Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Mg].[C:13](Cl)(=O)[CH2:14]C.S(=O)(=O)(O)O>C(O)C.C(OCC)C.C(Cl)(Cl)(Cl)Cl>[C:3]([CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:13][CH3:14]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
A solution of diethyl malonate (80 g.) in ethanol (40 ml.) was added dropwise over 20 minutes to a mixture of magnesium (12.5 g.), carbontetrachloride (0.5 ml.) and ethanol (12.5 ml.) was stirred at room temperature for 10 minutes. Diethyl ether was added dropwise to the solution and refluxed under heating for 30 minutes. To the solution was added dropwise a solution of propionyl chloride (49 g.) in diethyl ether (50 ml.) under cooling over 10 minutes, and the mixture was refluxed under heating for 30 minutes. 20% sulfuric acid (200 ml.) was added to the solution, and the diethyl ether layer was separated, washed with 10% sulfuric acid and water successively, dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo. To the oily residue was added β-naphthalene sulfonic acid hydrate (8 g.) and the mixture was heated at 200° C. for 1 hr. After cooling, diethyl ether (100 ml.) was added to the mixture and washed with 10% aqueous sodium carbonate (100 ml.) three times. The aqueous layer was extracted with diethyl ether (100 ml.) five times, and the extract was washed with water, dried over magnesium sulfate and then distilled under reduced pressure (24 mmHg). The distillate at 100° to 110° C. was collected and distilled again under reduced pressure (25 mmHg). The distillate at 97° to 99° C. was collected to give ethyl propionylacetate (19.8 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[NH:21][CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)[C:27]([OH:29])=[O:28]>C(Cl)Cl>[C:2]([O:29][C:27]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)=[CH:24][N:23]=2)[CH2:18][CH2:19][CH2:20]1)=[O:28])([CH3:7])([CH3:3])[CH3:1]
Reactant: c1ccc(COc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21

Procedure:
6-(5-Benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method IV, as illustrated above. It is then used to synthesize 6-(5-benzyloxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:17])[CH:9]=2)=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>COCOC.O>[C:20]([C:23]1[CH:28]=[C:27]([C:2]2[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:17])[CH:9]=3)=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1ccc(OCc2ccc(Br)cc2)cc1O
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCOC
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(COc3ccc(C(=O)O)c(O)c3)cc2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-bromo-benzyloxy)-2-hydroxy-benzoic acid (196.3 mg; 0.6075 mmol), 3-acetylbenzene boronic acid (99.7 mg; 0.6080 mmol) and Na2CO3 (−4 eq.) was dissolved in dimethoxymethane (4 mL) and H2O (2 mL). The solution was flushed with argon, Cl2Pd(PPh3)2 (˜2.5 mol %) was added and the mixture stirred under an atmosphere of argon at 100° C. for 16 hours. The resulting black solution was filtered (Gelman Acrodisc GHP, Ø25 mm) and slowly added to a cold 1 M HCl (aq.; 15 mL) solution. The precipitate was filtered off and thoroughly washed with water. Drying in vacuo yielded 195 mg (88%) of a greyish, solid compound with satisfactorily purity. Mp. 215-220° C. (decomposes); MS (ESI−): 361 (MH−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][OH:29].Cl>CN(C)P(=O)(N(C)C)N(C)C>[OH:29][CH2:28][CH2:27][CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: OCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(-c2nc(SCCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide under nitrogen at 45°, 0.73 g of 50% strength sodium hydride suspension (in mineral oil, de-oiled with hexane) is added in portions and the mixture is stirred at room temperature for 1 hour. 2.22 g of 3-bromopropanol are then added dropwise. The mixture is then stirred at room temperature for 90 minutes, poured into a mixture of 400 ml of ice-water and 20 ml of 2 N hydrochloric acid, extracted by stirring twice with 100 ml of ethyl acetate each time, washed twice with 100 ml of water each time, dried over sodium sulphate and concentrated by evaporation under reduced pressure. The oily crude product is dissolved in 30 ml of toluene, and chromatographed over a column of 30 g of silica gel with toluene as eluant. The 800-1200 ml fractions are combined, concentrated to dryness by evaporation and dried for 3 hours at 0.01 mbar. Analytically pure 2-(3-hydroxypropylthio)-4,5-bis-(p-methoxyphenyl)-thiazole is obtained in the form of a pale yellow oil, Rf value 0.25 (silica gel thin layer/toluene:ethyl acetate 3:1).
Reaction SMILES: [N:1]12[CH2:9][CH:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:10]12([CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12]>C(O)C>[C:10]12([CH2:20][S:21]([OH:24])(=[O:22])=[O:23])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12].[N:1]12[CH2:9][C@@H:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCCC1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=C1CN2CCC[C@H]1C2
Temperature: 70 °C

