Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[NH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][C:15]=2[NH:28][C:29]2[C:30]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[N:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:27])=[CH:16][C:15]=2[NH:28][C:29]2[C:30]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[N:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)NC4CCCC4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC4CCCC4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
A solution of the product of Example 155A (39.9 mg, 0.0592 mmol) in 1,4-dioxane (2 mL) was treated with a solution of sodium hydroxide (5.9 mg, 0.148 mmol) in water (1 mL), then heated at 60° C. for 1 hour. The reaction was then cooled to room temperature and diluted with ethyl acetate (50 mL) and water (25 mL). The aqueous pH was adjusted to 5 with 1N aqueous hydrochloric acid, the layers were separated, and the organic phase washed with water (2×25 mL) and brine (25 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 4% methanol/methylene chloride provided the title compound as a white solid (19 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 1.43-1.58 (m, 4 H) 1.59-1.75 (m, 2 H) 1.78-1.96 (m, 2 H) 3.12-3.32 (m, 1 H) 4.11-4.26 (m, 1 H) 5.57 (s, 2 H) 6.61 (d, J=8.46 Hz, 2 H), 6.81 (d, J=8.82 Hz, 1 H) 7.11 (d, J=8.46 Hz, 2 H) 7.64 (t, J=9.01 Hz, 1 H) 7.83 (s, 1 H) 8.21 (d, J=6.62 Hz, 1 H) 8.56 (s, 1 H) 8.86 (d, J=8.82 Hz, 1 H) 10.10 (s, 1 H); MS (ESI+) m/z 499 (M+)+, (ESI−) m/z 497 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[CH:6]=[O:7])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(Cl)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-3-hydroxy-benzaldehyde* (0.354 g), 4-N,N-dimethylaminopyridine (0.028 g), tert-butyldimethylsilyl chloride (0.409 g) and triethylamine (0.473 ml) in DCM (15 ml) was stirred at room temperature under nitrogen for 19 h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The combined organic extracts were concentrated under reduced pressure to give an oil which was purified using SPE (silica, eluting with cyclohexane followed by 10% to 30% ethyl acetate-cyclohexane) to give the title compound (0.42 g) as an oil. *Kelley, J; Linn, J; Selway, J. W. T., J. Med. Chem. (1989), 32(8), 1757-63.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:38]([NH2:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:46][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (1.96 g, 4.48 mmol) (Preparation 10) and triethylamine (1.8 g, 17.8 mmol) in acetonitrile (20 ml) was treated with phenethylamine (0.60 g, 4.96 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (75 ml) and water (20 ml). The organic phase was separated and the solvent was removed under reduced pressure. The foam was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 by volume) to give a product which was then azeotroped with diethyl ether to afford the title compound as a foam (2.05 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18].[OH-].[Na+].CCCC(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl.C1(C)C=CC=CC=1>[O:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g, 49.69 mmol), tetrabutylammonium hydrogensulfate (0.844 g, 2.48 mmol) and 2-chloro-1-morpholinoethanone (8.13 g, 49.69 mmol) were added to toluene (75 mL) to this was added NaOH (40 g, 400.03 mmol) in water (45 mL) and the reaction was stirred at 25° C. overnight. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a white solid. This was redissolved in DCM and evaporated carefully to give a yellow gum, diethyl ether was added followed by iso-hexane until a cloudy solution was observed. The system was stirred to afford a solid which was collected by filtration and dried under vacuum to give the desired compound as a white solid (15.30 g, 94% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.45 (9H, s), 1.58-1.49 (OH, m), 1.72-1.61 (2H, m), 1.89-1.82 (2H, m), 3.12-3.06 (2H, m), 3.61-3.54 (6H, m), 3.68-3.67 (4H, m), 3.80-3.72 (1H, m), 4.18 (2H, s).
