Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1(=[O:18])=[O:17].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O>CN(C=O)C>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[S:10](=[O:12])(=[O:11])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7]2(=[O:18])=[O:17])[CH2:27][CH2:26]1
Reactant: O=S1(=O)c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1
Temperature: 0 °C

Procedure:
0.028 mol of 2-(4-bromobutyl)-1,3,2-benzodithiazole 1,1,3,3-tetroxide and 0.056 mol of 1-(2-pyrimidinyl)piperazine in 125 ml of absolute DMF are stirred at 25° C. for 6 hours. The mixture is then cooled to 0° C., 150 ml of water are added dropwise with stirring, and the substance which has crystallised out is filtered off with suction. The product is purified by chromatography on silica gel; the eluting agent is ethyl acetate.
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH3:20])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:21].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:21].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH3:20])[CH2:15]1)[CH2:5][OH:6]
Reactant: C[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 7.56 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-methyldihydrofuran-2-one obtained in Example (76e) (27.5 mmol), 15.0 ml of a solution of 4 N hydrochloric acid in dioxane (60.0 mmol) and 1.88 g of 10% palladium-carbon (50% wet) in ethanol (150 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 100 ml of ethanol. Palladium-carbon was separated by filtration washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-methyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[C:5]([O:7]C)=[O:6].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(Oc2ccc(O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.8 %

Procedure:
To a stirred solution of methyl 3,5-dichloro-4-(4′-methoxyphenoxy)benzoate (1.5 g, 4.5 mmol) in CH2Cl2 (50 mL) at −78° C. was added BBr3 (11.4 mL, 11.4 mmol, 1 M solution in CH2Cl2). The reaction mixture was stirred at room temperature for 14 h, poured into ice water (100 mL) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from CH2Cl2, filtered and dried under reduced pressure to afford 3,5-dichloro-4-(4′-hydroxyphenoxy)benzoic acid as a brown solid (1.02 g, 75%): mp 163-165° C.; 1H NMR (300 MHz, DMSO-d6): δ 9.02 (bs, 1H), 8.0 (s, 2H), 6.67 (m, 4H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:3); Rf=0.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[N+]1([O-:36])C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:36])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: [O-][n+]1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1cccc(CCCCCC=O)c1CCC(=O)OCC
Yield: 81.2 %

Procedure:
4-[3-(6-Bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (10.0 g, 21.2 mmol), pyridine N-oxide (10.06 g, 106 mmol), and sodium bicarbonate (10.0 g, 1 19 mmol) were heated at reflux with vigorous stirring in toluene (100 mL) for 24 hr. The mixture was cooled down and filtered. The filtrate was then evaporated under vacuo and the crude material was purified by column chromatography using 30% EtOAc-Hexane as eluant to give the title compound (7.0 g, 81%) as an oil. HR-MS-EI(+): calculated for C23H34O6 [M] 406.2350, found 406.2355.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([O:14]C)=[CH:4][CH:3]=1.[CH3:16][S-:17].[Na+]>CN(C)C=O>[CH3:16][S:17][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([OH:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)nc1-c1ccccn1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(O)c(-c2ccccn2)n1
Temperature: 160 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
6-Fluoro-3-methoxy-[2,2′]bipyridine (12 mg) and sodium thiomethoxide (41 mg) were suspended in N,N-dimethylformamide (1.5 ml), and the suspension was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give 6-methylsulfanyl-[2,2′]bipyridin-3-ol (6 mg, yield 47%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[O:8]=[C:6]1[NH:7][C@@H:3]([CH2:2][O:1][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@H](CO)N1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)N2)cc1
Yield: 66.4 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (1.68 g) and p-toluenesulfonyl chloride (2.92 g) and by the reaction and treatment in the same manner as in Preparation Example 219, the title compound (2.61 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C(B(CC)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)C>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCB(CC)c1cccnc1
Reactant: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OC(C)(C)C
Yield: 47 %