Procedure:
To a solution of (±) 1-azabicyclo[3.2.1]octan-6-one (124 g, 1 mol) in ethanol (100 ml) was added a solution of (+) camphorsulfonic acid (232 g, 1.0 mol) in 200 ml ethanol. The mixture was heated to 70° C. and slowly cooled over 2 hours to 5° C. The precipitated crystals were collected by filtration and washed with cold ethanol (3×40 ml). The crude compound was crystallized from ethanol (150 ml) giving the title compound in 57.3 g yield. M.p. 267-268° C. (decomp.). [α]D=+48° (water).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:19][C:20]([F:50])([F:49])[C:21]1[CH:34]=[CH:33][C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][C:41]([O:45][CH2:46][CH2:47][OH:48])([CH3:44])[CH2:40][CH2:39]3)[C:23]=2[CH:22]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:49][C:20]([F:19])([F:50])[C:21]1[CH:34]=[CH:33][C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][C:41]([O:45][CH2:46][CH2:47][O:48][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:44])[CH2:42][CH2:43]3)[C:23]=2[CH:22]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(OCCO)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OCCOC1(C)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
A solution of 3.3 g of hexadecanoic acid chloride in 20 ml of anhydrous benzene was added dropwise at 10° C to a solution of 5 g of 2-trifluoromethyl-10-[3-(4-{2-hydroxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in 50 ml of anhydrous benzene containing 1.2 g of triethylamine and the mixture was stirred for 20 hours at room temperature. The mixture was washed with water and then was stirred for 4 hours with 100 ml of an aqueous saturated sodium bicarbonate solution. The organic phase was decanted and concentrated. The oily residue was subjected to chromatography over silica gel with a 98-2 benzene-triethylamine mixture as eluant to obtain 6.4 g of 2-trifluoromethyl-10-[3-(4-{2-hexadecanoyloxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in the form of a yellow oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([CH3:16])[CH:4]1[CH3:25])C.Br.C(O)(=O)C.C(OC(OCC)C=C)C>C(O)C>[CH3:25][C:4]1[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([CH3:16])[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([OH:15])(=[O:14])=[O:13])[CH:7]=2)[N:3]=1
Reactant: CCN1c2ccc(S(=O)(=O)O)cc2C(C)(CCCCCC(=O)O)C1C
Agent: Br
Agent: C=CC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCCC(=O)O
Temperature: 70 °C

Procedure:
6-(2,3-Dimethyl-5-sulfo-3H-indol-3-yl)hexanoic acid was synthesised as described in Example 5. To a stirred solution of 6-(1-ethyl-2,3-dimethyl-5-sulfo-3H-indol-3-yl)hexanoic acid (1.8 g, 5.3 mmol) in ethanol (200 ml) at ambient temperature was added hydrobromic acid (10 ml 48% aqueous solution). After 1 Hr the reaction solvent was removed in vacuo. The hydrobromide salt was re-dissolved in acetonitrile (150 ml) and acetic acid (1.54 ml) and acrolein diethyl acetal (6.6 g, 51 mmol). The reaction mixture was heated to 70° C. for 30 minutes. The solution was cooled and the solvent removed in vacuum. The product was rapidly purified by preparative HPLC on reverse phase C18 column using gradient elution of water containing 10% acetonitrile to acetonitrile (containing 0.1% TFA) as solvent over 30 minutes. All fractions were monitored by MALDI-TOF mass spectrometry (M/Z=498). Fractions containing product mass were pooled. Evaporation of the solvent gave a sticky mass (162 mg 11%). It was immediately used for the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[O:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(Cl)(Cl)=O>[O:1]=[C:2]1[C:7]([C:8]([O:10][C:16]2[C:17]3[C:18](=[CH:14][CH:4]=[CH:5][CH:6]=3)[CH:19]=[CH:20][N:15]=2)=[O:9])=[CH:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[O:3]1
Reactant: c1ccncc1
Reactant: O=C(O)c1cc2ccccc2oc1=O
Solvent: O=S(Cl)Cl
Product: O=C(Oc1nccc2ccccc12)c1cc2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.0 g of the commercially available 2-oxo-2H-1-benzopyran-3-carboxylic acid and 10 ml of thionyl chloride were refluxed for 3 h. The resulting solution was evaporated under reduced pressure. The residue was suspended in 10 ml anhydrous toluene. The solvent was eliminated by distillation under reduced pressure. The two last steps were repeated twice. The residue was dispersed in 10 ml dioxane. To this suspension were added 1-hydroxyquinoleine (1.1 éq.) and anhydrous pyridine (1.1 eq.). After 90 min stirring at room temperature, the solvent was removed by distillation under reduced pressure. The residue was solubilized in chloroform and the organic phase was washed three times with HCl 0.1N, then dried over MgSO4. The solvent was evaporated under reduced pressure and the residue obtained was recrystallized in ethyl acetate.
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>C1(C)C=CC=CC=1>[CH3:14][C:13]1([CH3:15])[C:16]([CH3:18])([CH3:17])[O:1][B:2]([C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[O:11]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=C(O)c1ccc(B(O)O)s1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OB(c2ccc(C(=O)O)s2)OC1(C)C
Temperature: 115 °C
Yield: 75 %

