Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[C:13](O)=[O:14].[BH4-].[Na+]>CCOCC.CO>[F:16][C:12]([F:17])([C:11]([F:19])([F:18])[F:10])[CH:13]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)[OH:14]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(C(O)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
In a three neck flask purged with nitrogen were charged magnesium (12.2 g, 502 mmol) and ether (100 ml). A solution of 4-bromotoluene (56.1 ml, 456 mmol) in ether (200 ml) was added dropwise, and the mixture was heated under reflux for 1.5 hrs. The reaction vessel was cooled in a dry ice-acetone bath. A solution of pentafluoropropionic acid (25 g, 152 mmol) in ether (100 ml) was added dropwise, and the temperature was slowly raised to room temperature. The mixture was heated under reflux for 3 hrs, and stirred overnight at room temperature. The reaction mixture was ice-cooled, and quenched with 3N hydrochloric acid. The mixture was diluted with ethyl acetate, and the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0, 30:1) to give a colorless transparent oil. This was dissolved in methanol, and sodium borohydride was added under ice-cooling. The temperature was raised to, room temperature, and the mixture was stirred for 1 hr. After completion of the reaction, the reaction was quenched with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, 5:1) to give 2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propan-1-ol (20.28 g, 56%) as a colorless transparent oil.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@H:11]([OH:12])[C@H:10]3[F:16])[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].CO>N1C=CC=CC=1>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@:11]([C:20](=[O:22])[CH3:21])([OH:12])[C@H:10]3[F:16])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H]1O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H]1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5,6-Dichloro-1-(2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.45 g, 1.5 mmoles) was dissolved in pyridine (Aldrich, Sure Seal, 20 mL) and boiled to remove water. The solution was chilled to 0° C. in an ice bath. Acetic anhydride (Aldrich, 260 μL, 2.9 mmoles, 2 eq.) was added and the reaction was allowed to warm to room temperature while stirring overnight. Methanol (3 mL) was added and the solvents removed in vacuo. Residual pyridine was removed by coevaporation with toluene (3×). The residue was partitioned between water and ethyl acetate. The ethyl acetate solution was dried with MgSO4, filtered, and the solvent removed in vacuo. The product was used without further purification. The yield was 0.45 g, 88%. MS (FAB+): m/z, 347; 1H NMR (DMSO-d6) δ8.61 (s,1H, H-2), 8.08 (s,1H, Ar—H), 8.00 (s,1H, Ar—H), 6.38 (d, 1H, H-1′, J=18 Hz), 5.70 (d, 1H, H-2′, J=53 Hz), 5.1 (m, 1H), 4.2 (m, 1H), 2.1 (s, 3H, acetyl), 1.38 (d, 3H, H-5′, J=6 Hz).
Reaction SMILES: [OH-:1].[Li+].CC1(C)C2CC[C@@]31[C@H](C2)N([C:14](=[O:24])[C@H:15]([CH3:23])[C@H:16]([O:21][CH3:22])[CH2:17][CH2:18][CH:19]=[CH2:20])S(=O)(=O)C3>O.O1CCCC1>[CH3:22][O:21][C@H:16]([CH2:17][CH2:18][CH:19]=[CH2:20])[C@@H:15]([CH3:23])[C:14]([OH:24])=[O:1]
Reactant: [OH-]
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)N1[C@H]2CC3CC[C@@]2(CS1(=O)=O)C3(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)O
Temperature: 60 °C

Procedure:
A solution of 2M lithium hydroxide in water (5 ml) was added to a stirred solution of 10c (223 mg, 0.60 mmol.) in tetrahydrofuran (15 ml). The stirred mixture was heated to 60° C. for 15 hours. The reaction mixture was partially evaporated before adding 2M hydrochloric acid (20 ml). The solution was extracted with ethyl acetate (3×15 ml). The extract was dried over sodium sulfate filtered and evaporated to give a yellow gum (209 mg). The gum was purified on a silica column eluting with 25% ethyl acetate, 75% hexane to yield 10d as a yellow gum (68 mg, 66%). 