Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]2[CH:15]=[C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]([CH3:27])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)=O.O1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>CCOC(C)=O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:27])[CH:17]=[C:16]2[C:14]1[NH:13][C:10]2[N:11]=[CH:12][C:7]3[N:8]([C:3]([C:2]([F:1])([F:29])[F:28])=[N:5][CH:6]=3)[C:9]=2[CH:15]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)C(F)(F)F)cnc3[nH]1)cn2C
Agent: CC(=O)[O-]
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C(F)(F)F)n43)[nH]1)cn2C
Temperature: 85 °C
Reaction time: 3 h
Yield: 8.5 %

Procedure:
To a round bottom flask was added 2,2,2-trifluoro-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide (0.086 g, 0.213 mmol, prepared using J.1 from Preparation #I.1 with trifluoroacetic anhydride and M with TBAF), 1,4-dioxane (5 mL) and Lawesson's reagent (0.052 g, 0.128 mmol). The mixture was heated at about 85° C. for about 90 min. More Lawesson's reagent (0.052 g, 0.128 mmol) was added and the mixture was stirred at about 85° C. for about 3 h. The mixture was cooled to rt and stirred overnight. To the mixture was added mercury(II) acetate (0.075 g, 0.235 mmol) and the mixture was stirred at rt for about 16 h. The mixture was diluted with EtOAc (50 mL) and filtered through Celite®. The organic layer was washed with water (50 mL), dried with anhydrous MgSO4, filtered and concentrated in vacuo to give a residue. The residue was added to a round bottom flask and 1,4-dioxane (5 mL) and mercury(II) trifluoroacetate (0.122 g, 0.286 mmol) were added. The mixture was stirred at rt for about 30 min. The mixture was diluted with EtOAc (50 mL), filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatograph (40 g silica gel column, DCM/MeOH 1:0 to 10:1) to give a solid. The material was purified again by flash chromatography (120 g silica gel column, heptane/EtOAc 1:0 to 0:1) to give a solid. The solid was purified by reverse phase preparatory HPLC (Table 2, method e) to give fractions with product. The fractions were combined and extracted with EtOAc (50 mL). The organic was washed with water (50 mL), dried with anhydrous MgSO4, filtered and concentrated in vacuo. The solid was dried in under reduced pressure at about 60° C. for about 16 h to give the title compound (0.007 g, 7%): LC/MS (Table 2, Method a) Rt=2.41 min; MS m/z 386 (M+H)+. Syk IC50=B.
Reaction SMILES: O.C([O-])(=O)C.[K+].O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=1.[C:31](B1OC(C)(C)C(C)(C)O1)([CH3:33])=[CH2:32]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(#N)C>[Br:30][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([C:31]([CH3:33])=[CH2:32])[CH:29]=1
Reactant: Brc1cncc(Br)c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: C=C(C)c1cncc(Br)c1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A mixture of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct; 98.0 mass %, potassium acetate hydrate (7.4997 mmol; 3.7 mL), sodium carbonate decahydrate (7.4997 mmol; 3.7 mL), Acetonitrile (15 mL) and 3,5-dibromopyridine (4.9998 mmol; 1184.4 mg) in 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9998 mmol; 840.0 mg; 0.940 mL) in a pressure tube was heated under microwave at 120° C. for 3 min. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was concentrated. The residue was purified on silica eluted with 0 to 10% MeOH in DCM to afford 3-bromo-5-isopropenyl-pyridine as a dark tan solid (512.6 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[C:8](=[N:10]\[NH2:11])/[CH3:9])[CH:3]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:11]=[N:10][C:8]([CH3:9])=[C:4]2[CH:3]=1
Reactant: C/C(=N/N)c1cc(Br)ccn1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: ClCCl
Product: Cc1nnn2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirring solution of (Z)-4-bromo-2-(1-hydrazonoethyl)pyridine (2.53 g, 11.8 mmol) in DCM (40 mL) was added (diacetoxyiodo)benzene (3.8 g, 11.8 mmol) in small portions over several minutes and stirred at room temperature for 45 minutes. The reaction was quenched with saturated 1:1 Na2S2O3/NaHCO3 solution (40 mL) and stirred until gas evolution ceased. The aqueous layer was extracted with DCM, dried over MgSO4, and purified by column chromatography (gradient 0 to 45% EtOAc in hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=6.9 Hz, 2H), 7.79 (s, 2H), 6.97 (d, J=6.5 Hz, 2H), 2.57 (s, 7H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17]C)=[O:16])[N:10]=1)[CH2:3]C(OCC)=O.O.S(Cl)([Cl:23])(=O)=O>C(OCC)(=O)C>[Cl:23][CH2:3][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[N:10]=1)=[O:1]
Reactant: CCOC(=O)CC(=O)c1cccc(C(=O)OC)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(C(=O)CCl)n1
Temperature: 90 °C
Yield: 85.1 %