Procedure:
To a solution of 5-(dihydroxyboryl)-2-thiophenecarboxylic acid (4.0 g) in toluene (50 ml) was added pinacol (2.75 g). The reaction mixture was heated at 110-120° C. and the water set free during the reaction was continuously removed by a Dean-Stark apparatus. After 4 hours heating, the reaction mixture was cooled down to room temperature thus providing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophene-carboxylic acid as a white solid which was filtered off (4.43 g, yield: 75%) and used as such for further reaction. The pure compound was characterized by its 1H NMR spectrum (300 MHz, CD3OD) as follows: peaks at 1.42 (12H, s), 7.63 (1H, d) and 7.89 (1H, d) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([N:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[S:13]2)[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[C:33]([Cl:41])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>CC#N>[Cl:41][C:33]1[CH:32]=[C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][O:22][C:20]3[CH:19]=[CH:18][C:15]4[C:16](=[O:17])[N:12]([CH:7]5[CH2:8][CH2:9][CH2:10][CH2:11]5)[S:13][C:14]=4[CH:21]=3)[CH:26]=2)[CH:36]=[CH:35][C:34]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)c1ccc(-c2cccc(CBr)c2)cc1Cl
Reactant: O=c1c2ccc(O)cc2sn1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)cc1Cl
Temperature: 80 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
Potassium carbonate (0.052 g, 0.38 mmol) was added to a solution of 2-cyclopentyl-6-hydroxybenzo[d]isothiazol-3(2H)-one (0.075 g, 0.32 mmol) and methyl 3′-(bromomethyl)-3-chlorobiphenyl-4-carboxylate (0.129 g, 0.38 mmol) in CH3CN (5 mL). After stirring for 12 h at 80° C., the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×15 mL). The organic layer was dried over Na2SO4 and evaporated to give methyl 3-chloro-3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylate (0.158 g, quantitative yield). The crude product was used for the next step without further purification. LC-MS (ESI) Calcd for C27H24NO2S [M+H]+: 494.11. Found: 494.00.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]1[CH:72]=[CH:71][C:18]([C:19]([NH:32][C:33]2[N:41]=[CH:40][N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3[C@H:42]2[O:47][C@@H:46]([CH2:48][O:49][C:50]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[C@@H:44]([OH:45])[CH2:43]2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:92](O)(=[O:99])[C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1>C1COCC1.CO>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:32][C:33]2[N:41]=[CH:40][N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3[C@H:42]2[O:47][C@@H:46]([CH2:48][O:49][C:50]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:51]3[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=3)[C@H:44]([O:45][C:92](=[O:99])[C:93]3[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=3)[CH2:43]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:71][CH:72]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](OC(=O)c3ccccc3)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of diethylazodicarboxylate (0.38 mL, 2.49 mmol) in dry tetrahydrofuiran (20 mL) was added dropwise to a cooled solution (0° C.) of nucleoside 7 (0.66 g, 0.83 mmol), triphenylphosphine (0.66 g, 2.49 mmol) and benzoic acid (0.30 g, 2.49 mmol) in dry THF (20 mL). The mixture was stirred at room temperature for 18 h and methanol (1 mL) was added. The solvents were removed under reduced pressure and the crude material was purified by silica gel column chromatography (0-5% ethyl acetate in dichloromethane) to give compound 8 slightly contaminated by triphenylphosphine oxide.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:24]1([S:30]([NH:12][NH:11][C:9](=[O:10])[C:8]2[CH:13]=[CH:14][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1ccc(C(=O)NN)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
4-tert-Butyl-benzoic acid hydrazide (0.5 g, 2.60 mmol) was dissolved in THF (29 mL). N,N-diisopropylethylamine (1.81 mL, 10.4 mmol) was added, and the reaction was cooled to 0° C. Phenylsulfonyl chloride (0.36 mL, 2.86 mmol) was added followed by DMAP (5 mg, 0.04 mmol). The reaction was allowed to warm to room temperature, and the reactants all dissolved. The solution went from a yellow color to a deep red over the course of 4 hours. The reaction was then concentrated down and purified by flash chromatography eluting with 3:1 hexanes/EtOAc. The desired product was isolated (0.32 g, 37.1%). MS: 333.1 (M+1 for C17H20N2O3S); mp 197-199° C.; TLC: SiO2 Rf=0.56 (1:1 hexane/EtOAc). Analysis C17H20N2O3S: (calc) C, 61.42; H, 6.06; N, 8.43. (found) C, 61.38; H, 6.09; N, 8.27. IR (KBr, cm−1) 3213, 2965, 1648, 1403, 1349, 1179. 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 7.39-7.55 (m, 8H), 7.92-7.93 (m, 2H), 8.06 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2Br)[C:16]1=[O:25].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[C:16]1=[O:25]
Reactant: OB(O)c1cccnc1
Reactant: Nc1ccccc1NC(=O)CCCCCN1Cc2c(Br)cccc2C1=O
Product: Nc1ccccc1NC(=O)CCCCCN1Cc2c(cccc2-c2cccnc2)C1=O
Yield: 94 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-6-(4-bromo-1-oxoisoindolin-2-yl)hexanamide obtained in Example 36 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-pyridinyl boronic acid instead of phenyl boronic acid, to obtain the title compound (94%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[CH:32]([F:34])[F:33])[N:12]=1.COCCOCCN(CCOCCOC)CCOCCOC>O.O1CCOCC1>[F:34][CH:32]([F:33])[C:24]1[N:23]([C:13]2[N:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:12]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: Oc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Oc2ccccc2)nc(N2CCOCC2)n1
Yield: 43.8 %