1H NMR δ (300 MHz NMR, CDCl3) 1.15-1.19 (d, 3H), 1.57-1.67 (m, 2H), 2.11-2.23 (m, 2H), 2.74-2.85 (m, 1H), 3.39-3.42 (s, 3H), 3.45-3.53 (m, 1H), 4.97-5.10 (m, 2H), 5.76-5.91 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[O:29][N:28]=[C:27]([C:30]([NH2:32])=O)[N:26]=2)([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)([C:25]2[O:29][N:28]=[C:27]([C:30]#[N:32])[N:26]=2)[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(c1ccc(Cl)cc1)(c1nc(C(N)=O)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(c1ccc(Cl)cc1)(c1nc(C#N)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 37 step F above (6.8 mg, 0.014 mmol) in pyridine (1.0 mL) was added POCl3 (32.8 mg, 0.28 mmol) at 0° C. After stirring at RT overnight, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=457.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH:15]([CH3:16])[CH:14]3[C:17](OCC)=[O:18])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:24][C:2]([CH3:1])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH:15]([CH3:16])[CH:14]3[CH2:17][OH:18])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: CCOC(=O)C1C(C)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC1C(CO)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-3-methylcyclopropanecarboxylate (33-2, 192 mg, 0.55 mmol, 1.0 equiv) was added to anhydrous THF (2.7 mL) and cooled to 0° C. DIBAL-H (2.78 mL, 2.78 mmol, 5.0 equiv, 1.0M in THF) was added dropwise and the resulting solution was stirred at 0° C. for 2 h. The reaction was then quenched by the addition of saturated Rochelle salts (20 mL), diluted with EtOAc (10 mL) and stirred at RT for 18 h. Following this duration, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. Purification by reverse-phase HPLC (10-100% 0.1% TFA in H2O:CH3CN) provided 35-1 as a colorless oil. MS m/z (M+H): observed=304.1
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[NH4+]>N1C=CC=CC=1>[NH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCCOCCOCCOCCN
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phospine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixutre stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 nl) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]([C:23]1[C:24]([O:48][CH3:49])=[C:25]2[C:30](=[C:31]([O:37][Si](C(C)C)(C(C)C)C(C)C)[C:32]=1[C:33]([O:35][CH3:36])=[O:34])[N:29]=[CH:28][CH:27]=[CH:26]2)=[O:22].[C:50]1([C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N+]=[N-])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1COCC1>[CH3:19][O:20][C:21]([C:23]1[C:24]([O:48][CH3:49])=[C:25]2[C:30](=[C:31]([O:37][CH:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:32]=1[C:33]([O:35][CH3:36])=[O:34])[N:29]=[CH:28][CH:27]=[CH:26]2)=[O:22]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(C(=O)OC)c(O[Si](C(C)C)(C(C)C)C(C)C)c2ncccc2c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)OC)c(OC(c2ccccc2)c2ccccc2)c2ncccc2c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A 1M solution of TBAF in THF (4 ml) was added to 5-methoxy-8-triisopropylsilanyloxy-quinoline-6,7-dicarboxylic acid dimethyl ester (0.85 g, 1.9 mmol) in 20 ml dry THF. The reaction was stirred at rt for 1 h, at which time the reaction mixture was concentrated and the residue dissolved in 100 mL diethyl ether and washed with 25 mL 1N HCl, followed by 25 mL of saturated aq. NaCl. The organic layer was concentrated and the residue was dissolved in 40 mL dichloroethane. Diphenyldiazomethane (0.7 g, 3.8 mmol) was added and the reaction temperature was raised to 70° C. for 24 h. The reaction mixture was concentrated and the residue chromatographed on silica gel (1/1 hexanes/EtOAc) to give 8-benzhydryloxy-5-methoxy-quinoline-6,7-dicarboxylic acid dimethyl ester (0.8 g, 61% yield overall). 1H NMR (CDCl3) δ 8.85 (d, 1H), 8.45 (d, 1H), 7.45 (dd, 1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H); MS: 480 (M+Na).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:4](=[O:20])[O:3]1>C(O)(C(F)(F)F)=O.O>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:20])=[O:3])=[CH:11][CH:12]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 0.67 h

Procedure:
To a 2 L flask containing 2,2-dimethyl-5-(4-(trifluoromethyl)benzyl)-1,3-dioxane-4,6-dione (65 g, 215 mmol, Intermediate 47: step a) was added a TFA/water solution (v/v, 560 mL/280 mL) at room temperature and the white suspension was heated between 70° C. and 78° C. in a large oil bath. The suspension did not dissolve until a temperature of 72° C. was reached. After approximately 40 minutes, the suspension became a clear homogeneous solution. After 3 hours, HPLC indicated that the reaction was complete. The mixture was concentrated on the rotary evaporator and azeotroped with toluene (4×100 mL) to give white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:59]=[CH:58][C:48]([N:49]=[S:50]([CH3:57])(=[O:56])[N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[CH:47][CH:46]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:43])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:45]2[CH:59]=[CH:58][C:48]([N:49]=[S:50]([CH3:57])(=[O:56])[N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=[CH:10][CH:9]=1
