Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N+:21]([O-])([OH:23])=[O:22]>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[C:12]([N+:21]([O-:23])=[O:22])[CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:20])(=[O:18])=[O:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: O=[N+]([O-])O
Product: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
4-(2-Acetoxy-ethyl)-naphthalene-1-sulfonyl chloride (76.96 g, 246 mmol) was added portionwise over 12 minutes to 90% nitric acid (154 mL, 3.278 mol) cooled in an ice-methanol bath (−20° C.). After the addition was complete, the reaction mixture was stirred at −20 ° C. for an additional 15 minutes. The reaction mixture was partitioned between ice water (800 mL) and chloroform (800 mL). The aqueous layer was extracted with chloroform (100 mL). The combined organic layers were washed with brine (400 mL, 200 mL), then dried over magnesium sulfate, filtered, and evaporated to a golden oil. Diethyl ether (300 mL) was added to the crude product and the mixure was shaken vigorously to afford an off-white solid. The solid was collected by filtration, washed with ether (2×50 mL), and dried under vacuum to afford 4-(2-acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride (41.85 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C)CC2)c(C)c1
Yield: 49.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (777 mg) described in Preparation Example 67 and oxazolidin-2-one (209 mg), the title compound (390 mg) was obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([NH2:12])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:57]=[CH:56][CH:55]=[CH:54][C:25]=1[O:26][C:27]1[CH2:31]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:29](=[O:53])[CH:28]=1>C(#N)C>[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([N:12]1[CH2:31][C:27]([O:26][C:25]2[CH:54]=[CH:55][CH:56]=[CH:57][C:24]=2[Cl:23])=[CH:28][C:29]1=[O:53])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CC(C)CC
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
A suspension of (S)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.05 g, 5.01 mmol) in acetonitrile (6 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and stirred at 60° C. for 15 min. To this mixture was added N,N-diisopropylethylamine (1.2 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 61, 1.6 g, 5.0 mmol) in acetonitrile (4 mL) via a dropping funnel and the resulting mixture refluxed for 20 h. The resulting mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL). The resulting solution was transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica column 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (950 mg, 52%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([O-:49])=[O:48])=[CH:26][N:27]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22]2=[N:21][CH:20]=1)(C(C)(C)C)(C)C.[CH3:50]CCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([O:49][CH3:50])=[O:48])=[CH:26][N:27]([C:28]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:22]2=[N:21][CH:20]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)[O-])cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(O)cc34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.5 %

Procedure:
To a solution of 2-(5-(tert-butyldimethylsilyloxy)-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (3.4 g, 4.9 mmol) in THF (25 mL) was added TBAF (6.42 mL, 12.85 mmol) at 0° C., after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 0.5 hour, then H2O (25 mL) was added to the mixture extracted with EtOAc (100 mL), the organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 2-(5-hydroxy-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (3.2 g, >100%) as a yellow solid. LCMS: (M+H)+=566; (M+Na)+=588.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH:38]([CH3:40])[CH3:39].[BH4-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:31]3[CH2:36][CH2:35][N:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(-c3ccncc3)n2)cc1Cl
Reactant: CC(C)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CC=C(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)CC1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
Dissolve 4-(3-chloro-4-fluorophenyl)-6-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-2-(pyridin-4-yl)pyrimidine (40 mg) and 2-bromopropane (0.1 mL) in DMF (1.5 mL) under nitrogen atmosphere. Heat the mixture in a sealed tube at 120° C. for 48 hours. Cool the mixture to room temperature and then add NaBH4 (50 mg). Stir the mixture at room temperature for 20 hours, dilute with water (5 mL), extract with EtOAc (3×3 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product and purify by flash column chromatography using 20% EtOAc/hexane to afford the title product as white solid. Mass spec m/z=561.27.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1.[CH3:17][NH:18][CH3:19]>O1CCOCC1>[CH3:17][N:18]([CH3:19])[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: O=Cc1cc2cc3c(cc2nc1Cl)OCO3
Reactant: CNC
Solvent: C1COCCO1
Product: CN(C)c1nc2cc3c(cc2cc1C=O)OCO3
Temperature: 160 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 6-chloro-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (1.0 g, 4.07 mmol) in dioxane (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added dimethylamine (40% in water, 5.1 mL, 40.7 mmol) and the reaction mixture was stirred for 45 min at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken back in water (30 mL). The precipitate formed was filtered through a fritted glass filter (porosity 3) to give after evaporation 6-(dimethylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde RBO 35166 (960 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5]2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:5]2)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CCN(C(=O)CCc1ccccc1)C2
