Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:34].[K+]>ClCCl>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:2]=[CH:3][C:4]([N:7]2[C:20](=[O:34])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:10]=[CH:9][C:8]2=3)=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc(N3Cc4ccccc4-c4cc(-c5ccccc5)ccc43)cc2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1c2ccccc2c2cc(-c3ccccc3)ccc2n1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
16 g (0.039 mol) of 5-biphenyl-4-yl-2-phenyl-5,6-dihydrophenanthridine are dissolved in 300 ml of dichloromethane. and 62.13 g (0.393 mol) of potassium permanganate are added in portions to this solution, and the mixture is stirred at room temperature for two days. After this time, the remaining potassium permanganate is filtered off, the solution is evaporated and purified by chromatography (eluent: heptane/dichloromethane, 5:1). The residue is recrystallised from n-heptane. The yield is 14 g (88%).
Reaction SMILES: C(Cl)(=O)OCC.[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[CH:27]=1)(O)=[O:8].C(N(CC)CC)C>O1CCCC1>[OH:8][CH2:7][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[CH:27]=1
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C(=O)O)ccc2O1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)N=C(c2ccccn2)c2cc(CO)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
Ethyl chlorocarbonate(80 mg) was added to a solution of Compound 113 (200 mg) and triethylamine (0.10 ml) in anhydrous tetrahydrofuran (1 ml) at -15° C. under an argon atmosphere and the mixture was stirred at -15° to -10° C. for 30 minutes. The resulting precipitate was filtered off and the filtrate was added to a solution of sodium borohydride (67 mg) in water (0.7 ml) at 10° C. After completion of the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was extracted by addition of water and ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 6-hydroxymethyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (110 mg) (Compound 115). Likewise, Compound 145 was prepared from Compound 114.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.C([O-])(=O)C.[Na+].[C:19]([O:24][CH2:25][CH2:26][OH:27])(=[O:23])[C:20]([CH3:22])=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:19]([O:24][CH2:25][CH2:26][O:27][CH2:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)OCCO
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OCCOCc1ccc(O)c2ncccc12

Procedure:
5-Chloromethyl-8-hydroxyquinoline (46 g) (prepared by the method of Kolobielski, J. Heterocyclic Chem. 275, (1966)), sodium acetate (16.4 g) and hydroxyethyl methacrylate (200 ml) were stirred and heated on a steam bath for 5 hours, and the resulting slurry was dissolved in water (1 liter). Solid sodium carbonate was added until alkaline, and then the precipitate was collected, washed with water, dissolved in ether (500 ml), dried with MgSO4, and then treated with HCl gas to precipitate the hydrochloride salt. The latter was collected, washed with ether, air dried, dissolved in water (1 liter), and treated with solid sodium carbonate until alkaline. The resulting precipitate was collected, washed with water, dried, and crystallized from light petroleum (b.p. 60°-80° C.) to give 23 g colorless needles, m.p. 90°-1° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:38]3[CH2:39][CH2:40]NCC=3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1>CS(C)=O>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][CH:39]3[CH2:40][CH2:23][N:22]([CH2:12][CH:13]4[O:27][C:17]5=[C:18]6[C:23](=[CH:24][CH:25]=[C:16]5[O:15][CH2:14]4)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]6)[CH2:21][CH2:20]3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCC(Cc2c[nH]c4cc(Cl)ccc24)CC1)O3
Temperature: 75 °C

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.55 g, 1.4 mmole) and 6-chloro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 3.4 mmole) were combined in 10 mL of DMSO. The mixture was heated at 70-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with 400 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was column chromatographed on silica gel using 0-2% methanol/chloroform. The product fractions were concentrated in vacuum to give 0.27 g of the (S)-enantiomer of the title compound as an amorphous orange solid, which retains 0.35 equivalents of chloroform.
Reaction SMILES: [CH:1]1([O:12][CH2:13][C:14]2[CH:20]=[CH:19]OC=2C=O)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[BH4-].[Na+]>CO>[C@H:1]1([O:12][CH2:13][C:14]2[O:3][C:2]([CH2:1][OH:9])=[CH:19][CH:20]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=Cc1occc1COC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
520 mg (1.8 mmol) glucosyloxymethylfurfural (formula 2, product of Example 1) was dissolved in 30 ml methanol, and 138 mg (3.6 mmol) sodium borohydride added. After stirring for 2 h at room temperature the thin-layer chromatogram showed no further educt. To work up the product, the solvent was removed under vacuum and the syrup remaining purified by elution with chloroform/methanol (3:1). After evaporation of the fractions 443 mg (85%) glucosyloxymethylhydroxymethylfuran of formula (3) remained as a colourless syrup with [α]D20 =+107° (c=1, methanol).