Reactant: CS(=O)(=Nc1ccc(Br)cc1)N1CCCC1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(N=S(C)(=O)N5CCCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromo-N-[methyl-(oxo)pyrrolidin-1-yl-λ6-sulfanylidene]aniline following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=726 [M+H]+.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[CH3:14])=O.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH2:27])=[S:26])=[CH:20][CH:19]=1)[CH3:16]>C(O)C>[BrH:2].[O:17]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]2[S:26][CH:3]=[C:4]([C:6]3[N:13]4[C:9]([S:10][CH:11]=[CH:12]4)=[N:8][C:7]=3[CH3:14])[N:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH3:16]
Reactant: CCOc1ccc(NC(N)=S)cc1
Reactant: Cc1nc2sccn2c1C(=O)CBr
Agent: Br
Solvent: CCO
Product: CCOc1ccc(Nc2nc(-c3c(C)nc4sccn34)cs2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-bromo-1-(6-methylimidazo[2,1-b]thiazol-5-yl)ethanone hydrobromide (18) (2.20 g, 6.5 mmol) and (p-ethoxyphenyl)thiourea (10) (1.30 g, 6.5 mmol) in 40 mL of anhydrous ethanol was refluxed under stirring for 20 h, and then cooled to room temperature. The solid was filtered. The crude white solid product was re-crystallized from methanol. The methanol solution was filtered while still hot to remove possible dust, and then heated into solution. It was re-crystallized two more times from methanol, and dried under vacuum to provide the desired product 20 as a white solid, yield 0.64 g (22.4%), HPLC purity 97.81%, mp >240° C. 1HNMR (CD3OD) δ 1.27 (t, 3H, J=6.8 Hz), 2.56 (s, 3H), 3.88-3.94 (m, 2H), 6.85 (d, 2H, J=8.8 Hz), 6.97 (s, 1H), 7.34 (d, 2H, J=8.8 Hz), 7.54 (d, 1H, J=4.4 Hz), 8.44 (d, 1H, J=4.4 Hz). ESI-MS m/z 357 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].Br[CH2:29][CH2:30][CH3:31]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:29][CH2:30][CH3:31]
Reactant: CCCBr
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCCOc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and 1-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: O1C=CC=C1C1C=CC(N2CCN(S(CC(C(C)C)C([NH:25][OH:26])=O)(=O)=O)CC2)=CC=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([S:48]([CH2:51][C:52]4([C:58]([OH:60])=O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)(=[O:50])=[O:49])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)[CH:31]=1>>[OH:26][NH:25][C:58]([C:52]1([CH2:51][S:48]([N:45]2[CH2:46][CH2:47][N:42]([C:39]3[CH:38]=[CH:37][C:36]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:41][CH:40]=3)[CH2:43][CH2:44]2)(=[O:49])=[O:50])[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)=[O:60]
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)NO
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 94 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide, from 4-[4-(4-pyridin-3-yl-phenyl)piperazine-1-sulfonylmethyl]-tetrahydropyran-4-carboxylic acid (0.20 g), to yield the title compound as a white solid (0.19 g, 94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[Cl:11][C:12]1[C:13]([OH:41])=[C:14]([S:19]([N:22]([CH2:27][C:28]2[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=[C:30]([Cl:40])[CH:29]=2)[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1.CCN(CC)CC>C1COCC1>[Cl:40][C:30]1[CH:31]=[C:32]([CH:33]=[C:28]([CH2:27][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[C:13]=2[OH:41])(=[O:21])=[O:20])[CH:29]=1)[CH2:34][N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8]