Procedure:
Phenol (200 mg, 21 mmol) and NaOH (85 mg, 21 mmol) were combined in water to give a clear solution, which was then evaporated to dryness. 1-[4-Chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (184 mg, 0.5 mmol) and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1; 16 mg, 0.05 mmol) were added and the mixture was heated under reflux in dioxane (10 mL) for 2 hr. After cooling, the mixture was diluted with water to give a white solid, which was collected and recrystallised from MeOH to give 93 mg (44% yield) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-phenoxy-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 228-231° C.; 1H NMR (CDCl3) δ 8.06 (d, J=8.2 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.49 (br t, J=7.9 Hz, 2H), 7.36 (br t, J=7.5 Hz, 2H), 7.30 (dt, J=7.6, 1.1 Hz, 1H), 7.22 (m, 2H), 7.11 (t, JHF=53.6 Hz, 1H), 3.99-3.93 (m, 4H), 3.86-3.79 (m, 4H); Anal. Calc. for C21H18F2N6O2: C, 59.4; H, 4.3; N, 19.8. Found: C, 59.65; H, 4.2; N, 19.9%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(C(=O)O)ccc2c1
Agent: Br
Product: O=C(O)c1ccc2cc(O)ccc2n1
Temperature: 25 °C

Procedure:
6-Methoxy-2-quinolinecarboxylic acid (80.6 g) was refluxed in 48% hydrobromic acid (450 ml) for twenty-four hours. After cooling to room temperature, the solid was collected by filtration and then dissolved in water (1300 ml) at 90° and the pH of this solution was adjusted to 8-9 with concentrated ammonium hydroxide. After cooling to room temperature, the pH of this solution was adjusted to 4-5 with acetic acid. The resulting 6-hydroxy-2-quinolinecarboxylic acid was collected by filtration and washed with water (400 ml); yield 70 g, m.p. 260°-261° (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)=[O:4].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH2:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c1OCCCO2
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(N)cc2c1OCCCO2
Temperature: 70 °C
Yield: 62.2 %

Procedure:
A mixture of 8-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (0.58 g), SnCl2 (2.17 g) and ethanol was refluxed at 70° C. for 2 hours. The reaction was poured over ice and the resulting aqueous solution treated with 5% NaHCO3 (pH 7-8) and extracted with EtOAc. The organic phase was dried with MgSO4 and solvent removed in vacuo to yield 0.318 g of product which was used directly in the next reaction. MS: M+ 224.