Reaction SMILES: [CH2:1]1[O:5][CH:4]([CH:6]([OH:9])[CH2:7][OH:8])[C@@H:3]([OH:10])[CH:2]1[OH:11].[C:12](OC)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CO.C[O-].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:8][CH2:7][CH:6]([OH:9])[C@H:4]1[O:5][CH2:1][C@H:2]([OH:11])[C@H:3]1[OH:10])=[O:30]
Reactant: OCC(O)C1OCC(O)[C@@H]1O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: C[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
After 469 g of a 70% by weight sorbitan aqueous solution (aldehyde value of sorbitan: 5.0 ppm) and 947 g of methyl oleate were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, dehydration was performed at 110° C. under a nitrogen stream at normal pressure for 1 hour and further at 110° C. under a nitrogen stream at 4 kPa for 1 hour. The whole was cooled to 65° C. and, after 51.0 g of a 10% by weight sodium methoxide methanol solution and 0.64 g of sodium hypophosphite were added thereto, was heated under a nitrogen stream at normal pressure to 180° C. as a reaction temperature. After the temperature reached 180° C., the reaction was carried out under a nitrogen stream at normal pressure. At the time point when the spot of methyl oleate as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 12 hours and, after the completion of the reaction was confirmed, the product was filtrated at 80° C. to obtain sorbitan monooleate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:12]=1.CCN(CC)CC.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([CH:9]1[NH:8][CH2:7][C:6]2[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10]1)(=[O:22])[CH3:21]
Reactant: Clc1ccc2c(c1)CNCCN2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)C1CNc2ccc(Cl)cc2CN1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
7-chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12.5 mmol) was dissolved in a mixture of THF (100 mL), Et3N (19.1 mmol) and acetic anhydride (12.4 mmol). The reaction mixture was heated under reflux for 18 h, cooled to room temperature and partitioned between H2O and EtOAc. The aqueous phase was extracted again 2× with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated to a yellow, oily solid. The crude material was purified by column chromatography on silia eluting with EtOAc to yield 3-acetyl-7-chloro-1,2,3,5-tetrahydro-4H-[1,4]benzodiazepine (2.8 mmol, 22%) as a clear oil.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:19](=O)[CH3:20].[NH2:22][NH2:23]>C(O)COCCO>[CH3:20][C:19]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:11][C:2]=2[NH:23][N:22]=1
Reactant: NN
Reactant: CC(=O)c1c(O)cc(-c2ccc(O)cc2)c2ccccc12
Solvent: OCCOCCO
Product: Cc1n[nH]c2cc(-c3ccc(O)cc3)c3ccccc3c12
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A solution of 1-[2-hydroxy-4-(4-hydroxyphenyl)napthalen-1-yl]ethanone (0.223 g, 0.8 mmol), and 35% aqueous hydrazine (0.72 mL, 8.0 mmol) in diethylene glycol (2.7 mL) was heated using a reflux condenser in a 170° C. oil bath for 12 h, then 190° C. for 2 h until 95% complete conversion was observed. The crude solution was purified directly via preparative reverse phase HPLC (CH3CN/H2O/TFA eluent) to give 0.132 g (60% yield) of 4-(1-methyl-3H-benzo[e]indazol-5-yl)phenol. 1H NMR (400 MHz, d6-DMSO): 9.62 (broad s, 1H), 8.37 (d, 1H), 7.82 (d, 1H), 7.65 (dt, 1H), 7.42 (dt, 1H), 7.39 (s, 1H), 7.30 (dd, 2H), 6.93 (s, 2H), 2.82 (s, 3H); MS (EI) for C18H14N2O: 275 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)ccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1Br
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-Bu4NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily 2-bromo-5-chloroanisole (2.94 g, 97%). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at −10° C. over five minutes. After stirred at 5° C. for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31%) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9].N1C=CC=CC=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][C:3]=1[Cl:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)c(Br)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(Br)n1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of Example 11A (400 mg, 1.928 mmol) in dichloromethane (20 mL) was added pyridine (0.468 mL, 5.78 mmol) followed by benzoyl chloride (0.325 g, 2.314 mmol) and the mixture was stirred for 2 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution, water and brine, and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography (silica gel, 10% ethyl acetate in hexane) afforded the title compound. LCMS: 311 (M+H)+.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C@@H:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23](O)[CH2:22]2)=[CH:13]1.C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1COCC1>[N:45]([C@@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][CH:13]=2)[CH2:22]1)=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (4.8 mL, 32.1 mmol, 1.45 equiv) was added to (1R,3S)-3-(1H-indol-3-yl)-indan-1-ol (22.2 mmol ) and diphenyl phosphoryl azide (6.0 mL, 27.8 mmol, 1.25 equiv) in 150 mL dry THF at 0° C. The reaction was stirred 0.5 hours at 0° C., then 2 hours at room temperature—TLC showed full conversion. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with 100 mL 0.5 N HCl, sat. NaHCO3, dried over MgSO4 and concentrated in vacuo to give the 3-((1S,3S)-3-azido-indan-1-yl)-1H-indole.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamine(1.96 ml), and then diphenylphosphinic chloride(1.33 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.94 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1), thereby yielding 2.26 g of the aimed compound.