Procedure:
A mixture of N-Boc-4-iodo-L-phenylalanine methyl ester (810 mg, 2 mmol, Lei, H et al, ibid) tetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol), aqueous sodium carbonate (4 mmol, 2 ml of a 2M solution) and diethyl(3-pyridyl)borane (294 mg, 2 mmol) in dimethoxyethane (30 ml) was refluxed for 6 hr. The solvent was removed in vacuo, the residue dissolved in EtOAc (100 ml) and washed with water (30 ml) aqueous sodium thiosulphate (20 ml) and brine (30 ml) dried (Na2SO4)and evaporated in vacuo. Purification by column chromatography (SiO2, EtOAc/hexane 30:70) gave the title compound (335 mg,47%) as a yellow oil. δH (CDCl3) 8.81 (1 H, d, J 1.7 Hz, PyrH), 8.56 (1 H, dd, J 4.8, 1.6 Hz, PyrH), 7.84 (1 H, dt, J 7.9, 2.0 Hz, PyrH), 7.49 (2 H, d, J 8.2 Hz, ArH), 7.34 (1 H, ddd, J 7.9, 4.8, 0.6 Hz, PyrH), 7.23 (2 H, d, J 8.2 Hz, ArH), 5.09 (1 H, br d, J 7.8 Hz, CONH), 4.62 (1 H, br q, J 6.8 Hz, CHα), 3.73 (3 H, s, CO2Me), 3.18 (1 H, dd, J 13.8, 5.6 Hz, CHAHBAr), 3.07 (1 H, dd, J 13.8, 5.8 Hz, CHAHBAr) and 1.40 (9 H, s, tBu); m/z (ESI, 15 V) 357 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[Cl:21])=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:18]1[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=1)=[N:13][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:20]=2
Reactant: Brc1ccccn1
Reactant: C#CCCn1cc2c(Cl)cccc2n1
Product: Clc1cccc2nn(CCC#Cc3ccccn3)cc12
Yield: 17.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.27 mmol) and 2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol). Reaction time: 8 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 12 mg (43 μmol, 17%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:6]1=O)=O.Cl.[NH2:19][C:20]([NH2:22])=[NH:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:22][C:20]1[N:21]=[C:3]([OH:2])[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[C:6]=2[N:19]=1
Reactant: COC(=O)C1CCCCc2ccccc2C1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)-c1ccccc1CCCC2
Temperature: 25 °C

Procedure:
A mixture of Example 20A (1.49 g, 6.4 mmol), guanidine hydrochloride (2.1 g, 22 mmol) and K2CO3 (3.26 g, 24 mmol) in anhydrous DMF (20 mL) was heated at 120° C. for 8 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and partitioned between EtOAc (200 mL) and H2O (150 mL). The aqueous layer was extracted with EtOAc three times. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to provide a residue. The residue was chromatographed on silica gel eluting with MeOH:EtOAc:CHCl3 (10:45:45) to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:22](=[O:28])[CH:23](OCC)O)[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[NH:14][C:13]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]([OH:28])[CH2:23][NH:40][C:37]([CH3:38])([CH3:39])[CH2:36][C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[NH:14][C:13]=2[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)Cc1ccc(F)cc1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2
Product: CC(C)(Cc1ccc(F)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2

Procedure:
385 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one and 167 mg (1 mmol) 2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamine are reacted and worked up analogously to Example 14. However, the resulting benzylether is chromatographed on a silica gel column (dichloromethane/methanol gradient).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[CH:15][C:16]([OH:18])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)c(OC)c1Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)c(OC)c1Cl
Yield: 95 %

Procedure:
A solution of compound (2a) (11.07 g, 55.2 mmol), malonic acid (8.639 g, 83 mmol) and piperidine (2 ml, 1.722 g, 20.2 mmol) in 80 ml of anhydrous pyridine was refluxed (bath temperature 110° C.) for 2 h. Reaction mixture was cooled, concentrated under vacuum and acidified 250 ml of 5% aqueous citric acid to a pH of 3. Resulted heterogeneous mixture was sonicated for a few minutes. The precipitated material was filtered off, washed with water (2×20 ml) and dried in vacuum over KOH to give 12.7 g (52.3 mmol, 95% yield) of pure (HPLC, 1H NMR) desired acid 3a as a white solid. 1H NMR (DMSO-d6): δ 7.77 (d, J=9.0 Hz, 1H), 7.67 (d, J=16.0 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[NH2:19].[CH2:20](OC(OCC)CN(C)C)[CH3:21].O.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[NH:19][CH2:20][CH3:21]
Reactant: Nc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reactant: CCOC(CN(C)C)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCNc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Temperature: 60 °C
Yield: 20.6 %