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS([N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1)(=O)=O.C(N(CC)CC)C>O1CCCC1.C(#N)C>[N:16]1([C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CS(=O)(=O)n1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)n1nnc2ccccc21

Procedure:
1.42 g (0.01 mol) of trans-cinnamic acid (compound of formula IV) and 1.97 g (0.01 mol) of 1-(methylsulfonyl)benzotriazole are stirred at room temperature in 50 ml of tetrahydrofuran, followed by dropwise addition of 0.014 mol of triethylamine. The solution is then refluxed for 24 hours, and then evaporated under reduced pressure. The residue is taken up in 60 ml of water and extracted with 70 ml of ethyl acetate. The organic phase is dried, filtered and then concentrated under vacuum. The powder obtained is taken up in 50 ml of acetonitrile and filtered off by suction.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:28])[C@H:15]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]([CH3:18])[CH3:17])C1C=CC=CC=1.OO.[Li+].[OH-].[O-:33]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:21]([O:20][CH2:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[C:14]([OH:28])=[O:33])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](COCc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of (R)-4-benzyl-3-((S)-2-(benzyloxymethyl)-3-methylbutanoyl)oxazolidin-2-one (127 g, 0.33 mol) in 3:1 THF/H2O (2 L), cooled in an ice bath, were added 30% aq H2O2 (235 mL, 2.07 mol) and LiOH (28 g, 0.66 mol). The mixture was stirred at 20° C. for 3 h, followed by cooling to 0° C. Then 1.5 M aq Na2SO3 (1.38 L, 3.83 mol) was added dropwise within 30 min. After addition of satd aq NaHCO3 (500 mL), volatiles were evaporated, and the aqueous phase was washed with Et2O (3×600 mL). The organic layers were discarded. The aqueous layer was adjusted to pH 3 by adding 2 N aq HCl and extracted with CH2 Cl2 (3×800 mL). The combined organic layers were washed with satd aq NaCl (1 L), dried over Na2SO4, and evaporated to give (S)-2-(benzyloxymethyl)-3-methylbutanoic acid (60 g, 82%). 1H NMR (400 MHz, CDCl3): 0.98 (m, 6H), 2.01 (m, 1H), 2.53 (m, 1H), 3.67 (m, 2H), 4.55 (s, 2H), 7.30 (m, 6H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][S:31]([C:29]2[S:30][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[CH:27][CH:28]=2)(=[O:32])=[O:33])[CH2:10][CH2:11]1
Reactant: NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
The product of Example 3, Step (d) (0.3 g) was dissolved in pyridine (1 ml) and CH2Cl2 (4 ml). 5-Pyridin-2-yl-thiophene-2-sulfonyl chloride (0.317 g) [dissolved in CH2Cl2 (4 ml)] was then added and the reaction left to stir for 1 hr. The reaction mixture was poured onto flash silica and the silica flushed with 5% MeOH/94% CH2Cl2/1% aq NH3 as eluent. Evaporation of solvent and purification using reverse phase HPLC {with a gradient eluent system [25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.120 g).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:19]([O:23][CH2:24][CH3:25])(=O)[CH:20]=[CH2:21].CC[O-].[Na+]>C(O)C>[CH2:24]([O:23][CH2:19][CH2:20][C:21]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1)[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Reaction time: 15 h
Yield: 95 %

Procedure:
12.6 g. 2-(theophyllin-7-yl)-acetamidoxime, 10 g. of ethyl acrylate, 220 cm3 of ethanol and 3.4 g. of sodium ethylate are heated under stirring for 15 hours. 16 g. (95% yield) of raw 7-[[5-(2-ethoxy-ethyl)-1,2,4-oxadiazol-3-yl]-methyl]-theophylline are obtained. This product is heated with 20 cm3 diethylamine under stirring for 8 hours on a 110° C. oil bath. The mixture is then evaporated at reduced pressure, washed by trituration with water and salt is formed with 5.8 g. of maleic acid in hot ethanol. 16.2 g. (68% yield) of 7-[{5-(2-diethylamino-ethan-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophilline-maleinate are are obtained. M.p.: 125°-128° C.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=1[CH3:21])([CH3:9])[CH3:8]>C(OCC)C>[CH3:9][C:7]1([CH3:8])[CH2:6][O:22][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[CH3:21])=[N:10]1