Procedure:
41.4 g of ethyl 3-oxo-3-(6-methoxycarbonyl-2-pyridyl)propionate was dissolved in a solution consisting of 42 ml of water and 414 ml of ethyl acetate, and the obtained solution was then cooled to a temperature between 5° C. and 10° C. Thereafter, a solution obtained by dissolving 35.6 g of sulfuryl chloride in 83 ml of ethyl acetate was added dropwise to the above cooled solution over approximately 30 minutes, while stirring. Thereafter, the obtained mixture was stirred at a temperature between 10° C. and 20° C. for 1 hour. Subsequently, the reaction solution was heated up to approximately 90° C., while the solvent was distilled away from the reaction solution. The reaction solution was continuously heated at a temperature between approximately 90° C. and 100° C. for 2 hours while stirring. Thereafter, the obtained mixed suspension (containing crystals) was cooled to approximately 10° C., and it was then stirred for 1 hour, followed by filtration, so as to obtain 27.99 g of 2-(2-chloroacetyl)-6-pyridine carboxylic acid in the form of yellow-brown crystals (melting point: 184° C. to 189° C.; purity: 98% to 99%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(C)(C)N
Product: Cc1cc(Br)ccc1C(=O)NC(C)(C)C

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-methylbenzoic acid and tertiarybutylamine.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]=[CH:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH3:19])([OH:3])=[O:2].[CH:21]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[K+]>C(O)C>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH:19]=[CH:33][C:32]1[CH:35]=[CH:36][C:29](/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:30][CH:31]=1)([OH:3])=[O:2]
Reactant: CCCCCCC=Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(OC=CC(C)C)cc1OCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC/C=C/c1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)O)cc1
Reaction time: 0.75 h
Yield: 57.5 %

Procedure:
To a solution of 9.35 g of 2'-carboxymethoxy-4'-(3-methyl-butenyloxy)acetophenone and 7.37 g of 4-(1-octenyl)benzaldehyde in 170 ml of ethanol was added 11.5 g of potassium hydroxide and the mixture was stirred for 45 minutes. After neutralization with dilute hydrochloric acid, the precipitated solid was collected by filtration and recrystallized from 90% ethanol to give 9.2 g of 2'-carboxymethoxy-4'-(3-methyl-2-butenyloxy)-4-(1-(E)-octenyl)chalcone of the title compound as a plae yellow powder.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1.C(N(CC)CC)C>C(Cl)Cl.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][B:20](/[CH:3]=[CH:2]/[CH2:1][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[O:19]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.162 g, 0.725 mmol) synthesized in Example B58, Step 1 in methylene chloride (1 mL) was added with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.139 g, 1.09 mmol) and triethylamine (0.00734 g, 0.0725 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with bis(cyclopentadienyl)zirconium(IV) chloride hydride (0.0281 g, 0.109 mmol), and the mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidine-1-carboxylate (0.132 g, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](O)=[O:15])[C:7](=[CH:12][CH:13]=1)[CH2:8][C:9](O)=[O:10])([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC.[OH-].[Na+]>C1COCC1>[OH:15][CH2:14][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CCO)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A solution of 4-nitrohomophthalic acid (313.12 g, 58.27 mmol, J. Amer. Chem. Soc., 1969, 91, 2467) in dry THF (291 mL) under N2 is treated with NaBH4 (6.61 g, 174.8 mmol) portionwise over 15 mins. The resulting mixture is cooled in an ice bath and BF3.Et2O (22.15 mL, 174.8 mmol) is added dropwise over 35 mins. The cooling bath is removed, and the reaction mixture is stirred vigorously at ambient temperature for 18 hrs and is then cooled in an ice bath, quenched by the slow addition of 1N aqueous NaOH (233 mL, 4 equiv.) and stirred at ambient temperature for an additional 4 hrs. The THF is then removed under reduced pressure, the resulting precipitate is isolated by filtration, the filtrate is extracted with MeOH/CH2Cl2 (10/90, 3×150 mL), and the precipitate is combined with the organic extracts, diluted with additional MeOH/CH2Cl2 (10/90, 400 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and recrystallized from EtOAc/hexane to give 8.16 g (71%) of the title compound as a beige solid, mp 80-81° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1I)[C:5]#[N:6].[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C(O)C.[O-]CC.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.O>[C:11]1([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[F:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: OB(O)C1=CCCCC1
Reactant: N#Cc1ccc(I)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(C2=CCCCC2)c(F)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a mixture of 3-fluoro-4-iodobenzonitrile (1.53 g), 1-cyclohexen-1-yl-boronic acid (938 mg), bis(triphenylphosphine)palladium(II) dichloride (435 mg) and ethanol (9.75 mL), sodium ethoxide (about 20%, solution in ethanol, 5.75 mL) was added and the mixture was stirred at 90° C. for 15 minutes under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and three extractions were conducted with chloroform. The combined organic layers were washed with saturated brine and passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-75:25) to give the titled compound as a pale yellow oil (980 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:29])C>>[C:1]1([CH2:7][CH2:8][N:9]2[C:10]3[N:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12](=[O:13])[O:14][C:15]2=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)c1cccnc1NCCC1=CCCCC1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: O=c1oc(=O)n(CCC2=CCCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 45A for the product of Example 3A (0.493 g, 91%). MS (DCI) m/z 290 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2>CO.[C].[Pd]>[F:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: CC(=O)NCC=C1CCc2c(F)cc3nn(C)cc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2c(F)cc3nn(C)cc3c21
Temperature: 25 °C
Reaction time: 32 h
Yield: 77.4 %