Reaction SMILES: CCCCCCCCC([O:11][C@@H:12]1[CH2:25][C:24]2[C@@:15]([CH3:38])([C@@H:16]3[C@@H:21]([CH2:22][CH:23]=2)[C@@H:20]2[CH2:26][CH2:27][C@H:28]([C@@H:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:30])[C@@:19]2([CH3:37])[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)=O.COC(=O)C(C)=C.N(C(C)(CC)C#N)=NC(C)(CC)C#N.[N+]([O-])([O-])=O.[Na+]>C(Cl)Cl>[CH3:36][CH:34]([CH2:33][CH2:32][CH2:31][C@H:29]([C@@H:28]1[C@:19]2([CH3:37])[C@H:20]([C@H:21]3[C@H:16]([CH2:17][CH2:18]2)[C@:15]2([CH3:38])[C:24]([CH2:25][C@H:12]([CH2:13][CH2:14]2)[OH:11])=[CH:23][CH2:22]3)[CH2:26][CH2:27]1)[CH3:30])[CH3:35]
Reactant: CCCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: C=C(C)C(=O)OC
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
30 wt % of cholesteryl nonanoate and 70 wt % of methylmethacrylate monomer were dissolved uniformly in 20 ml of methylene chloride under irradiation of ultrasonic wave. As an initiator, 2,2′-azobis(2-methylbutyronitrile) was added thereto in an amount of 1 wt % based on the weight of monomer. The obtained solution was added into 1.5% aqueous solution of polyvinyl alcohol with 87˜89% of saponification value and then was emulsified under 5,000 rpm of shear stress for 5 minutes. The emulsion and 0.01 wt % of sodium nitrate were introduced into the reactor heated at 60° C. and then polymerized for 4 hours. After the polymerization was terminated, the organic solvent was evaporated off under reduced pressure. The residue was filtrated, washed with distilled water several times, and then dried on vacuum oven, to give cholesterol liquid crystal polymer microcapsules as powders.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Clc1nccc2ccccc12
Reactant: OB(O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2nccc3ccccc23)c(F)c1
Temperature: 25 °C

Procedure:
2,4-difluorophenylboronic acid (Aldrich Chemical Co., 13.8 g, 87.4 mmol), 1-chloroisoquinoline (Adrich Chemical Co., 13 g, 79.4 mmol), tetrakistriphenylphosphine palladium(0) (Aldrich, 3.00 g, 2.59 mmol), potassium carbonate (EM Science, 24.2 g, 175 mmol), water (300 mL), and dimethoxyethane (Aldrich, 300 mL) were allowed to stir at reflux for 20 h under N2, after which time the mixture was cooled to room temperature and the organic and aqueous layers were separated. The aqueous layer was extracted with 3×150 mL of diethyl ether, and the combined organic fractions were dried with sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude material was chromatographed on a silica gel column, first by eluting the catalyst byproduct with 4:1 hexanes/CH2Cl2, and finally the product was eluted with CH2Cl2/MeOH (9.5:0.5, product Rf=0.7). The pure product fractions were collected and dried in vacuo, to afford 17.7 g (92% isolated yield) of a light yellow solid, >95% pure NMR spectroscopy. 1H NMR (CDCl3, 296 K, 300 MHz): δ 8.61 (1H, d, J=5.7 Hz), 7.89 (1H, d, J=8.2 Hz), 7.67–7.85 (3H, m), 7.52–7.63 (2H, m), 6.95–7.12 (2H, m) ppm. 19F NMR (CDCl3, 296K, 282 MHz) δ −109.01 (1F, brs), −109.87 (1F, d, JF-F=8.5 Hz).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[F:32][C@H:33]1[C@@H:38](OS(C)(=O)=O)[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34]1.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][C@@H:38]3[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:34][C@H:33]3[F:32])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2cccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (25 mg, 0.061 mmol; prepared according to Example 17, Step A) in DMA (2 mL) was added a mixture (approximately 9:1) of (3R,4S)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (prepared as described in WO 2008/124323) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (27 mg). Cs2CO3 (39 mg, 0.12 mmol) was added, the reaction vial was sealed, and the mixture was heated to 90° C. and stirred for 6 hours. DMA was removed under reduce pressure. The residue was diluted with EtOAc (20 mL), washed with saturated NaHCO3 aqueous solution and brine, and concentrated. Silica gel chromatography (DCM/MeOH 10:0.5) gave the desired product (12 mg). (The non-fluorinated product, which was also isolated, was utilized in Example 19, Step A).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:31])[C:7]([CH:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[NH2:21])=[CH:8][C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:31])[C:7]([CH:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])[NH2:21])=[CH:8][C:9](=[O:19])[C:10]=1[OH:11])=[O:4]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CNC(=O)c1c(O)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Yield: 33.3 %

Procedure:
6-(Benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl amide (16-01) (45.0 mg, 33.22%, purified by Prep-HPLC) was synthesized as an off white solid from 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl amide (15-01) (170.0 mg, 0.385 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).