Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:54])[CH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N:33]1[C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[N:45][C:46]([O:52][CH3:53])=[CH:47][CH:48]=2)[N:43]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][C:30](=[O:54])[CH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N:33]1[C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[N:45][C:46]([O:52][CH3:53])=[CH:47][CH:48]=2)[N:43]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCCO[Si](C)(C)C(C)(C)C)nc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCCO)nc2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Tetrabutylammonium fluoride (11.5 g) is added in small portions at a temperature in the region of 0° C. to a solution of 3-(5-tert-butyldimethylsilyloxy-2-oxopentyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (9.2 g) in anhydrous tetrahydrofuran (185 cc), and the solution obtained is stirred for 5 minutes at a temperature in the region of 0° C. The reaction mixture is then stirred for 1 hour 30 minutes at a temperature in the region of 20° C. and then poured into a mixture of ice (200 g) and water (600 cc). The insoluble product is separated by filtration, washed successively with water (5×25 cc) and diisopropyl ether (2×10 cc) and dried in the air. After recrystallization in acetonitrile, 3-(5-hydroxy-2-oxopentyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (5.6 g), m.p. 152° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(N(Cc2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-(tert-butoxycarbonylamino)benzoate (1.08 g) described in a document (Bioorg. Med. Chem. 2010, 18, 3175.) in DMF (40 mL) was added sodium hydride (258 mg). The reaction mixture was stirred at room temperature for 15 min, and benzyl bromide (613 μL) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: [N:1]1([CH:6]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=1)C(O)=O.[Li+].CC([N-]C(C)C)C.[CH:27](OCC)=[O:28]>C1COCC1>[Cl:18][C:16]1[C:15]([CH:27]=[O:28])=[C:11]([C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH:10]=[C:9]([Cl:8])[N:17]=1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CCOC=O
Reactant: O=CN1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(C(=O)N2CCCC2)cc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone (2.0 g, 8.2 mmol, prepared from commercially available 2,6-dichloro-isonicotinic acid) in THF (50 mL) is added slowly LDA (4 mL, 2M in heptane/THF/ethylbenzene), maintaining an internal temperature below −65° C. The solution is stirred at −78° C. for 1 hour, then treated dropwise ethyl formate (640 mg, 8.6 mmol), again maintaining an internal temperature below −65° C. The resulting mixture is gradually warmed to room temperature and stirred overnight. The mixture is quenched with saturated NH4Cl, extracted with ether and the combined extracts are washed with brine, dried over sodium sulfate and concentrated to give crude 2,6-dichloro-4-(pyrrolidine-1-carbonyl)-pyridine-3-carbaldehyde, which is used directly for the next step.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(OC([C:11]1C=C(C(OCC)=O)[NH:13][N:12]=1)=O)C.BrC[CH2:23][Cl:24].BrCCBr>>[N:4]1([CH2:3][CH2:23][Cl:24])[CH:5]=[CH:11][N:12]=[N:13]1.[NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: ClCCBr
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: c1nc[nH]n1
Solvent: BrCCBr
Product: ClCCn1ccnn1

Procedure:
When an equivalent amount of 1,2,4-triazole is substituted for 3,5-diethoxycarbonyl-1H-pyrazole and an equivalent amount of 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 4, 2-(1-H-triazol-1-yl)ethyl chloride is isolated 1,2,4-triazole, Aldrich, 43%, used directly after workup).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2>[N+](C1C=CC=CC=1)([O-])=O>[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:15][C:7]1=2
Reactant: CC1(C)OB(O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Temperature: -42.5 °C
Reaction time: 0.75 h
Yield: 51.8 %

Procedure:
To 106 mL fuming HNO3 at −45° C. was slowly added a solution of 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (16.9 g, 104.3 mmol) in 10.5 mL nitrobenzene via a syringe while maintaining the reaction temperature between −40 to −45° C. Once the addition was complete the resulting solution was allowed to stir at −45° C. for an additional 45 min before poured into crushed ice. The ice mixture was allowed to melt and the aqueous solution was extracted with DCM (3×). The combined DCM extracts were dried over Na2SO4 then evaporated. The crude oil remaining was mixed with one liter 1:1 DCM/heptanes. The volume of the solution was reduced under reduced pressure by half and the resulting solution was allowed to stand overnight in a −20° C. freezer. The precipitate formed was filtered out, washed with heptanes and vacuum dried to give the titled compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 7.69 (d, J=8.4 Hz, 1 H) 8.28 (dd, J=8.4, 2.3 Hz, 1 H) 8.48 (d, J=2.2 Hz, 1 H) 9.41 (br. s., 1 H). Amount obtained: 11.2 g (51.8% yield).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][OH:53])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCO)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2-hydroxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.7 mg in 0.6 ml 33% methylene chloride in cyclohexane), benzyl trichloroacetimidate (15.8 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 7 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:3)+1% methanol) gave the title compound (24 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.S(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([Cl:35])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Yield: 108 %