Procedure:
To a stirring solution of 2-chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamine (0.121 g, 0.386 mmol), (dimethylamino)acetaldehyde diethyl acetal (0.720 mL, 3.94 mmol), glacial acetic acid (24.0 mL) and water (0.100 mL, 5.55 mmol) was added sodium cyanoborohydride (0.140 g, 2.22 mmol). The solution was heated at 60° C. for 5 days and then the solution was stirred at room temperature until a precipitate formed. The suspension was filtered, the filter cake was washed with EtOAc (10 mL) and then the filtrate was concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5), gave 0.027 g (20%) of the title compound as a white solid. 1H NMR (CDCl3): 7.60 (d, 1H, J=5.2 Hz), 7.44-7.35 (m, 3H), 7.13 (d, 1H, J=5.2 Hz), 4.33 (br s, 1H), 3.37-3.28 (m, 2H), 1.36 (t, 3H, J=7.1 Hz).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:22]3[N:42]=[CH:43][CH:44]=[C:21]3[N:20]=2)[CH2:15][CH2:14]1)=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[N:22]3[N:42]=[CH:43][C:44]([I:1])=[C:21]3[N:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
N-Iodosuccinimide (811 mg, 3.6 mmol) was added into a solution of 4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (1.75 g, 3.27 mmol) in acetonitrile (25 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield the title compound (1.79 g, 82.8% yield) at clear oil. LC-MS: 661 [M+H].
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH2:20][C:19]2[C:18](=[O:21])[NH:17][C:16]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[C:14]=2[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CS(C)=O.O>[C:3]([N:11]1[CH2:20][C:19]2[C:18](=[O:21])[N:17]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:16]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[C:14]=2[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c3c(c(=O)n(CCN4CCCCC4)c2cc1OC)CN(C(=O)c1ccccc1)CC3
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
A suspension of 0.066 m NaH in 75 cc dimethylsulfoxide was cooled in a cold water bath and treated portionwise with 10 g (0.028 m) of 3-benzoyl-1,2,3,4-tetrahydro-8,9-dimethoxy-benzo[c][2,7]naphthyridin-5(6H)-one in 10 min. After stirring for 5 min the reaction was treated with 5.5 g (0.03 m) of N-(2-chloroethyl)piperidine hydrochloride in 2 min. After stirring an additional 2 hr the reaction was diluted with water to 800 ml to give 11.5 g of crude solid product, used as is for hydrolysis.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])C1C=CC=CC=1>[Pd].C1COCC1>[NH2:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([S:27]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])[CH:11]=2)=[C:17]([CH3:26])[CH:18]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)NCC(C)(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)NCC(C)(C)C)c1
Reaction time: 8 h