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN(C(=O)CCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Example 19 in pyridine (10 mL) at 0° C. is added dropwise methanesulfonyl chloride (0.86 mL). After 45 minutes at 0° C., the reaction is allowed to warm to room temperature and stirred an additional 30 minutes. The pyridine is removed and the residue taken up into CH2Cl2 and washed with 10% HCl. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel will provide the desired material.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][CH:16]=[CH:17][C:18]2[CH:70]=[C:21]3[N:22]=[C:23]([CH3:69])[C:24]([C@H:58]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[C:25]([N:26]4[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([O:40][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH3:39])([CH3:32])[CH2:28][CH2:27]4)[N:20]3[N:19]=2)=[C:13]([F:71])[C:12]([F:72])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:65]([O:64][C@@H:58]([C:24]1[C:23]([CH3:69])=[N:22][C:21]2[N:20]([N:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:14]3[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([F:72])[C:13]=3[F:71])[CH:70]=2)[C:25]=1[N:26]1[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([OH:40])[CH3:39])([CH3:32])[CH2:28][CH2:27]1)[C:59]([O:61][CH2:62][CH3:63])=[O:60])([CH3:66])([CH3:67])[CH3:68]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3c(OCc4ccccc4)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3c(O)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Yield: 45.6 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (114 mg, 0.114 mmol) in Ethanol (4 mL) was added 10% Pd—C (24 mg, 0.022 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vac. The residue was then treated with 1M TBAF (0.849 mL, 0.849 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(2,3-difluoro-6-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (35 mg, 0.052 mmol, 30% yield) as thick paste. 1H NMR (400 MHz, CDCl3) δ 6.90 (q, J=9.0 Hz, 1H), 6.59 (d, J=10.0 Hz, 1H), 6.36 (s, 1H), 5.91 (br. s., 1H), 4.32-4.15 (m, 2H), 3.85 (d, J=6.3 Hz, 2H), 3.44 (br. s., 3H), 2.94 (br. s., 1H), 2.89-2.71 (m, 4H), 2.63 (s, 3H), 2.15-2.04 (m, 2H), 2.04-1.94 (m, 2H), 1.90 (d, J=6.8 Hz, 2H), 1.75 (d, J=7.3 Hz, 1H), 1.57-1.44 (m, 6H), 1.38-1.27 (m, 12H), 0.94-0.87 (m, 6H). LCMS (M+H)=675.4.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:18])(=[O:14])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)CCCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
To a stirred solution of sodium diatrizoate (59.0 g, 92.8 mmol) in 350 ml of dry DMF was added ethyl 5-bromovalerate (14.7 ml, 92.8 mmol) in two portions and the resulting solution was stirred at ambient temperature for 12 hr. The reaction mixture was poured into 3.5 1 of water and the resulting white precipitate was collected, washed with ether and then air dried. The crude product was dissolved in acetonitrile-ethanol (5:2), filtered through a pad of silica gel and the filtrate was evaporated to give a solid (67 g, 97%). Recrystallization from methanol-water gave analytically pure product (mp 237°-239° C.) after drying under high vacuum; CI-MS: MH+ 743. The 1H-NMR (300 MHz) spectral data was consistent with the desired product. Calculated for C18H21I3N2O6 ; C 29.13, H 2.85, I 51.30; Found: C 29.13, H 2.78, I 51.15, N 3.75.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20](O)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43]>O>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
4-[4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (190 mg, 0.451 mmol) and CDMT (95.6 mg, 0.539 mmol) were charged into a flask. The flask was flushed with nitrogen and 2-MeTHF (10 ml) was added, followed by NMM (64 uL, 0.581 mmol). The reaction mixture was stirred at RT for 1 hour. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (64 mg, 0.539 mmol) was added to the reaction mixture and stirred for 16 hours at RT. Water (25 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×50 ml). The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. Crude material was purified by chromatography on silica gel (70% heptane:30% ethyl acetate to 100% ethyl acetate) to afford a white solid (220 mg, 79%). MS (LC/MS) m/z 511.1 (M−1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.93 (t, J=7.02 Hz, 3H) 1.12-1.42 (m, 9H) 1.49-1.99 (m, 10H) 2.25-2.43 (m, 1H) 2.45-2.64 (m, 1H) 3.12 (d, J=5.07 Hz, 3H) 3.51-3.68 (m, 2H) 3.82-4.03 (m, 4H) 4.08-4.26 (m, 2H) 5.03-5.14 (m, 1H) 5.94 (d, J=2.54 Hz, 1H) 6.07-6.21 (m, 1H) 7.45-7.60 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([B:10]([OH:12])[OH:11])=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: COc1ccc(B(O)O)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(B(O)O)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 3-amino-4-methoxyphenylboronic acid (1 eq, 2.10 mmol, 0.35 g) in CH2Cl2 (5 mL) at −78° C. was added Et3N (6 eq, 13.0 mmol, 1.7 mL). The reaction was stirred for 30 minutes then methanesulfonyl chloride (1.1 eq, 2.30 mmol, 0.26 g) was added. The reaction was then stirred at −78° C. for 1 hour. The reaction was allowed to warm to room temperature and diluted with CH2Cl2. The reaction washed with 1.0N aqueous HCl and the organic phase was extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 4-methoxy-3-(methylsulfonamido)phenylboronic acid (1.92 mmol, 0.49 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:4][C:5]([N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:27]#[C:28][Si](C)(C)C)=[CH:10][N:9]=1)=[O:6])[CH3:3].