Reactant: Cc1c(C(=O)NC(C)(C)CO)cccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Cc1c(C2=NC(C)(C)CO2)cccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Thionyl chloride, 37 ml, is added dropwise with stirring to 39.7 g (0.1575 mol) of N-(2-hydroxy-1,1-dimethylethyl)-2-methyl-3-nitrobenzamide. The mixture is allowed to stand overnight, poured into diethylether, filtered and the solvent evaporated to give 33.4 g of 4,5-dihydro-4,4-dimethyl-2-(2-methyl-3-nitrophenyl)oxazole as a pale yellow oil which crystallizes on cooling; mp 60°-61° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:3][CH2:2]1.[Br-].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C.[C-:30]#[N:31].[Na+]>O.C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:9][C:30]#[N:31])[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: COc1ccc(C=O)cc1OCC1CC1
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC#N)cc1OCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
To 3-cyclopropylmethoxy-4-methoxybenzaldehyde (21.2 g, 103 mmol) was added lithium bromide (17.8 g, 206 mmol) and acetonitrile (10 mL). Upon dissolution, the reaction mixture was cooled to 0° C. Trimethylsilylchloride (19.6 mL, 154 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature and was stirred for 15 min. The reaction mixture was again cooled to 0° C., 1,1,3,3-tetramethyldisiloxane (27.2 mL, 154 mmol) was added and the resulting mixture was allowed to warm to room temperature. After stirring for 2 h, the mixture was separated into two layers. The lower layer was removed, was diluted with methylene chloride, was filtered and the filtrate was concentrated under reduced pressure; this procedure was repeated a total of three times. The resulting light tan oil was dissolved in dimethylformamide (90 mL) under an argon atmosphere and was treated with sodium cyanide (11.3 g, 232 mmol). The resulting mixture was stirred at room temperature for 2 h, then poured into cold water and extracted twice with ethyl acetate. The combined organic extract was washed three times with water, once with brine and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil (21.4 g, 96%), which was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3cccnc3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3cccnc3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12](O)=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:10]2(=[O:23])=[O:22])=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:35][C:12]1[C:13](=[O:14])[N:9]([CH2:8][C:7]2[CH:24]=[CH:25][C:4]([O:3][CH:2]([F:26])[F:1])=[CH:5][CH:6]=2)[S:10](=[O:23])(=[O:22])[C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C(O)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Yield: 61.4 %

Procedure:
2-[4-(Difluoromethoxy)benzyl]-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.98 g, ca.60% purity, 1.80 mmol)) was dissolved in DCM (40 mL) and DMF (0.14 mL) was added. Under an atmosphere of nitrogen, oxalyl chloride (0.46 g 3.61 mmol) was dropped in. The mixture was then heated to reflux for 5 h and then evaporated to dryness. Water (20 mL) was added and the reaction mixture was extracted with DCM (20 mL×3). The extracts were combined and washed with water (50 mL×3) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20 g/70 mL), eluting with DCM:heptane (30:70), to give the title compound (0.442 g, 62%) as a semi-solid; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H), 7.48-7.58 (m, 5H), 7.11 (d, 2H), 6.51 (t, 1H), 4.86 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 155.8, 151.2, 143.5, 132.5, 130.8, 130.5, 129.4, 128.8, 127.2, 123.2, 119.5, 115.7 (t), 43.1.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:47])[C@@H:9]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][CH:11]([O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:12](=[O:27])[NH:13][CH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])([CH3:6])([CH3:5])[CH3:4]>CC(O)C>[C:3]([O:7][C:8](=[O:47])[C@@H:9]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@@H:11]([O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:12](=[O:27])[NH:13][CH2:14][C:15]1[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1cc(OC)c(CNC(=O)C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(OC)c(CNC(=O)[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1