Procedure:
To a stirred solution of 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (0.400 g, 0.93 mmol) in anhydrous chloroform (20 mL) was added thionyl chloride (0.27 mL, 3.7 mmol). The solution was heated at reflux for 2 h and concentrated in vacuo to afford 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoyl chloride (0.45 g) as a pale yellow solid. To a solution of 2-fluoroaniline (0.1 mL, 1.0 mmol) and triethylamine (0.43 mL, 3.1 mmol) in anhydrous dichloromethane (10 mL) at 0° C. under nitrogen was added 4-((2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.46 g, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 42 h and was washed with 10% w/v hydrochloric acid (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (1/1) to afford N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.262 g, 49%) as a colorless solid: mp 245-251° C.; 1H NMR (300 MHz, CDCl3) δ 8.48-8.43 (m, 1H), 8.11-8.04 (m, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.24-7.02 (m, 6H), 6.75 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.16 (d, J=15.9 Hz, 1H), 4.95 (d, J=8.7 Hz, 1H), 4.89 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.21-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 164.9, 155.3, 152.7 (d, J=241.4 Hz), 144.7, 141.7, 140.0, 138.3, 134.1, 132.2, 128.8, 127.8 (d, J=4.1 Hz), 126.4 (d, J=9.8 Hz), 124.7-124.6 (m), 124.1, 123.7, 121.8, 120.8, 114.8 (d, J=19.1 Hz), 111.4, 109.1, 99.5, 80.1, 64.5, 63.9, 58.0, 43.8; MS (ES+) m/z 523.0 (M+1).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14]2)=[C:9]([CH3:22])[CH:8]=1>C(OCC)(=O)C>[CH3:6][C:7]1[CH:8]=[C:9]([CH3:22])[C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]([F:20])([F:21])[F:19])=[N:14]2)=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C)c1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 2.5 g (22 mol) of chlorosulfonic acid and then 1.8 g (7.4 mmol) of 1,3-dimethyl-4-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)benzene. The mixture was stirred at 70° C. for 2 hours. The mixture was cooled to room temperature and then added onto ice in small portions. Thereto was added 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Then, vacuum distillation was conducted to distil off ethyl acetate to obtain a title compound as 2.5 g of brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][C:12]2[CH:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:15][C:13]=2[NH2:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=2)[CH:27]=[CH:26]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:20]([NH:19][C:17]1[CH:18]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C:13]([NH:14][C:34]([C:31]2[CH:32]=[C:33]3[C:28]([CH:27]=[CH:26][NH:25]3)=[CH:29][CH:30]=2)=[O:35])=[CH:15][CH:16]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC(=O)c2ccc3cc[nH]c3c2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reaction time: 72 h
Yield: 71.1 %

Procedure:
To a stirring solution of 2-(4-t-butylbenzoyl)amino-4-(acetylamino)aniline (40 mg, 0.12 mmol), 6-indolecarboxylic acid (40 mg, 0.24 mmol) and bromotris(pyrrolidino)phosphonium hexafluorophosphate (112 mg, 0.12 mmol) in dichloromethane (10 mL) and DMF (1 mL) was added N,N-diisopropylethylamine (42 mg, 0.36 mmol). After 3 days, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed once with 1 N HCl, once with satd aq sodium bicarbonate, dried with MgSO4, filtered and concentrated in vacuo. The residue was then chromatographed over silica gel, eluting with 10% methanol/dichloromethane and the product containing fractions were combined and concentrated to give 40 mg (71%) of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:27].C(O)C>>[NH2:27][C:9]1[C:10]([F:21])=[C:11]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:12]=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: N
Reactant: CN1CCN(c2cc3c(c(F)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Solvent: CCO
Product: CN1CCN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
In a sealed tube, 1-cyclopropyl-5,6-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was aminated with ammonia/ethanol as in Example 13 to give 5-amino-1-cyclopropyl-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxlic acid. m.p 216°-218° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][O:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCCO1

Procedure:
Prepared similarly to Intermediate 213 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Br:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br-:10].[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N+:20]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: c1cc(-c2ccncc2)ccn1
Reactant: BrCCCc1ccccc1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc(CCC[n+]2ccc(-c3ccncc3)cc2)cc1
Reaction time: 24 h
Yield: 85 %