Procedure:
A mixture of the title F compound, 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-N-(2,2-dimethylpropyl)benzenesulfonamide (1.22 g, 2.45 mmol) and palladium on activated carbon (10 wt. %; 250 mg) in 40 mL of THF is stirred under hydrogen atmosphere (H2, 1 atm) for 8 h. The catalyst is removed by vacuum filtration through celite, washed with THF and the combined filtrate and washings are concentrated. The residue is suspended in CH2Cl2 and the product is collected by vacuum filtration, washed with CH2Cl2 and dried to give 5-(4-amino-2,6-dimethyl-phenoxy)-2-hydroxy-N-(2,2-dimethylpropyl)benzenesulfonamide: NMR (DMSO-d6) 0.80 (s, 9H), 1.90 (s, 6H), 2.55 (d, 2H, J=7.5), 4.90 (br s, 2H), 6.31 (s, 2H), 6.87 (br s, 1H), 6.93 (br s, 2H), 6.97 (t, 1H, J=7.5), 10.13 (s, 1H).
Reaction SMILES: [F-].[K+].[C:3]([O:7][CH3:8])(=[O:6])[CH:4]=[CH2:5].[F:9][C:10]([F:16])([F:15])[CH2:11][N+:12]([O-:14])=[O:13]>C(#N)C>[F:9][C:10]([F:16])([F:15])[C:11]([N+:12]([O-:14])=[O:13])([CH2:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:5][CH2:4][C:3]([O:7][CH3:8])=[O:6]
Reactant: C=CC(=O)OC
Reactant: O=[N+]([O-])CC(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCC(CCC(=O)OC)([N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 g (0.465 mol) of potassium fluoride (calcined) and 86 g (1 mol) of methyl acrylate are initially charged to 50 ml of acetonitrile at 0°-5° C. and 60 g (0.465 mol) of 2,2,2-trifluoronitroethane are added dropwise with stirring over a period of 60 min. The reaction is notably exothermic (up to about 60° C.). After being cooled to room temperature the reaction mixture is further stirred for 16 h. The mixture is filtered, the salt is washed with acetonitrile, and the solvent and unreacted starting material are stripped off on a rotary evaporator.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([Si](C)(C)C)([F:17])([F:16])[F:15].C1COCC1>CCOCC>[F:15][C:14]([F:17])([F:16])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of methyl 4-acetylbenzoate (5.0 g, 28.1 mmol) and CF3SiMe3 (12.5 mL, 84.2 mmol) in THF (150 mL) TBAF (1.0 M, 78.6 mL, 78.6 mmol) was added dropwise at 0° C. The mixture was then stirred for 2.5 h at room temperature, diluted with Et2O (100 mL). The solution was washed with saturated aqueous NaHCO3, and brine, dried, and concentrated. Flash chromatography of the residue, using 2:8 EtOAc-hexane, gave methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate: 1H NMR (CDCl3) δ 8.07 (d, J=8.5 Hz, 2H), δ 7.67 (d, J=8.5 Hz, 2H), 3.93 (s, 3H), 2.70 (br, 1H), 1.80 (s, 3H); ms 249.1 (M+H+).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@@H:45]1[C@@H:50]([CH2:51][O:52]C(=O)C2C=CC=CC=2)[O:49][C@H:48]([O:61][C@@H:62]2[C@@H:67]([CH2:68][O:69]C(=O)C3C=CC=CC=3)[O:66][C@H:65]([O:78][C@@H:79]3[C@@H:108]([CH2:109][O:110]C(=O)C4C=CC=CC=4)[O:107][C@@H:82]([O:83][CH2:84][CH2:85][CH2:86][NH:87][C:88](=[O:106])[CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH3:105])[C@H:81]([O:119]C(=O)C4C=CC=CC=4)[C@H:80]3[O:128]C(=O)C3C=CC=CC=3)[C@H:64]([O:137]C(=O)C3C=CC=CC=3)[C@H:63]2[O:146]C(=O)C2C=CC=CC=2)[C@H:47]([O:155]C(=O)C2C=CC=CC=2)[C@H:46]1[O:164]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO.C1COCC1>[C@H:11]1([O:44][C@@H:45]2[C@@H:50]([CH2:51][OH:52])[O:49][C@H:48]([O:61][C@@H:62]3[C@@H:67]([CH2:68][OH:69])[O:66][C@H:65]([O:78][C@@H:79]4[C@@H:108]([CH2:109][OH:110])[O:107][C@@H:82]([O:83][CH2:84][CH2:85][CH2:86][NH:87][C:88](=[O:106])[CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH3:105])[C@H:81]([OH:119])[C@H:80]4[OH:128])[C@H:64]([OH:137])[C@H:63]3[OH:146])[C@H:47]([OH:155])[C@H:46]2[OH:164])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@H:10]1[OH:9]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](O[C@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](O[C@H]4O[C@H](COC(=O)c5ccccc5)[C@@H](OC(=O)c5ccccc5)[C@H](OC(=O)c5ccccc5)[C@H]4OC(=O)c4ccccc4)[C@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCO[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
Glycoside 126 (377 mg, 161 μmol) was dissolved in MeOH/THF 1:1 (10 mL). NaOMe (60 μL of an 11M solution) was added and the solution was stirred at room temperature for 24 hrs. The mixture was neutralized with acidic resin and the solution filtered before the solvent was evaporated to yield the white solid product which was triturated with EtOAc and the solvent decanted (×3). The solid was dried under vacuum to yield 159 mg of the white solid product (quantitative) which was reacted on without further purification or characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:13])=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccn(C(F)F)n1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nn(C(F)F)cc1Cl
Temperature: 50 °C

Procedure:
A mixture of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (535 mg, 3 mmol) and N-chloro-succinimide (1.22 g, 9.1 mmol) in N,N-dimethylformamide (5 ml) was heated at 50° C. overnight. The reaction mixture was cooled, poured into water (20 ml), then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulphate, finally evaporated at reduced pressure. The yellowish crude material was purified by chromatography on silica gel using a 3:1-mixture of cyclohexane and ethyl acetate as the eluent. The 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester was obtained as a white solid (540 mg, 84%); (calculated) C6H5ClF2N2O2 [210.57]; (found) [M]+=210.