Procedure:
Following the procedure in the preparation of 11, compound 11′ was prepared from alcohol 10′ (2.010 g, 4.04 mmol) as a pale white foamy solid (2.599 g, 99% yield): [α]26D=−30.5 (c=1.04, MeOH); HPLC of 11′ for purity: 98.0%, [major peak: Rt=15.9 min; minor peaks: 19.0 min and 24.6 min; column: Chiralcel ODH (250×4.6 mm), UV detector, 210 nm, 5% 2-propanol in hexanes; flow rate: 1.0 mL/min]. 1HNMR (200 MHz, CD2Cl2) δ 7.72 (d, 2H, J=8.4 Hz), 7.28 (d, 2H, J=8.2 Hz), 6.73 (br s, 1H), 6.15 (s, 2H), 5.12 (br s, 1H), 4.84 (t, 1H, J=6.0 Hz), 4.39 (dd, 1H, J1=13.9 Hz, J2=5.7 Hz), 4.27 (dd, 1H, J1=13.9 Hz, J2=5.3 Hz), 3.96 (q, 1H, J=7.4 Hz), 3.821 (s, 3H), 3.817 (s, 6H), 2.41 (s, 3H), 2.20 (t, 2H, J=6.4 Hz), 1.43 (s, 9H), 1.42 (s, 9H). 13C NMR (50 MHz, CD2Cl2) δ 170.6, 167.1, 161.2, 159.4, 155.4, 145.5, 132.9, 130.1, 128.1, 106.1, 90.9, 82.1, 79.9, 77.5, 56.0, 55.5, 51.6, 34.8, 32.6, 28.4, 28.1, 21.8. HRMS calcd for C31H45N2O11S (M+H)+: 653.2744. found: 653.2740.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:17][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][OH:16]
Reactant: COCOc1cc(CO)cc(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(CO)c(Br)c(OCOC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
The above-obtained 3,5-bis(methoxymethoxy)phenylmethanol (5.3 g, 23 mmol) was dissolved in N,N-dimethylformamide (20 mL) and obtained solution was added with N-bromosuccinimide (4.3 g, 24 mmol) followed by stirring at a room temperature for 5 hours. The reaction mixture was added with water and extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/1 to 2/1) to obtain [2-bromo-3,5-bis(methoxymethoxy)phenyl]methanol (4.9 g, 69%).
Reaction SMILES: C([Li:5])CCC.Cl[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.BrC(Br)CC[C].O>CCCCCC.O1CCCC1>[C:8]1([P:7]([Li:5])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [C]CCC(Br)Br
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]P(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
Diphenylphosphino lithium was prepared by adding n-butyl lithium (12.5 ml, 1.6 molar, 0.02 mole) in hexane to a solution of chlorodiphenylphosphine (3.76 g, 0.02 mole) in tetrahydrofuran. The dibromopropyl carbon of step 2 was added and the mixture was stirred for 15 hours. Water (100 ml) was added and the mixture stirred for 15 hours. Water (100 ml) was added and the product filtered. After washing with tetrahydrofuran and drying at 55° C. and 0.1 mm Hg pressure for three hours, the product contained 1.24 wt. % phosphorus.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH2:22][CH2:23][CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1
Yield: 8.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.013 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:19].[NH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=[N:20][OH:21])[CH:14]=[N:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ON=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Yield: 35.4 %

Procedure:
Prepare in a similar manner as described in EXAMPLE 6 using 5-(3,4-difluorophenylethynyl)-pyridine-3-carbaldehyde (0.28 g, 1.15 mmol), (prepared essentially as described in EXAMPLE 101), hydroxylamine hydrochloride (0.64 g, 9.21 mmol) and potassium carbonate (0.80 g, 5.76 mmol) to give the title compound (0.120 g, 35%).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@@H:11]1[CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO.[Cl-].[Na+].O>[O:20]([CH2:19][C@H:11]1[C@@H:12]2[C@@H:13]([O:14][C:15](=[O:17])[CH2:16]2)[CH2:18][C@H:10]1[OH:9])[Si:21]([C:34]([CH3:35])([CH3:36])[CH3:37])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](OC[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 3 (15.7 g, 30.0 mmol) in methanol (100 mL) was added potassium carbonate (4.14 g, 30.0 mmol). After 1 h, saturated ammonium chloride (100 mL) and saturated brine (100 mL) were added, the mixture was extracted with methylene chloride (3×100 mL), dried (magnesium sulfate), filtered, concentrated, and chromatographed on a 15 cm tall×41 mm diameter silica gel column eluting with 40% ethyl acetate in hexane to afford 4 (9.93 g, 79%).