Procedure:
To a solution of N-[2-(5-fluoro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethyl]acetamide (82.0 mg, 0.300 mmol) in methanol (3 mL) was added palladium-carbon powder (8.2 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 32 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (63.9 mg, yield 77%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@H:11]([CH2:14][OH:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][C@@H:11]2[O:10][C:9]3[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1

Procedure:
Preparation according to Preparation 10 using [[(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (1.2 g, 5.0 mmol), DCM (25 ml), p-toluenesulfonyl chloride (1.4 g, 7.5 mmol), TEA (1.0 ml, 12.8 mmol) and 4-DMAP (0.6 g, 5.0 mmol). Yield: 1.8 g. MS m/z (rel. intensity, 70 eV) 398 (M+, 49), 226 (bp), 225 (24), 213 (30), 91 (68).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C[C@@H]1CCCN1)[C:13]1C=CC=CC=1.CCOCC.C[Mg]I.[Cl-].[NH4+]>C1C=CC=CC=1>[OH:9][C@:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[CH:10]=[O:11]
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Reactant: O=CC(=O)c1ccccc1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[C@@](O)(C=O)c1ccccc1
Temperature: -70 °C
Yield: 66.8 %

Procedure:
In 15 ml of benzene, were dissolved 714 mg of phenylglyoxal monohydrate and 828 mg of (S)-2-(anilinomethyl)pyrrolidine. The resulting solution was refluxed for one hour while removing the formed water by azeotropic distillation. Benzene was removed by distillation in vacuo and the residue was dissolved in 20 ml of ether. To the resulting solution cooled to -70° C., was added dropwise 1.5 equivalents of an ether solution of methylmagnesium iodide. After having been allowed to react for one hour at -70° C., the solution was admixed with 4 ml of saturated aqueous ammonium chloride solution and brought to room temperature. After separating the ether layer, the aqueous layer was neutralized with saturated aqueous sodium hydrogencarbonate solution and then extracted with ether. The ether layer was combined with the previously separated ether layer, admixed with 30 ml of 25% hydrochloric acid and allowed to react for 12 hours at 0° C. The ether layer was separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the ether by distillation in vacuo, the residue was purified by means of a silica gel column chromatography to obtain 471 mg (67%) of (S)-(+)-2-hydroxy-2-phenylpropionaldehyde. [α]D =+244° (C=1.138, benzene); optical yield was 95%. The optical yield was determined by converting the substances into methyl atrolactate methyl ether of known optical rotation.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][N:10]([CH3:19])[CH2:9][C@H:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(Br)ccc1OC1CNCC1O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(Br)ccc1O[C@@H]1CN(C)C[C@H]1O
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Dissolve 4-(4-bromo-2-methoxy-phenoxy)-pyrrolidin-3-ol (409 mg, 1.42 mmol) in dichloroethane (15 mL) and add formaldehyde (0.117 mL, 1.56 mmol, 37% aqueous solution), sodium triacetoxyborohydride (451 mg, 2.13 mmol), and acetic acid (0.325 mL, 5.68 mmol). Stir the mixture overnight. Dilute with saturated sodium bicarbonate and extract three times with dichloromethane. Combine all the organics and dry over sodium sulfate, filter, and evaporate the filtrate. Purify by silica gel chromatography, eluting with 0-6% MeOH in dichloromethane with 2 N ammonia to give 410 mg (95%) of the title compound as a clear oil. LC-MS/ES m/z (81Br) 304.0 [M+H]−.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:35][CH3:36])=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])(=[O:14])=[O:13])[CH:11]=1)(=[O:5])=[O:4])=[CH2:2].C[N:38]1[CH2:43][CH2:42]N[CH2:40][CH2:39]1>C1COCC1.C(Cl)Cl>[CH3:36][O:35][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH2:2][N:38]2[CH2:43][CH2:42][CH2:40][CH2:39]2)(=[O:4])=[O:5])=[CH:11][C:10]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:13])=[O:14]