Reactant: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of pyridine-3-sulfonyl chloride (70 mg, 0.40 mmol) in THF (4 mL) were added 3,5-dichloro-N-(3-chloro-5-((isobutylamino)methyl)benzyl)-2-hydroxy-N-isobutylbenzenesulfonamide (100 mg, 0.20 mmol) and Et3N (0.14 mL, 0.98 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was concentrated. To the residue was added 1 N NaOH/THF/MeOH. After 4 h, the mixture was concentrated and the residue was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the desired product as a white solid (60 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1.C(N(CC)CC)C.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:38]([CH3:40])[CH3:37])[CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1
Reactant: O=C1N(CC2CCNCC2)c2c(F)cccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3cccc(F)c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a stirred solution of 7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one (120 mg, 0.28 mmol) and triethylamine (3.9 μL, 0.028 mmol) in 5.00 mL dichloromethane was added acetone (4.1 μL, 0.56 mmol) followed with sodium triacetoxyborohydride (124 mg, 0.56 mmol) at ambient temperature. The mixture was stirred at ambient temperature overnight, quenched with water (10.0 mL). The mixture was extracted with dichloromethane (3×30.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (2% methanol in ethyl acetate/hexane) to give 7′-fluoro-1′-[(1-isopropylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (85 mg, 69%) as a white solid, which was treated with 2.0 M HCl in diethyl ether to give the title compound: mp 157-160° C.; 1H NMR (300 MHz, CD3OD) δ 7.22-7.05 (m, 2H), 7.05-6.98 (m, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.68 (d, 1H), 3.95-3.77 (m, 2H), 3.55-3.42 (m, 3H), 3.12-2.96 (m, 2H), 2.30-2.10 (m, 1H), 2.10-1.97 (m, 2H), 1.76-1.52 (m, 2H), 1.34 (d, 6H); 13C NMR (75 MHz, CD3OD) δ 179.7, 157.6, 150.6, 150.4, 147.1, 143.9, 136.6, 125.8, 121.2, 120.3, 118.0, 103.9, 103.0, 94.3, 81.8, 60.1, 59.7, 47.6, 35.33, 35.30, 28.6, 28.5, 16.98, 16.96; MS (ES+) m/z 439.27 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>COCCOC>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:29]#[N:30])[CH:36]=2)=[C:16]([F:21])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)CCN(Cc1ccc(Br)c(F)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)CCN(Cc1ccc(-c2cccc(C#N)c2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 78.8 %

Procedure:
(4-Bromo-3-fluoro-benzyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-5c: 1.5 g, 4.00 mmol) was dissolved in 1,2-dimethoxyethane (15 ml) under nitrogen. Palladium tetrakis(triphenylphospine) (5 mol %) was added followed by an aqueous 2 M sodium carbonate solution (7 ml) and 3-cyano-phenyl boronic acid (0.883 g, 6.01 mmol) was added. The reaction mixture was heated at reflux for 24 hours before being cooled to room temperature and filtered through Celite, rinsing with dimethoxyethane. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford 1.25 g (78%) of title product (I-5d).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20].[C:21]1([Se:27]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([Se:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:20]
Reactant: Cl[Se]c1ccccc1
Reactant: CN1CCCCC1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1CCCC([Se]c2ccccc2)C1=O
Reaction time: 0.08 h

Procedure:
A solution of diisopropylamine (3.02 mL, 21.21 mmol) in tetrahydrofuran (44.2 mL) under argon was cooled to −78° C. and added butyllithium solution, 2.5M in hexanes (8.48 mL, 21.21 mmol). After 5 min, a solution of 1-methylpiperidin-2-one (2 g, 17.67 mmol) in tetrahydrofuran (2 mL) was added dropwise. After stirring for 10 min, a solution of phenylselenenyl chloride (4.06 g, 21.21 mmol) in 16 mL of tetrahydrofuran was added, and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with aqueous saturated NH4Cl solution and diluted with CH2Cl2; the aqueous layer was back-extracted with CH2Cl2 (1×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford a crude crop of 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane. To the crude 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane (50 mL) at 0° C. under argon was added 3-chlorobenzoperoxoic acid (7.92 g, 35.3 mmol). The resulting mixture was allowed to gradually warm to room temperature overnight. The orange suspension was filtered, and the filtrate was concentrated in vacuo and partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (5×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methyl-5,6-dihydropyridin-2(1H)-one (1.33 g, 67.7% yield) as a brown oil. [M+1]=112.2.