Procedure:
9.6 g of 3-phenyl-1-bromopropane were added dropwise over the course of 45 min to 15.0 g of 4,4′-bipyridyl in 90 ml of toluene at 70° C. The mixture was stirred for 24 h at reflux temperature, cooled down and the solid was filtered off with suction. The solid was stirred in 90 ml of toluene for 4 h at reflux temperature, cooled down, filtered off with suction and washed with toluene. Drying in vacuo gave 14.3 g (85% of theory) 4-(4-pyridyl)-1-(3-phenylpropyl)pyridinium bromide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(F)c2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
A mixture of methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1, 177 mg, 0.50 mmol), 3-fluorophenol (224 mg, 2.0 mmol) and sodium bicarbonate (105 mg, 1.25 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 100° C. for 24 h. After cooling, the reaction mixture was partitioned between water (50 mL) and dichloromethane (50 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated. The residue was purified by flash column chromatography on silica gel (10 g) eluting with hexane/ethyl acetate (4/1) to afford 180 mg (84%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.07–7.98 (3H, m), 7.47–7.37 (3H, m), 7.07–6.99 (1H, m), 6.98–6.88 (2H, m), 5.42–5.31 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=7.0 Hz); MS (ESI) m/z 429 (M+H)+, 427 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16]1.FC1C=C(F)C=CC=1[C@]1([C@H](N2C3=NC=CC=C3N=C2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1cnc2nc[nH]c2c1
Agent: C[C@@H](n1cnc2cccnc21)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnc2ncccc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 22.7 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (981 mg) and 1H-imidazo[4,5-b]pyridine (472 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(3H-3-imidazo[4,5-b]pyridyl)ethyl]oxirane (501 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1-imidazo[4,5-b]pyridyl)ethyl]oxirane (271 mg) were obtained by the same way as in Reference Example 2.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([N+:15]([O-])=O)[CH:8]=2)[CH2:3][CH2:2]1.[N:18]([C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:30])[CH2:23][CH2:22]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P(OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:14]=[CH:13][C:10]3[C:9]([CH:8]=2)=[N:15][N:18]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:30])[CH2:23][CH2:22]2)[CH:11]=3)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Reactant: C[C@@H](CO[C@H]1CC[C@H](N=[N+]=[N-])CC1)NC(=O)OC(C)(C)C
Agent: CCOP(OCC)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](CO[C@H]1CC[C@H](n2cc3ccc(OCCC4CC4)cc3n2)CC1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2-cyclopropylethoxy)-2-nitrobenzaldehyde (0.79 g), tert-butyl {(1S)-2-[(trans-4-azidocyclohexyl)oxy]-1-methylethyl}carbamate (1.0 g), triphenylphosphine (3.08 g) and triethyl phosphite (3.08 g) in toluene (10 mL) was refluxed for 3 hr. The reaction mixture was allowed to cool, and concentrated under reduced pressure. To the obtained residue was added triethyl phosphite (4.0 g), and the mixture was stirred at 160° C. for 4 hr. The reaction mixture was allowed to cool, and purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.2 g).
Reaction SMILES: [Mg].[H-].C([Al+]CC(C)C)C(C)C.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[CH3:23][C:24]([S@@:27](/[N:29]=[CH:30]/[C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:28])([CH3:26])[CH3:25]>C1COCC1.CCOCC>[CH3:26][C:24]([S@@:27]([NH:29][C@H:30]([C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:28])([CH3:23])[CH3:25]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Cc1cccnc1/C=N/[S@@](=O)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccnc1[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A 250 mL round-bottomed flask containing magnesium turnings (0.685 g, 28.2 mmol) and Et2O (25 mL) was added diisobutylaluminum hydride 1.0 M solution in hexanes (0.18 mL, 0.180 mmol) followed by dropwise addition of 4-bromobenzotrifluoride (2.0 mL, 14.28 mmol). The solution was stirred for 1.5 hours during which it turned from turbid to dark brown in color. The reaction mixture was cooled to −78° C. in a dry ice/acetone bath and then a solution of (S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide (2.15 g, 7.67 mmol) in THF (15 mL) was added dropwise over 5 minutes. The reaction was stirred for 5 hours during which it warmed to rt. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and H2O (25 mL). The reaction mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the initial product which was purified by silica gel flash column chromatography (using a 80G ISCO cartridge) and eluted using hexanes/EtOAc gradient to yield the desired product
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.C(N(CC)CC)C.[C:24]([O:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30])(=[O:26])[CH3:25]>CN(C)C(=O)C.C(OCC)(=O)C>[C:24]([O:27][C:28]([CH3:33])([CH3:32])[C:29](=[O:30])[NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(=O)OC(C)(C)C(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (220 mg) and triethylamine (0.182 mL) in N,N-dimethylacetamide (1.5 mL) chilled to 0° C. was added 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.175 mL) dropwise. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid aqueous solution 3 times then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (290 mg, 83%).