Reactant: CN1CCNCC1
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)CCN2CCCC2)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl] amide (0.2 mmol, prepared as in Example 19) in dry THF (2 mL) was added 0.2 mL of 1-methylpiperazine. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated sodium chloride aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc then DCM/methanol/AcOH (100:2:1 to 100:10:2) to furnish 118 mg of benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]-phenyl}-amide. LC: Tr 0.84 min; MS: 666.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.[CH2:21](Br)[C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:21][C:22]([CH3:25])([CH3:24])[CH2:23][N:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[C:12]1[S:13][CH2:14][C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:16]=1
Reactant: CC(C)(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N(CC(C)(C)C)C1=N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with neopentyl bromide according to Method D2a to afford (4S)-2-(N-(2,2-dimethylpropyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3-thiazoline.
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:17]C)=[CH:5][CH:4]=1.C1C=CC2C(=O)C3C(=C(O)C=CC=3O)C(=O)C=2C=1.[BH4-].[Na+]>COCCOCCOC.CO>[C:3]1(=[O:2])[C:16]2[C:7](=[CH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6](=[O:17])[CH:5]=[CH:4]1
Reactant: COc1ccc(OC)c2cc3ccccc3cc12
Agent: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CO
Product: O=C1C=CC(=O)c2cc3ccccc3cc21
Yield: 95 %

Procedure:
Although the preparation of 1,4-dimethoxyanthracene (1) has been reported (Criswell, et al., J. Org. Chem. 1974, 39, 770-774) by using methylation of quinizarin (3) followed by sequential reduction of the diketo function with sodium borohydride in diglyme, the difficulty in the reduction steps prompted us to investigate an easier method in the preparation of 1. Reduction of 3 with sodium borohydride in MeOH followed by quenching with HCl gave a 95% yield of 1,4-anthraquinone (4) (Scheme 2). Reduction of the quinone moiety of 4 with aqueous sodium hydrosulfite in 1,4-dioxane provided 1,4-dihydroxyanthracene (5). Methylation of 5 with sodium hydride in DMF at room temperature gave excellent yield of 1.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]=2[CH:16]=1)(=[O:5])=[O:4].[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.S(=O)(=O)(O)O>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([Br:17])[C:9]2[O:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:16]=1)(=[O:5])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNS(=O)(=O)c1ccc2c(c1)C(C)(C)CO2
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid methylamide (215 mg, 0.89 mmol) in trifluoroacetic acid (5 mL) and sulfuric acid (1 mL) was added portionwise N-bromosuccinimide (317 mg, 1.78 mmol). The mixture was stirred at room temperature overnight, poured into a solution of ice-water and rinsed with dichloromethane. The layers were separated. The aqueous layer was extracted twice with dichloromethane and the organic combined extract was washed with water, an aqueous solution of sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (30% ethyl acetate in hexane) to afford 91 mg of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid methylamide. 32% yield. 1H-NMR (300 MHz, CDCl3): 1.40 (s, 6H), 2.68 (d, J=5.3 Hz, 3H), 4.21 (m, 1H), 4.45 (s, 2H), 7.52 (d, J=1.8 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H).