), 8.04 (s, broad, 1H), 7.89 (m, 1H), 7.74 (m, 2H), 7.62 (m, 3H), 7.44 (m, 2H), 7.43 (s, broad, 1H), 7.39 (dd, J=7.8, 0.6 Hz, 1H), 7.30 (s, broad, 1H), 2.54 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([F:41])[CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:36]=[C:35]([F:34])[CH:40]=[C:39]([F:41])[CH:38]=4)(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cc(F)cc(F)c3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3,5-difluorobenzene-1-sulfonyl chloride (38.26 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 25 mg (35%); 1H NMR (CDCl3, 300 MHz): δ 9.553 (s, 1H), 8.002-8.032 (d, 1H, J=9 Hz), 7.752-7.798 (m, 4H), 7.664-7.701 (dd, 1H, J=8.7, 2.1 Hz), 7.466-7.495 (d, 2H, J=8.7 Hz), 7.175 (m, 1H), 7.002-7.009 (d, 1H, J=2.1 Hz), 1.831 (s, 6H); MS: m/z 583 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].N[CH:44]([OH:46])[CH3:45].C[N:48](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:48][CH2:45][CH2:44][OH:46])=[O:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CC(N)O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NCCO

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and aminoethanol with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:21]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(C)c1ccc2c(c1)OCO2
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccccc1)OCO2
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of methyl 2-(3,4-methylenedioxyphenyl)propionate (1.04 g, 5 mmol) in CH2Cl2 (30 mL) at 0° C. was added SnCl4 (1M solution in CH2Cl2, 9 mL, 9 mmol). Then a solution of benzoyl chloride (1 mL) in CH2Cl2 (10 mL) was added dropwise and the mixture obtained was warmed to 25° C. for 20 h with stirring. The reaction mixture was poured into a separatory funnel containing Na2CO3 solution (sat. 50 mL) and some ice. The organic layer was separated and the aqueous was extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water (50 mL), NaHCO3 (sat. 40 mL) and brine (50 mL) and dried over Na2SO4. The pure product (360 mg, 23%) was obtained by chromatography on silica gel (hexane/ethyl acetate=4:1). 1H NMR (CDCl3) 7.80-7.45 (m, 5H), 6.96 (s, 1H), 6.79 (s, 1H), 6.03 (s, 2H) 3.70 (m, 1H), 3.58 (s, 3H), 1.47 (d, J=7.4, 3H).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([S:20][CH3:21])[N:9]=2)[C:6]2[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=2[N:4]=1.ClC1C=CC=C(C(OO)=[O:35])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:26][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([S:20]([CH3:21])=[O:35])[N:9]=2)[C:6]2[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=2[N:4]=1
Reactant: CSc1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (3 g) in dichloromethane (60 mL) was added m-chloroperbenzoic acid (75% wet) (1.9 g) under ice-cooling, and the mixture was stirred at 0° C. for 15 minutes. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 2-(difluoromethyl)-1-[2-(methylsulfinyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.8 g) as a white amorphous substance.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][O:24][Si](C(C)C)(C(C)C)C(C)C)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:36])[CH3:35])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OC(=O)C)C>[F:37][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][OH:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:35])[CH3:36])=[O:4]
Reactant: CC(C)[Si](OCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)s1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@H](c2ccc(-c3cnc(CO)s3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(2-((triisopropylsilyloxy)methyl)thiazol-5-yl)phenyl)oxazolidin-3-yl)ethanone (2.6 g, 4.8 mmol) in tetrahydrofuran (50 mL) is added tetrabutylammonium fluoride (5.2 mL of a 1M solution). The reaction is stirred at room temperature for 1 hour. The reaction is diluted with ethylacetate (100 mL) and washed with water and brine. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude material is chromatographed eluting from 100% hexanes to 75:25 ethylacetate:hexanes to afford the title compound (1.8 g): m/z (CI) M+H 401.