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:38][C:36]([CH3:39])([O:35][C:33]([N:7]([C:5]([O:4][C:2]([CH3:40])([CH3:3])[CH3:1])=[O:6])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:27]#[CH:28])=[CH:10][N:9]=1)=[O:34])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#C[Si](C)(C)C)cc1-c1nnnn1-c1cccc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnnn2-c2cccc(F)c2F)c1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
N,N-Di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (713 mg, 1.2 mmol) was dissolved in methylene chloride (10 mL) and cooled to 0° C. To this was added tetrabutylammonium fluoride hydrate (163 mg, 625 μmol) in methylene chloride (1 mL). The reaction was loaded directly onto silica and chromatographed (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-ethynylpyridin-2-amine (496 mg, 1.0 mmol, 83%) as a yellow solid; 1H NMR (CDCl3): 1.37 (s, 18H), 3.35 (s, 1H), 7.30 (m, 1H), 7.40 (m, 2H), 7.89 (s, 1H), 8.75 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]([CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:10]1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:15]=[N+:16]([O-:35])[CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]([CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:10]1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc[n+]([O-])c1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 3-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-pyridine (9 mg, 0.023 mmol) (Example 44) in 1 mL of DCM at Rt was added m-chloroperoxybenzoic acid (60%)(7.9 mg, 0.028 mmol) and the mixture stirred for 1 hr at Rt. The solvents were evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 30-70% CH3CN in 0.1% TFA/H2O over 10 mins to give 8 mg (71%) of the title compound as white solid containing 0.5 eq of TFA.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]3[N:28]=[N:29][N:30](COC)[N:31]=3)[CH2:22]2)=[O:20])=[CH:13][C:12]=1[N+:35]([O-:37])=[O:36])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]3[NH:28][N:29]=[N:30][N:31]=3)[CH2:22]2)=[O:20])=[CH:13][C:12]=1[N+:35]([O-:37])=[O:36])([CH3:3])[CH3:2]
Reactant: COCn1nnc(C2CCCN(C(=O)/C=C/c3ccc(Sc4ccccc4C(C)C)c([N+](=O)[O-])c3)C2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)N2CCCC(c3nnn[nH]3)C2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 74.6 %

Procedure:
The compound from Example 279 (75 mg, 0.14 mmol) was dissolved in 1 mL of neat TFA and left at ambient temperature for overnight. The reagent was then removed in vacuo and the residue was evaporated twice with benzene. The crude product was purified using Gilson Preparative HPLC as described in Example 38B to give the title compound as a light-yellow solid (50 mg, 72%); 1H NMR (CDCl3, 300 MHz) δ 1.17 (d, J=6.5 Hz, 6H), 1.25-1.39 (m, 1H), 1.69-1.81 (m, 1H), 2.09 (br s, 1H), 2.14-2.30 (m, 1H), 2.57-2.71 (m, 1H), 3.35-3.66 (m, 3H), 3.90-4.03 (m, 1H), 4.66-4.78 (m, 1H), 6.73 (d, J=8.7 Hz, 1H), 6.86 (d, J=15.3 Hz, 1H), 7.32 (dd, J=2.1, 6.9 Hz, 1H), 7.42 (dd, J=2.1, 8.7 Hz, 1H), 7.47-7.57 (m, 3H), 7.76 (d, J=15.3 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H). MS (ESI+) (M+H)+ at m/z 479. Anal. Calcd for C24H26N6O3S.0.28H2O: C, 59.61; H, 5.54; N, 17.38. Found: C, 59.71; H, 5.44; N, 16.99.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)(O)[O-].[Na+]>C(O)C>[O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][N:13]([CH2:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C1c2ccccc2CC12CCNCC2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2CC12CCN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 56.2 %

Procedure:
A mixture of 0.60 g (3.0 moles) 1,3-dihydro-1-oxospiro[2H-indene-2,4'-piperidine], 0.71 g (3.1 mmoles) 4-nitrophenethyl bromide, and 0.28 g (3.3 mmoles) sodium bicarbonate in 3 ml ethanol was heated at reflux for 6 hours. The solvent was removed in vacuo and the residue was partitioned between 20 ml ethyl acetate and 5 ml dilute bicarbonate solution. The layers were separated and the aqueous layer was extracted with 20 ml ethyl acetate. The combined extract was washed wth 5 ml water and brine, dried, and the solvent was removed in vacuo to give 1.08 g crude product as a gum. This was purified by flash chromatography on silica gel eluting with methanol:chloroform (2:98). The material obtained was crystallized from 1:10 methylene chloride:ether to give 0.61 g (58%) product, m.p. 187°-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](OC)=[O:21]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20](=[O:21])[CH2:19][S:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 50 °C
Yield: 73.8 %

Procedure:
To a stirred suspension of 2-amino-5-nitrobenzenethiol (Step 1, 29 g, 139.8 mmol) and potassium carbonate (115.93 g, 838.8 mmol) in dry DMF (150 mL) is added methyl bromoacetate (15.88 mL, 167.8 mmol). The reaction mixture is heated at 50° C. for 16 h at which time the reaction is quenched with ice and water (50 mL). The precipitate is filtered and dried under high vacuum to give the title compound as a yellow solid (21.69 g, 74%), MS m/z 211.5 (M+H)+.